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SStudy Material for
Basic Workshop on
RESEARCH METHODOLOGY
22 – 24 July 2019 [09:00 AM – 04:00 PM]
Venue Pushpanjali Auditorium, 1st floor,
D.Y. Patil Hospital, Nerul, Navi Mumbai
Jointly Organized by Department of Obstetrics & Gynecology and
Institutional Ethics Committee (IEC), Department of Pharmacology
Organizing Secretary Dr M. N. Satia, Dr. Deepak Langade
Contact: [email protected] / [email protected] 98690 84018 / 99305 50009
This document contains study material and slides for Basic Workshop on Research Methodology conducted on 22 – 24 July 2019. Organizing team thank Dr. Shirish Patil (Vice-chancellor, D Y Patil Deemed to be University, Navi Mumbai), Dr. Surekha Patil (Dean, D Y Patil Deemed to be University School of Medicine, Navi Mumbai), all workshop faculty workshop and the participating delegates. Resource:
Dr. Abhay Chowdhary
Dr. M. N. Satia
Dr. Deepak Langade
Dr. Anant Patil
Dr. Padmaja Samant
Dr. Mrudula Solanki
Dr. Nirmala Rege
Dr. Pratap Jadhav
Dr. Varsha Vyas
Dr. Vaishali Thakare
Dr. Vidita Morepatil
Dr. Kavitha VD
Complied by: Dr. Deepak Langade Prof. & Head, Dept. of Pharmacology Member Secretary, IEC for Clinical Trials Chairman, Pharmacovigilance (PV) Committee Chairman, Institutional Animal Ethic Committee D Y Patil University School of Medicine Nerul, Navi Mumbai 400 706 Contact: [email protected] / 99305 50009
Contact: [email protected] / [email protected] 9930550009
BBasic Workshop on
RESEARCH METHODOLOGY
22 – 24 July 2019 [09:00 AM – 04:00 PM]
Venue Pushpanjali Auditorium, 1st floor,
D.Y. Patil Hospital, Nerul, Navi Mumbai
Organized by Department of Obstetrics & Gynecology and
Institutional Ethics Committee (IEC), Department of Pharmacology
Organizing Secretary Dr M. N. Satia, Dr. Deepak Langade
Contact: [email protected] / [email protected] 98690 84018 / 99305 50009
D.Y. Patil University School of Medicine BASIC WORKSHOP ON RESEARCH METHODOLOGY Organizing Secretary: Dr M.N.Satia, Dr. Deepak Langade
Contact: [email protected] / [email protected] 9930550009
DAY 1, MONDAY 22 JULY 2019
Time Topic Method Faculty 8.30-9.00 Registration & Pretest -
9:00-9:45 L-1 Welcome & Introduction to
Research Methodology Management of Shock and Blood Transfusion in Obstetrics
Lecture Dr. Meena Satia Prof. of Ob. Gyn.
09:45-10:15 L-2 Scope of Research Methodology
Lecture Dr. Abhay Chowdhary Prof. & Head, Microbiology
10:15-11.00 L-3 Research Question, Study Designs & Hypothesis
Lecture Dr. Deepak Langade Prof. & Head, Pharmacology
11.00 - 11.15 Tea 11.15-12.15 L-4 Research Protocol Lecture Dr. Anant Patil
Pharmacology
12.15-12.45 GA-1 (Group Activity) Participants will be divided into 4 groups.
Each group will discuss and come out with at-least 2 research questions and related hypotheses
Indicate why the topic was selected
Type of study of study design
Group Activity
Dr Anant Patil Pharmacology Dr. Kavitha VD Dr. Vaishali Thakare
12.45 - 1.15 pm Lunch 1.15-2.00 L-5 Quantitative Research Methods Lecture M. N. Satia,
Professor Ob. Gyn. Dr Kavitha VD Pharmacology
2.00-3.15 GA-2: Divide into groups and discuss and present
Indicate why the topic was selected, Indicate type of study
Indicate dependent and independent variables in the study
Group Activity
3.15 - 3.30 pm Tea 3.30-4.30 L-6 Principles of GCP Guidelines
Documents in Healthcare Research Lecture Dr. Vidita Morepatil
Abbott India Ltd.
4.30 - 4.45 Day One feedback
D.Y. Patil University School of Medicine BASIC WORKSHOP ON RESEARCH METHODOLOGY Organizing Secretary: Dr M.N.Satia, Dr. Deepak Langade
Contact: [email protected] / [email protected] 9930550009
DAY 2, TUESDAY 23 JULY 2019 Time Topic Method Faculty
9.00-10.00 L-7 Qualitative Research Methods Lecture Dr. Padmaja Samant Professor Ob. Gyn.
10.00-11.00 L-8 Ethical Issues in Research GA-3: Groups will present
ethical issues in their respective studies
Lecture & Group Activity
Dr. Padmaja Samant Professor Ob Gyn. Seth G.S. Medical College
11:00-11:30 L-9 RPA Lecture Dr. Vijaya Badhwar Professor Ob. Gyn.
11:30 - 11:45 Tea 11:45-12:30 L-10 Sampling Methods Lecture Dr. Mrudula Solanki
Prof. Community Medicine Seth G.S. Medical College
12.30-01.00 L-11 Literature search GA-4: Participants will be
divided into groups Each group will try to search
references related to topics finalized and discussed
Lecture & Group Activity
Dr. Anant Patil Asst. Prof. Pharmacology Dr Kavitha Vivek Asst. Prof. Pharmacology
01.00 - 1.30 Lunch 1.30-2.15 L-12 Introduction to Biostatistics,
Descriptive Statistics Lecture Dr. Pratap Jadhav
Biostatistician Seth G.S. Medical College
2.15-3.00 L-13 Hypothesis testing & Inferential Statistics GA-5: The groups will discuss
about the inferential statistics (statistical tests) to be applied for the study design discussed in earlier group exercises
Lecture & Group Activity
Dr. Pratap Jadhav Biostatistician Seth G.S. Medical College
3.00 - 3.15 Tea 3.15-4.30 L-14 Sample size in research
Lecture Dr. Vidita Morepatil
Abbott India Ltd.
4.30 - 4.45 Day Two Feedback
D.Y. Patil University School of Medicine BASIC WORKSHOP ON RESEARCH METHODOLOGY Organizing Secretary: Dr M.N.Satia, Dr. Deepak Langade
Contact: [email protected] / [email protected] 9930550009
.
DAY 3, WEDNESDAY 24 JULY 2019 Time Topic Method Faculty
09.00-09.30 L-15 Hand hygiene and Management of sharps in labour room & OT
Lecture Dr. Y.S. Nandanwar Asso. Prof. Ob Gyn.
9.30-10.45 L-16 Questionnaire designing Lecture Dr. Nirmala Rege Prof. Emeritus in Pharmacology Seth G.S. Medical College
10.45 - 11.00 Tea 11.00-12.15 L-17 Submission of Synopsis Lecture Dr. Vaishali Thakare
Asso. Prof. Pharmacology
12.15-1.00 L-18 Regulations in Research Lecture Dr. Deepak Langade Prof. & Head, Pharmacology
1.00 - 1.30 Lunch 1.30-2.00 L-19 Roles & Responsibilities of
Researcher / Investigator Lecture Dr. Varsha Vyas
Prof. of Anesthesiology
2.00-3.00 L-20 Critical Evaluation of Journal Article GA-6: Journal articles
(different study designs) will be presented and discussed by members
Lecture & Group Activity
Dr. Vidita Morepatil Abbott India Ltd.
3.00 - 3.30 Post-test, Day 3 feedback & Workshop evaluation
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INTRODUCTION TO RESEARCH METHODOLOGY
Dr.M.N.SatiaProfessor And Head of Unit Dr D Y Patil School of Medicine Department of obstetrics and gynaecology
WHAT IS RESEARCH
Research is an endeavour to discover answersto intellectual and practical problems throughscientific methods or procedures. It is practically a search for knowledge.
By definition…. Scientific & systematic searchfor pertinent information on a specific topic.
Redman and Mory…..Systematized effort to gain newknowledge.
Advanced learner’s dictionary of current English….. A careful investigation or enquiry specially throughsearch for new facts in any branch of knowledge.
For philosophers and thinkers, research means the outlet for new ideas and insights.
For literary men and women, research means development of new styles and creative work.
For analysts and intellectuals, research means generalizations of new theories.
Research for decision making
SCOPE / SIGNIFICANCE OF RESEARCH
TECHNICAL ASPECTS OF RESEARCH
Define & redefine problems
Formulate hypotheses or suggested solutions
Collect, organize, evaluate data
Make deductions
Reach Conclusions
Careful testing of conclusions to determine whether they conform to the formulating hypothesis.
CHARACTERISTICS OF RESEARCH
Is objective and logical – applying every possible test tovalidate the data collected and conclusions reached.
Involves the quest for answers to unsolved problems.
Requires courage.
Is characterized by patient and unhurried activity.
Is carefully recorded and reported.
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SCIENTIFIC METHOD
‘Science’ refers to the body of systematic and organised knowledge which makes use of scientific method to acquire knowledge in a particular field of enquiry.
Scientific method is the systematic collection of data (facts) and their theoretical treatment through proper observation, experimentation and interpretation.
Scientific method attempts to achieve a systematic interrelation of facts by experimentation, observation, and logical arguments from accepted postulates and a combination of these three in varying proportions.
Purpose clearly defined.
Research process detailed.Research design thoroughly planned.
High ethical standards applied.
Limitations frankly revealed.Adequate analysis for decision maker’s needs.
Findings presented unambiguously.Conclusions justified.
Researcher’s experience reflected.
GOOD RESEARCH CRITERIA
RESEARCH PROCESS
Define ResearchProblem
Review Concepts
And theories
Review PreviousResearchfindings
Formulatehypothesis
DesignResearch
(IncludingSampleDesign)
CollectData
(Execution)
AnalyseData(Test
Hypothesisif any)
Interpretand
report
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Feed BackFeed Forward
Review the literature
CRITERIA OF A GOOD RESEARCH PROBLEM
Clear and Unambiguous
Empirical
Verifiable
Interesting
Novel and Original
Availability of Guidance
Statement of Research Objectives
Defining Problem, Results inClear Cut Research Objectives..
Analysis of the Situation
Symptom Detection
Problem Definition
ESTABLISHMENT OF RESEARCH OBJECTIVES
Research Objectives should be clear and achievable, as they directly assist in answering the research problem.
The objectives may be specified in the form of either statements or questions.
Generally, they are written as statements, using the word “to”. (For example, ‘to discover …’, ‘to determine …’, ‘to establish …’, etc. )
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• The objective is to design a feasible & inexpensive study that will produce a correct answer to the research question.
• In the pursuit of this objective.1.Choose the research question2.Develop the protocol3.Pretest and review protocol
ESTABLISHMENT of RESEARCH OBJECTIVES
Thank You
♪ EXPLORATION
♪ DESCRIPTION
♪ DIAGNOSIS
♪ HYPOTHESES
♪ INDUCTIONS AND DEDUCTIONS
NEED FOR RESEARCH
RESEARCH OBJECTIVESObjectives Type of Research
To gain familiarity with a phenomenon or to achieve new insights into it
Exploratory or Formulative Research
To portray accurately the characteristics of a particular individual, situation or a group
Descriptive Research
To determine- the frequency with which something occurs -and its association with anyanother factor
Diagnostic Research
To test a hypothesis of a causal relationship between variables
Hypothesis-Testing Research
CHARACTERISTICS OF RESEARCHIs directed towards the solution of a problem.
Is based upon observable experience or empirical evidence
Demands accurate observation and description.
Involves gathering new data from primary sourcesor using existing data for a new purpose.
Activities are characterized by carefully designedprocedures.
Requires expertise i.e., skill necessary to carry outinvestigation, search the related literature and to understand and analyze the data gathered.
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SCIENTIFIC METHODBASIC POSTULATES
It relies on empirical evidence.
It utilizes relevant concepts.
It is committed to only objective considerations.
It presupposes ethical neutrality.
It results into probabilistic predictions.
The methodology is made known.
Aims at formulating scientific theories.
GOOD RESEARCHQUALITIES
• Systematic
• Logical
• Empirical
• Replicable
• Creative
• Use of multiple methods
SCOPE / SIGNIFICANCE OF RESEARCH
Throws light on risks and uncertainty
Identifies alternative courses of action
Helps in economic use of resources
Helps in project identification
Contd …..
Solves investment problems
Solves pricing problems
Solves allocation problems
Solves decision making issues in HR
Solves various operational and planning problems of business and industry
contd….
SCOPE / SIGNIFICANCE OF RESEARCH
Provides the basis for all government policies in our economic system.
Helps social scientists in studying social relationships and in seeking answers to various social problems.
For students, research means a careerism or a way to attain a high position in the social structure.
For professionals in research, it may mean a source of livelihood.
contd….
SCOPE / SIGNIFICANCE OF RESEARCH PROBLEMS IN RESEARCH
Not similar to science
Uncontrollable variables
Human tendencies
Time and money
Inadequate electronic data facilitiesLack of scientific training in the methodology of research
Contd …
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Insufficient interaction between university research departments and business establishments
Lack of confidence on the part of business units to give information
Lack of code of conduct
Difficulty of adequate and timely secretarialassistance
Contd …
PROBLEMS IN RESEARCH
Poor library management and functioning
Difficulty of timely availability of published data.
Ignorance
Research for the sake of research-limited practical utility though they may use high sounding business jargon.
Contd …
PROBLEMS IN RESEARCH
ROLE OF RESEARCH IN DECISION-MAKING
♪ Decision-making is the process of selecting the best alternative from the available set of alternatives.
♪ Management is chiefly concerned with decision-making and its implementation.
♪ These decisions should be based on appropriate studies, evaluations and observations.
♪ Research provides us with knowledge and skills needed to solve the problems and to meet the challenges of a fast paced decision-making environment.
Contd …
Decision-making involves three activities:
Intelligence Activity - scanning the environment for identifying conditions necessary for the decision.
Designing Activity - identifying, developing and analyzing the alternative courses of action.
Choice Activity - choosing the best course of action from among the alternatives.
- Herbert A Simon
FACTORS THAT AFFECT MANAGERIAL DECISIONS
INTERNAL FACTORS – factors present inside an organisation such as resources, technology, trade unions, cash flow, manpower etc.
EXTERNAL FACTORS – factors present outside the organisation such as government policies, political factors, socio-economic factors, legal framework, geographic and cultural factors etc.
QUANTITATIVE FACTORS – factors that can be measured in quantities such as time, resources, cost factors etc.
Contd …
QUALITATIVE FACTORS –factors that cannot be measured in quantities such as organizational cohesiveness, sense of belonging of employees, risk of technological change etc.
UNCERTAINITY FACTORS –factors which cannot be predicted.
FACTORS THAT AFFECT MANAGERIAL DECISIONS
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TYPES OF RESEARCH
Descriptive vs Analytical Research
Descriptive Research is a fact finding investigation which is aimed at describing the characteristics of individual, situation or a group (or) describing the state of affairs as it exists at present.
Analytical Research is primarily concerned with testing hypothesis and specifying and interpreting relationships, by analyzing the facts or information already available.
Applied vs Fundamental Research
Applied Research or Action Research is carried out to find solution to a real life problem requiring an action or policy decision.
Fundamental Research which is also known as basic or pure research is undertaken for the sake of knowledge without any intention to apply it in practice. It is undertaken out of intellectual curiosity and is not necessarily problem-oriented.
Quantitative vs Qualitative Research
Quantitative Research is employed for measuring the quantity or amount of a particular phenomena by the use of statistical analysis.
Qualitative Research is a non-quantitative type of analysis which is aimed at finding out the quality of a particular phenomenon.
Conceptual vs Empirical Research
Conceptual Research is generally used by philosophers and thinkers to develop new concepts or to reinterpret existing ones.
Empirical Research is a data based research which depends on experience or observation alone. It is aimed at coming up with conclusions without due regard for system and theory.
Other Types of Research..
One-time Research – Research confined to a single time period.
Longitudinal Research – Research carried on over several time periods.
Diagnostic Research – It is also called clinical research which aims at identifying the causes of a problem, frequency with which it occurs and the possible solutions for it.
Contd …..
Exploratory Research – It is the preliminary study of an unfamiliar problem, about which the researcher has little or no knowledge. It is aimed to gain familiarity with the problem, to generate new ideas or to make a precise formulation of the problem. Hence it is also known as formulative research.
Experimental Research – It is designed to assess the effect of one particular variable on a phenomenon by keeping the other variables constant or controlled.
Historical Research – It is the study of past records and other information sources, with a view to find the origin and development of a phenomenon and to discover the trends in the past, in order to understand the present and to anticipate the future.
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RESEARCH PROBLEM
What is a research problem?
The term ‘problem’ means a question or issue to be examined.
Research Problem refers to some difficulty/need which a researcher experiences in thecontext of either theoretical or practical situation and wants to obtain a solution for the same.
HOW DO WE KNOW WE HAVE A RESEARCH PROBLEM?
Customer complaints
Conversation with company employeesObservation of inappropriate behaviour orconditions in the firmDeviation from the business plan
Success of the firm’s competitor’sRelevant reading of published material (trends, regulations)Company records and reports.
The first step in the research process –definition of the problem involves two activities:
Identification / Selection of the Problem
Formulation of the Problem
Definition of the problemIDENTIFICATION / SELECTION OF
THE RESEARCH PROBLEM
This step involves
identification of a few problems and
selection of one out of them,
after evaluating the alternatives against
certain selection criteria.
SOURCES OF PROBLEMS
Reading
Academic Experience
Daily Experience
Exposure to Field Situations
Consultations
Brainstorming
Research
Intuition
CRITERIA OF SELECTION
The selection of one appropriate researchable problem out of the identified problems is based on evaluation certain criteria. They are:
Internal / Personal criteria
Researcher’s Interest,
Researcher’s Competence,Researcher’s own Resource: finance andtime.
Contd….
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CRITERIA OF SELECTION
External Criteria or FactorsResearchability of the problem,
Importance and Urgency,
Novelty of the Problem,
Feasibility,
Facilities,
Usefulness and Social Relevance,
Research Personnel.
DEFINITION / FORMULATION OF THE RESEARCH PROBLEM
Formulation is the process of refining the research ideas into research questions and objectives.
Formulation means translating and transforming the selected research problem/topic/idea into a scientifically researchable question.It is concerned with specifying exactly what the research problem is.
Problem definition or Problem statement is a clear, precise and succinct statement of the question or issue that is to be investigated with the goal of finding an answer or solution.
There are two ways of stating a problem:
1) Posting question / questions
2) Making declarative statement / statements
DEFINITION / FORMULATION OF THE RESEARCH PROBLEM
PROCESS INVOLVED INDEFINING THE PROBLEM
Statement of the problem in a general way
Understanding the nature of problem
Surveying the available literature
Developing ideas through discussions
Rephrasing the research problem
ESTABLISHMENT OF RESEARCH OBJECTIVES
Research Objectives are the specific components of the research problem, that will be answered or completed, in order to answer the overall research problem.
The objectives refer to the questions to be answered through the study. They indicate the aims of the study or the expected results / outcome of the study.
Thank You
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Prof Dr Abhay ChowdharyMD, DHA, DM Virology, FIMSA, FRSTMH
Prof & Head of Microbiology
D Y Patil deemed to be University
School of [email protected]
Outline of PresentationWhat is Research? Why to Research?Need for Medical Research(MR).Characteristics of Research Type of Research-Descriptive/Analytical, Cross sectional, Case control, Cohort, Ecological, Experimental/Interventional, RCT/RT and Non RCT, Blinding- Single, Double…Evidence Based Medicine- Levels of evidenceGlossary of Terms in Research
What is Research: Research derived from French “Recherche” wherein cherchermeans search“A careful consideration of study regarding a particular concern or a problem using scientific methods”. “Research is a systematic inquiry to describe, explain, predict and control the observed phenomenon”. Research is search for knowledge.Research gets generated due to Human curiosity and inquisitiveness.Research involves inductive and deductive methods.Inductive research methods are used to analyze the observed phenomenon . Qualitative methods are used.Deductive research methods are used to verify the observed phenomenon. Quantitative methods are used.PICO- Problems, Intervention, Comparison, Outcome
Research- Why ?One of the most important aspects of research is the statistics associated with it for conclusion or result.It is about the “thought” that goes behind the research. Research is conducted with a purpose to understand:What do organizations or businesses really want to find out?What are the processes that need to be followed to chase the idea?What are the arguments that need to be built around a concept?What is the evidence that will be required that people believe in the idea or concept?
Need for Medical Research(MR)MR to generate new knowledge and improve scientific
understanding for diagnosis of disease, understanding of
disease, causative organisms, investigations, management.
MR to develop a scientific attitude.
MR to enhance career prospects. “Publish or Perish”.
MR for mandatory curriculum requirement.
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Medical Research Question Research topic is broad concept that is generalized and
not clearly defined.
Research question is more specific, logical objective of
doing study and accurate approach to the problem.
Research focus should be narrow ,not broad.
A strong research idea should pass the ”so what” test.
Generating Research QuestionA step ahead based on earlier work.Repeat the work done by other scientists.Serendipity, the accidental discovery.Need of the society or country at that point of time.Question that interests you.Discussion with research guide, colleagues , students.Keen observation of a prepared mind.Persistence on an issue.Intuition.
Characteristics of a good Research Question
FINER criteria by Hulley and Cummings.
Feasible- time, money, materials and expertise
Interesting- you and your guide
Novel-innovative approach
Ethical-moral principles, Respect, Beneficence, Justice
Relevant-current needs at current times
Characteristics of Research1. A systematic approach. Rules and procedures are an
integral part of research that set the objective of a research process.
2. Researchers need to practice ethics and code of conduct while making observations or drawing conclusions.
3. Research is based on logical reasoning and involves both inductive and deductive methods.
4. The data or knowledge that is derived is in real time, actual observations in the natural settings
5.There is an in-depth analysis of all the data collected from research so that there are no anomalies associated with it.
6. Research creates a path for generating new questions. 7. Research is analytical in nature. It makes use of all the
available data so that there is no ambiguity in inference.8. Accuracy is one of the important character of research,
the information obtained while conducting the research should be accurate and true to its nature.
Types of ResearchBasic researchApplied ResearchProblem oriented researchProblem solvingQuantitative ResearchQualitative Research
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Types of Research Descriptive researchAnalytical researchFundamental researchConceptual researchEmpirical researchOne time research or longitudinal researchField-setting research or laboratory research or simulation researchClinical or diagnostic researchExploratory researchHistorical researchConclusion oriented researchCase study researchShort term research
Types of research Quantitative Research: -Describes, infers, and resolves problems using numbers.-Emphasis is placed on the collection of numerical data.
- summary of data and the drawing of inferences from the data.Qualitative Research: - Based on words, feelings, emotions, sounds and other
non-numerical and unquantifiable elements.- Information is considered qualitative in nature if it cannot
be analyzed by means of mathematical techniques. - It also mean that an incident does not take place often
enough to allow reliable data to be collected”
Types of Research Based on Nature of the Study.
Descriptive research-- usually involves surveys and studies that aim - mainly deals with the description of the present
state of affairs as it is. - There is no control over variables in descriptive
research.Analytical research-
-It is fundamentally different ,-Researcher has to use facts or information already available and Analyze these to make a critical evaluation.
Types of Research Based on Basis:Purpose of the Study
Applied research is also referred to as an action research,
Fundamental research is sometimes called basic or pure research.
SR . No.
Applied Research Fundamental Research
1 Tries to eliminate the theory by adding to the basics of a discipline
Aims to solve a problem by adding to the field of application of a discipline
2 Problems are analyzed from the point of one discipline
Often several disciplines work together for solving the problem
3 Generalizations are preferred Often researches individual cases without the aim to generalize
4 Forecasting approach is implemented
Aims to say how things can be changed
5 Assumes that other variables do not change
Acknowledges that other variables are constant by changing
6 Reports are compiled in a language of technical language of discipline
Reports are compiled in a common language
Exploratory Research Descriptive Research Explanatory
Research
Research approach used Unstructured Structured Highly structured
Research conducted through
Asking research questions
Asking research questions
By using research hypotheses.
When is it conducted?
Early stages of decision making
Later stages of decision making
Later stages of decision making
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EBM- Levels of EvidenceIA - Evidence from meta-analysis of RCT (randomized controlled trials)IB - Evidence from at least one RCTIIA - Evidence from at least one controlled study without randomizationIIB - Evidence from at least one other type of quasi-experimental studyIII - Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studiesIV - Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both
EBM- Grades of RecommendationsA-Directly based on Level I evidence
B-Directly based on Level II evidence or extrapolated
recommendations from Level I evidence
C-Directly based on Level III evidence or extrapolated
recommendations from Level I or II evidence
D-Directly based on Level IV evidence or extrapolated
recommendations from Level I, II, or III evidence
organisms, Sir Peter Medawar, won the Nobel Prize with Sir Macfarlane Burnet in 1960 for demonstrating the possibility of transplanting tissues between genetically different organisms.
The Absence of Proofis Not
The Proof of Absence !
Meta-AnalysisA way of combining data from many different research studies.A meta-analysis is a statistical process that combines the findings from individual
studies.Example: Anxiety outcomes after physical activity interventions: meta-analysis
findings.Systematic ReviewA summary of the clinical literature.
A systematic review is a critical assessment and evaluation of all research studies that address a particular clinical issue.
The researchers use an organized method of locating, assembling, and evaluating a body of literature on a particular topic using a set of specific criteria.
A systematic review typically includes a description of the findings of the collection of research studies.The systematic review may also include a quantitative pooling of data, called a
meta-analysis.Example: Complementary and alternative medicine use among women with breast
cancer: a systematic review.
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Randomized Controlled TrialA controlled clinical trial that randomly (by chance) assigns participants to two or more groups. There are various methods to randomize study participants to their groups.
Example: Meditation or exercise for preventing acute respiratory infection: a randomized controlled trial.
Cohort Study (Prospective Observational Study)A clinical research study in which people who presently have a certain condition or receive a particular treatment are followed over time and compared with another group of people who are not affected by the condition.
Example: Smokeless tobacco cessation in South Asian communities: a multi-centre prospective cohort study. Case-control StudyCase-control studies begin with the outcomes and do not follow people over time. Researchers choose people with a particular result (the cases) and interview the groups or check their records to ascertain what different experiences they had. They compare the odds of having a experience with the outcome to the odds of having an experience without the outcome.
Example: Non-use of bicycle helmets and risk of fatal head injury: a proportional mortality, case-control study.
Cross-sectional studyThe observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously.
Example: Fasting might not be necessary before lipid screening: a nationally representative cross-sectional study.Case Reports and SeriesA report on a series of patients with an outcome of interest. No control group is involved.
Example: Students mentoring students in a service-learning clinical supervision experience: an educational case report.Ideas, Editorials, OpinionsPut forth by experts in the field.
Example: Health and health care for the 21st century: for all the people. Animal Research StudiesStudies conducted using animal subjects.
Example: Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO).Test-tube Lab Research"Test tube" experiments conducted in a controlled laboratory setting.
Glossary of Terms Related to Research Design
Before-After StudyA pre-post investigation of a discrete procedure, experience or event that is not managed by the researcher. Data are collected at baseline and one or more times after the procedure, experience or event.
Case Control StudyA study which involves identifying patients who have the outcome of interest (cases) and matching them with individuals who have similar characteristics, but do not have the outcome of interest (controls), and then looking back to see if these two groups differed with regard to the exposure of interest (i.e., the hypothesized causal or contributing factors).
Case Study or Case SeriesA descriptive study of one (case study or case report) or a series of patients (case series) defined by eligibility criteria, and where the unfolding course of events (disease progression, therapies, outcomes, etc.) is described in detail. The study researchers do not manipulate interventions. This study design is used to provide a detailed description of an uncommon disease or condition, a unique situation, or the introduction of a new technique.
Cluster Randomized TrialA special type of a randomized controlled trial (RCT) where groups of individuals (e.g., clinic sites, classrooms, communities), rather than independent individuals, are randomized to the intervention alternatives.
Cohort StudyA study that involves the identification of a group (cohort) of individuals with specific characteristics in common and follows them over time to gather data about exposure to factors and the development of the outcome of interest. Comparison groups can be defined at the beginning or created later using data from the study (e.g., age group, smokers/non-smokers, amount of a specific food group consumed). Prospective cohort studies enroll individuals and then collect data at many intervals. Retrospective cohort studies use an existing longitudinal data set to look back for a temporal relationship between exposure factors and outcome development. In the medical field, many studies labeled a “population-based clinical study” could be classified as retrospective cohort studies.
Cost Benefit Analysis or Cost Effectiveness AnalysisAn analysis that assesses the cost of an intervention in relation to the magnitude of outcome achieved. In cost benefit analysis, the inputs (i.e., intervention alternatives) and the resulting outcomes are quantified and expressed in monetary terms. In cost effectiveness analysis, inputs (i.e., intervention alternatives) are expressed in monetary terms but the outcomes are expressed in a standard unit, such as quality adjusted life years (QALY) or hospitalizations avoided. These are considered a synthesis of primary studies when data from multiple studies are used to derive estimates of inputs and outcomes.
Crossover Study DesignA study where two or more experimental therapies are administered, one after the other, in a specified or a random sequence, to the same group of patients. Usually there is a washout (no treatment) period between therapies. Individuals serve as their own controls. A crossover study is a special type of a randomized or non-randomized trial.
Cross-Sectional StudyA study where exposure factors (e.g., individual or environmental risk factor, nutrition education) and outcomes (e.g., disease occurrence, eating behavior) are observed or measured at one point in time in a sample from the population of interest, usually by survey or interview. In this design, a researcher examines the association among factors and outcomes using a statistical test for association, but cannot infer cause and effect.
Descriptive StudyDescriptive studies, as a research category, use a variety of methods to observe existing natural or man-made phenomena without influencing it (no researcher intervention). Data are gathered, organized and analyzed to depict and describe “what is”. Descriptive studies can be quantitative and/or qualitative and provide an in-depth look at processes, characteristics and patterns. Descriptive studies can result in a theory or framework, but they do not try to determine cause and effect.
Reasons for rejection of manuscripts-related to Study Design
Poor experimental designVague/inadequate method descriptionMethods lack sufficient rigorFailure to account for confoundersNo control or improper controlNo hypothesisBiased protocolSmall sample sizeInappropriate statistical methods, or statistics not applied properly.
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Thank You……..
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21-07-2019 11:00 DR. DEEPAK LANGADE 1
Basic workshop onRResearch methodology, Biostatistics &
Principles of GCP
22 – 24 July 2019Pushpanjali, 3rd floor Auditorium,
D Y Patil Hospital, Nerul
Jointly organized byDept. of Obs. & Gynaecology
Institutional Ethics Committee (IEC)
OBJECTIVES OF THE SESSION
Types of Research
Research Question
Research Hypothesis
Study Designs
Blinding & Randomization
Bias
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TYPES OF RESEARCH
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Descriptive Analytical
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RESEARCH METHODOLOGY DR.DEEPAK LANGADE
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QuantitativeQualitative
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Researcher decides what to study;
asks specific, narrow questions,
collects quantifiable data from large number of participants;
analyzes these numbers using statistics;
and conducts the inquiry in an unbiased, objective manner.
Post-positivism – singular reality; objective; deductive
Researcher relies on the views of participants;
asks broad, general questions;
collects data consisting largely of words (or text) from participants;
describes and analyzes text for themes; and
conducts the inquiry in a subjective, biased manner.
Constructivism – multiple realities; biased; inductive
Quantitative research Qualitative research
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Conceptual Empirical
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Cross-sectional Longitudinal
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Field
LaboratoryLibrary
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TYPES OF RESEARCH
Descriptive vs. Analytical
Applied vs. Fundamental
Quantitative vs. Qualitative
Conceptual vs. Empirical
Other types:Cross-sectional or longitudinal research
Simulation research
Clinical or diagnostic research
Exploratory or formulative research
Hypothesis-testing research
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Research Methods
Research Methodology
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RESEARCH QUESTION
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FIRST STEP
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RESEARCH QUESTION ?
First methodological steps towards research
Research question must be accurately and clearly defined
Good research question is the central element of research
A strong research question should never leave room for ambiguity or interpretation
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WHAT IS A RESEARCH QUESTION?
Unanswered question Unsolved question Concern Conditions that could be improved Difficulties that need to be eliminatedQuery Statement of inquiry
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WHAT MAKES A GOOD QUESTION?
MotivationInteresting?
FeasibleResearchable?
Have impact on practice/life/outcomeSignificant?
ReachManageable?
UnambiguousClear?
DENTAL -DYP 19
FINER CRITERIA
F • Feasible
I • Interesting
N • Novel
E • Ethical
R • Relevant
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PURPOSE OF RQ ?
Determines where and
what kind of research is
planned
Identifies the specific
objectives of Research
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EXAMPLES OF RQ ?
How is Diabetes Mellitus harmful in males?
Unclear:
Clear:
How is male sexual function affected by Diabetes Mellitus?
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EXAMPLES OF RQ ?
What is the effect on the environment from global warming?
Unfocused:
Focused:
How is glacial melting affecting penguins in Antarctica?
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EXAMPLES OF RQ ?
How are doctors addressing diabetes in the India?
Appropriately Complex:
What are common traits of those suffering from diabetes in India, and how can these be used in prevention of the diabetes?
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SOME RESEARCH TITLES
Observational Study Of Endotracheal Intubation In Emergency Department
Study of thyroid disorders in Diabetes Mellitus
Clinico-radiological profile in patients of Rheumatoid Arthritis
Role of Laparoscopy in Acute Appendicitis
Clinical Study of Acute Pancreatitis and its management
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RESEARCH HYPOTHESIS
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HYPOTHESISAfter extensive literature survey, researcher should state in clear terms the working hypothesis or hypothesesWorking hypothesis is tentative assumption made in order to draw out and test its logical or empirical consequencesHypothesis should be very specific and limited to the piece of research in hand because it has to be testedThe role of the hypothesis is to guide the researcher by delimiting the area of research and to keep him on the right trackIt also indicates the type of data required and the type of methods of data analysis to be used
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APPROACH TO HYPOTHESIS
Study Hypothesis
Discussions with colleagues and experts about the problem, its origin and the objectives in seeking a solution
Examination of data and records
Review of similar studies
Exploratory personal investigation (pilot)
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NULL HYPOTHESIS (H0)
The purpose of most statistical tests, is to determine if the obtained results provide a reason to reject the hypothesis that they are merely a product of chance factors
State a null hypothesis (that there is no effect) and then test whether the obtained data allows rejection of the hypothesis
Alternate Hypothesis (H1)Opposite of null hypothesis
HYPOTHESIS & DESIGN
Non-inferior
Non-equivalenceEquivalenceSuperiority
/ Inferiority
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SUPERIORITY HYPOTHESISNull Hypothesis (H0)
‘Test therapy’ is NOT SUPERIOR to ‘Reference therapy’
H0 : ET = ER
Alternate Hypothesis (H1)‘Test therapy’ is SUPERIOR to ‘Reference therapy’
H1 : ET > ER
Superiority defined as at least 10% greater improvement with ‘Test therapy’ relative to “Reference therapy’
EQUIVALENCE HYPOTHESISNull Hypothesis (H0)
‘Test therapy’ is EQUIVALENT to ‘Reference therapy’
H0 : ET = ER
Equivalence is defined as efficacy between 80% to 125% relative to efficacy of ‘Reference’
Alternate Hypothesis (H1)‘Test therapy’ is NOT EQUIVALENT to ‘Reference therapy’
H1 : ET ≠ ER
NON-INFERIORITY HYPOTHESISNull Hypothesis (H0)
‘Test therapy’ is SIMILAR to ‘Reference therapy’
H0 : ET = ER
Alternate Hypothesis (H1)‘Test therapy’ is NOT INFERIOR to ‘Reference therapy’
H1 : ET ≥ ER
Non-inferiority defined as improvement with ‘Test therapy’ similar or greater to “Reference therapy’
HYPOTHESIS & DESIGN
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SUPERIORITY / INFERIORITY
EQUIVALENCE NON-EQUIVALENCE
NON-INFERIOR
1-SIDED / 2-SIDED
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E.G. WOULD YOU USE QUANTITATIVE RESEARCH HERE?
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WE WANT TO STUDY THE PREFERENCES OF PEOPLE FOR
TOOTHPASTE
WE HAVE TO STUDY THE EFFECT OF COUNSELLING ON SMOKING
HABITS & BEHAVIOUR.
STUDY DESIGNS
APPROPRIATE METHODOLOGY?
Quantitative
Qualitative
Mixed
Critical & Action Oriented
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STUDIES
STUDY DESIGNSPilot study
Open
Comparative vs Non-comparative
Parallel group / Cross-over study
Randomised Controlled
Factorial design
Blinded study
Observational vs interventional
Cross-Sectional
Case-Control Study
Cohort Study
PILOT STUDY
Small sample from population
Feasibility and need for the
study
Draw an provisional inferences
Estimate the sample size for a conclusive study
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OPEN STUDY
All participants are aware of the study medication received by the patients.It could be a comparative or non-comparative study
COMPARATIVE STUDY
Also called as Controlled Study Either a
PLACEBO (Placebo controlled) or
ACTIVE drug is used for comparison with the drug under study
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PARALLEL GROUP STUDY
Applicable for Comparative studiesAll treatment groups receive the same treatment throughout the study period.
i.e. The study and the control groups run parallel to each other
PARALLEL GROUP STUDY
GROUP I
GROUP II
DRUG A
DRUG B
DRUG A
DRUG B
Study Initiation Study Completion
CROSS-OVER STUDY
Treatment groups receive both study and control medication in the study. There is a cross-over of treatments.E.g.:
Two-Way Crossover Study
Three-Way Crossover Study
2-WAY CROSS-OVER DESIGN
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Study Initiation
InterimVisit
Drug free Washout period
GROUP IDRUG A
GROUP IIDRUG B
GROUP IDRUG B
GROUP IIDRUG A
CROSSOVER
Study Completion
FIRST CYCLE
SECOND CYCLE
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4-WAY CROSS-OVER DESIGN
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ABCD
DABC
CDAB
BCDA
CASE – CONTROL STUDY
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A type of observational study in which two existing groups differing
in outcome are identified and compared on the basis of some
supposed causal attribute.
Used to identify factors that may contribute to a medical condition by comparing subjects who have
that condition/disease (the "cases") with patients who do not have the
condition/disease but are otherwise similar (the "controls").
SMOKING & CANCER
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CASE – CONTROL STUDY
They require fewer resources but provide less evidence for causal inference than a randomized controlled trial.
We only get odds ratio from a case–control study which is an inferior measure of strength of association as compared to relative risk.
E.g. Link between tobacco smoking and lung cancer.
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RETROSPECTIVE
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COHORT
Prospective
A group of people who share a defining characteristicThose who experienced a common event in a selected period, such as birth or graduation
Cohort studies differ from clinical trials
No intervention, treatment, or exposure is administered
No control group is defined
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COHORT STUDY
Define your cohort
Both exposure/treatment and control variables are measured at baseline.
Participants are then followed over time to observe the incidence rate of the disease or outcome in question.
Regression analysis can then be used to evaluate the extent to which the exposure or treatment variable contributes to the incidence of the disease, while accounting for other variables that may be at play.
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CASE CONTROL VS COHORT
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RETROSPECTIVE CASE-CONTROL STUDYAdvantages:
Useful for rare diseases or unusual exposuresSmaller sample sizesStudies take less time, because the data is readily available (it just has to be collected and analyzed)Costs are generally lower
Disadvantages:Missing dataRecall biasConfounding variables are difficult or impossible to measureCannot make causal statements, although correlations are okay
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PROSPECTIVE COHORT
-BACK-ACHE
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BLINDING
Blinding is a procedure by which the participants are kept unaware of the treatment given
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SINGLE BLIND
DOUBLE BLIND
TRIPLE BLIND
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RANDOMISATIONRandom numbers
Computer generated charts Rando, True Epistat
Latin square For more than two treatment groups
Types of Randomization:Simple Randomization
Block Randomization
Stratified Randomization
RANDOMISATION
Concealment Of Randomization Code Is The Most Important Aspect Of
A Randomised Controlled Trial (RCT)
FOR OPEN CONTROLLED TRIALS:
Treatment to be received by the patient is provided in SEALED ENVELOPS
with only Patient serial numbers on the cover.
The envelop is opened by the investigator only after a serial number is
allotted to the patient.
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OBSERVATIONAL VS INTERVENTIONAL
OBSERVATIONAL
Retrospective / Prospective
Non-experimental
INTERVENTIONAL
Prospective
Experimental
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BIAS
Observer / Evaluator
Enrollment / Recruitment / Selection
Detection bias
Instrumentation
Methods to minimize bias:
Matching
Randomization
Blinding
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Error in research
Confounding
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GROUP ACTIVITY - 1RESEARCH QUESTION
Each group will discuss and come out with 2 research questions and related hypotheses
Indicate why the topic was selected & the type of study Study design
Objective
Study parameters
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Orthopaedics Comparative study of anticoagulants in prevention of pulmonary embolism after Hip & Knee replacement
General surgery Comparative study of open Vs laproscopic appendicectomy
21-07-2019 11:00DR. DEEPAK LANGADE 75
Ophthalmology Evaluation of topical latanoprost for acute congestive glaucoma
AnaesthesiaOndensetron Vs Metoclopramide for PONV
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General medicine Tenaligliptine for type 2 DM – Efficacy
DermatologyDrug use pattern in Dermatophytosis
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21-07-2019 11:00DR. DEEPAK LANGADE 1
BASIC WORKSHOP ONRESEARCH METHODOLOGY,
BIOSTATISTICS & PRINCIPLES OF GCP
22 – 24 July 2019Pushpanjali, 1st floor Auditorium,
D Y Patil Hospital, Nerul
Jointly organized byDept. of Obs. & Gynaecology
Institutional Ethics Committee (IEC)
GROUP ACTIVITY - 1RESEARCH QUESTION
DR. DEEPAK LANGADE
1
2
24-07-2019
Each group will discuss and come out with 2 research questions and related hypotheses
Indicate why the topic was selected & the type of study Study design
Objective
Study parameters
24-07-2019 17:42DESCRIPTVE RESEARCH : DR. DEEPAK LANGADE 3
Orthopaedics Comparative study of anticoagulants in prevention of pulmonary embolism after Hip & Knee replacement
General surgery Comparative study of open Vs laproscopic appendicectomy
3
4
24-07-2019
Ophthalmology Evaluation of topical latanoprost for acute congestive glaucoma
AnaesthesiaOndensetronVs Metoclopramide for PONV
General medicine Tenaligliptine for type 2 DM – Efficacy
DermatologyDrug use pattern in Dermatophytosis
24-07-2019 17:42DESCRIPTVE RESEARCH : DR. DEEPAK LANGADE 6
5
6
24-07-2019
24-07-2019 17:42DESCRIPTVE RESEARCH : DR. DEEPAK LANGADE 7
7
1
Research Protocol
Dr. Anant PatilMBBS, MD (Pharmacology), MBA
Department of Pharmacology
Protocol Writing: Dr.Anant Patil 1 Protocol Writing: Dr.Anant Patil 2
The Plan…
To discuss
• What is research protocol?
• Why, when and how to write the research protocol
Protocol Writing: Dr.Anant Patil 3
Protocol definition
• A document containing background, rationale, objective, design, methodology (including matters concerning
performance, management, conduct, analysis), adverse event, withdrawal, statistical consideration and record keeping pertaining to clinical trial
New Drugs and Clinical Trial Rules 2019
Everything and anything that should happen and can happen in a study
Protocol Writing: Dr.Anant Patil 4
Protocol
• Why ?• Where ?• What ? • Who ? • When ?• How ?
• Design• Organization• Execution• Monitoring• Analysis• Reporting
• Design• Organization• Execution• Monitoring• Analysis• Reporting
Protocol Writing: Dr.Anant Patil 5
Science
Ethics and regulations
Compliance with
• Ethics committee (and DCGI*) approved protocol
• Good Clinical Practice (GCP) guidelines• All applicable regulations
*Investigator initiated studies with 'new drugs', DCGI approval is not needed; only an EC approval is required
Protocol Writing: Dr.Anant Patil 6
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Protocol Writing: Dr.Anant Patil 7
Components of protocol
ICMR Guidelines 2017
Protocol Writing: Dr.Anant Patil 8
1. Title page
• Title of the study
• Protocol number
• Date and version
• Signatures of investigators, sponsor and statistician
Protocol Writing: Dr.Anant Patil 9
Other information
• Names, titles, and addresses of
– Sponsor and monitors, if different– Person authorized to sign protocol and protocol amendments for
sponsor– Sponsor’s medical expert– Investigator(s) responsible for conducting the study– Study site(s)– Qualified physician who is responsible for all Study-related
medical decisions, if different than investigator– Clinical lab(s) and other medical and/or technical department(s)
Protocol Writing: Dr.Anant Patil 10
Protocol Writing: Dr.Anant Patil 11
Good Title
“Efficacy and safety of rabeprazole plus itopride in peptic ulcer disease: A randomized, placebo controlled multi-centric trial in Indian patients”
Protocol Writing: Dr.Anant Patil 12
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Poor Title
“Rabeprazole plus itopride in peptic ulcer disease”
Protocol Writing: Dr.Anant Patil 13
2. Background
• Rationale of why study is needed
• Description of population to be studied
• A summary of findings from relevant nonclinical and clinical studies
• Summary of known and potential benefits and risks to human subjects
Protocol Writing: Dr.Anant Patil 14
Background
• Description of and justification for, route of administration, dosage, dosage regimen, and treatment period(s)
• Statement that the study will be conducted in compliance with the protocol, good clinical practices (GCP), and applicable regulatory requirement(s)
Protocol Writing: Dr.Anant Patil 15
3. Eligibility criteria and participant recruitment procedures
• Inclusion criteria
• Exclusion criteria
• Withdrawal criteria
Protocol Writing: Dr.Anant Patil 16
Procedures for subject withdrawal
• When and how to withdraw subjects?
• What is the type and timing of the data to be collected for withdrawn subjects?
• Are subjects replaced? If so, how?
• What is the follow-up, if any, for subjects withdrawn?
Protocol Writing: Dr.Anant Patil 17
4. Justification of inclusion/exclusion of vulnerable population
PrisonersStudents Protocol Writing: Dr.Anant Patil 18
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5. Clinical research objectives
• Primary objectives• Secondary objectives
Protocol Writing: Dr.Anant Patil 19
6. Methodology
• Type of study design (observational, experimental, pilot, randomized, blinded, etc.)
• Types of data collection• Intended intervention (dosages, route of
administration, duration of treatment) • Details of invasive procedures, if any
Protocol Writing: Dr.Anant Patil 20
Study design
• A description of type/design of study to be conducted
• A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the study
• A schematic diagram of study design, procedures, and stages
• A description of the measures taken to minimize/avoid biasProtocol Writing: Dr.Anant Patil 21
Intervention
• Description: Randomization, blinding• Dosing• Packaging & labelling• Medication(s)/treatment(s) permitted and not permitted
before and/or during the study• Procedures for monitoring subject compliance• Follow up• Accountability procedures for the investigational
product(s)• Maintenance of study treatment randomization codes and
procedures for breaking codesProtocol Writing: Dr.Anant Patil 22
Placebo use
• Justification for placebo, benefit–risk assessment, plans to withdraw.
• If standard therapies are to be withheld, justification for the same
Protocol Writing: Dr.Anant Patil 23
Assessment of efficacy
• Specification of efficacy (primary and secondary) parameters
• Methods and timing for assessing, recording, and analyzing efficacy parameters
Protocol Writing: Dr.Anant Patil 24
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Assessment of safety
Specification of safety parameters
• Clinical adverse events• Adverse event (AE) reporting• Definition of AE and serious AE
(SAE) • Procedures and timing for assessing,
recording, reporting and analyzing adverse event
• Type and duration of the follow-up of subjects after adverse events
Protocol Writing: Dr.Anant Patil 25
7. Management of risk or injury
• For research involving more than minimal risk, an account of management of risk or injury
Protocol Writing: Dr.Anant Patil 26
Protocol Writing: Dr.Anant Patil 27
8. Compensation/reimbursement
• Proposed compensation, reimbursement of incidental expenses and management of research related injury/illness during and after research period
Protocol Writing: Dr.Anant Patil 28
9. Ancillary care
• Provision of ancillary care for unrelated illness during the duration of research
Protocol Writing: Dr.Anant Patil 29
Duration of study
Protocol Writing: Dr.Anant Patil 30
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10. Statistical analysis
• Data collection and management• Plan for statistical analysis of the study• Statistical methods to be employed• Number of subjects planned to be enrolled
(sample size)• Selection of subjects to be included in the analyses• Level of significance to be used
Protocol Writing: Dr.Anant Patil 31
Statistics
• Criteria for termination of the study
• Procedure for accounting for missing, and unused data
• Interim analysis (if applicable)
Protocol Writing: Dr.Anant Patil 32
11. Ethical considerations
• Ethical considerations and safeguards for protection of participants
• Ethics committee permission
Protocol Writing: Dr.Anant Patil 33
Informed consent
• Procedure for seeking and obtaining informed consent with a sample of the patient/participant information sheet and informed consent forms in English and local languages.
• AV recording if applicable; informed consent for stored samples
Protocol Writing: Dr.Anant Patil 34
Confidentiality
• Plan to maintain the privacy and confidentiality of the study participants
Protocol Writing: Dr.Anant Patil 35
Direct access to source document
• Investigator(s)/ institution(s) will permit Study-related monitoring, audits, IRB/IEC review, and regulatory inspection(s) by providing direct access to source data/documents
Protocol Writing: Dr.Anant Patil 36
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12. Storage and maintenance of data
• An account of storage and maintenance of all data collected during the trial
Protocol Writing: Dr.Anant Patil 37
13. Plan of publication
• Plans for publication of results – positive or negative – while maintaining confidentiality of personal information/identity.
Protocol Writing: Dr.Anant Patil 38
14. Others
• Quality Control and Quality Assurance• Data Handling and Record Keeping• Financing and Insurance (if not addressed in
a separate agreement)• QC and QA procedures• Supplements
Protocol Writing: Dr.Anant Patil 39
Protocol amendment
• A written description of a change(s) to or formal clarification of a protocol
Protocol Writing: Dr.Anant Patil 40
Summary
• Protocol is an essential document in clinical research
• Required for IEC review and approval
• Can be amended (safety reasons, suggestions from IEC, administrative changes)
• Amended version needs to be submitted to IECProtocol Writing: Dr.Anant Patil 41
Thank you
Protocol Writing: Dr.Anant Patil 42
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Group activityNumber of groups: 4
• Prepare a research question and related hypothesis• Indicate why topic was selected• Suggest appropriate study design and methodology in brief
Time: 30 minutes
• Preparation: 10 minutes (all groups together)• Presentation: 05 minutes (each group)
Protocol Writing: Dr.Anant Patil 43
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1
Experimental StudiesDR M.N.Satia
Professor Dept. Of OBGYN
D. Y. Patil Hospital, Nerul, Navi Mumbai
Dr. Meena Satia 2
Session Objectives
3
▪ 1. To enable participants to understand experimental study design
▪ 2. To understand the threats to internal and external validity
▪ 3.To know different types of experimental study designs and their applications
▪ 4.To give hands on experience of designing a study with the help of exercises
Dr. Meena Satia
Experimental Research
Experimental research is an attempt by the researcher to maintain control over all the factors that may affect the result of an experiment. In doing this, the researcher attempts to determine or predict what may occur.
Dr. Meena Satia 4
Types of Clinical Studies
Descriptive•Case report•Case series•Cross sectional (Survey)
Analytic
Observational•Cross sectional•Case-control•Cohort studies
Experimental•Randomized controlled trials
Strength of evidence for causality between a risk factor and outcomeDr. Meena Satia 5
Why Conduct an RCT?
An RCT is conducted to test whether an intervention or treatment works.The key methodological components of an RCT (1) Use of a control condition to which the experimental intervention is compared(2) Random assignment of participants to conditions. Advantages of using an RCT design include:Random assignment ensures that known and unknown person and environment characteristics that could affect the outcome of interest are evenly distributed across conditions..
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What is a Randomised controlled trial……
Simplest Definition: Individuals are allocated at random to receive one of several interventions (at least two total).
RCT’s are experimental—the intervention is controlled by the investigator
RCT’s are usually comparative studies (“controlled” in the RCT)
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Random allocation means that all participants have a defined probability of assignment to a particular intervention .
Allocation is not determined by the investigator, clinicians, or participants.
Allocation is not predictable based on a pattern
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What purpose is served by random allocation?
Covariates are distributed equally across the groups at baseline
� Affects both measured and, more importantly, unmeasured variables� The risk of imbalance remains even after properly executed randomization� In most RCTs will provide a comparison of treatment and comparison groups, with p-valuesIf randomisation has been performed correctly, chance is the only explanation for any observed difference between groups, in which case statistical tests are considered superfluous Dr. Meena Satia 9
What elements of a trial can be randomized?
Most common unit is individual patientSometimes groups are randomized=cluster randomizationExamples: families, schools, towns, hospitals, communitiesWorry about contamination in cluster randomizationSpecial statistical techniques needed to cope with the loss of independence of the individual units
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Choosing research question-Hulley 1988
▪ Feasible in terms of resources, expertise etc.
▪ Interesting to the investigator
▪ Novel: gen. new data/confirm/ refute earlier findings
▪ Ethical
▪ Relevant
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Experimental Design
Experimental design is a blueprint of the procedure that enables the researcher to test his hypothesis by reaching valid conclusions about relationships between independent and dependent variables.
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Research Essentials
▪ Manipulation of an independent variable.
▪ All variables except the dependent variable are held constant (control).
▪ Manipulation of the dependent variable by the independent variable is observed (observation).
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Aims of Experimental studies:
To provide scientific proof of aetiological factors which may permit the modification or control of those diseases
To provide a method of measuring the effectiveness and efficiency of health services for prevention, control and treatment of disease and improve health of the community
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In addition to all the advantages and disadvantages of the usual prospective cohort studies, experimental studies have three additional problems of-
1. Cost
2. Ethics &
3. Feasibility
They may be conducted in animals or human beings
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Animal studies
Contributed to our knowledge of anatomy, physiology, pathology, microbiology, genetics, immunology, chemotherapy, etc.Applications:
1. experimental reproduction of human disease in animals to confirm aetiological hypotheses and to study pathogenesis
2. Testing efficacy of preventive and therapeutic measures such as vaccines and drugs
3. Completing the natural history of disease
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Classical Animal Experiments
▪ Webster (USA)
▪ Topley, Wilson, Greenwood ( UK)
▪ Induced epidemics in animals and in studies of herd immunity under lab. conditions
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Advantages:Animals can be bred in laboratories and manipulated
according to the wishes of the investigator
Multiply rapidly and enable investigators to carry out certain experiments which in human population would take several years
Limitations:Not all human diseases can be reproduced in animals
All the conclusions derived may not be strictly applicable to human beings
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Human experiments :
More essential in the investigation of diseases that can not be reproduced in animals
Ethical and logistic considerations prevent its application to study of disease in humans
Benefits of the experiment to be weighed against risks involved
Volunteers made fully aware of all possible consequences of the experimente.g.
James Lind (1747)
Edward Jenner’s (1796) experiment with cowpox
Finlay & Reed - mosquito borne nature of yellow feverDr. Meena Satia 19
Types of experimental studies
A. Randomized controlled trials
B. Non-randomized or non-experimental trials
These depart from randomization for practical purposes Non randomization does not seriously affect theoretical basis of conclusions.
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Randomized controlled trials
▪ Steps:1. Drawing up a protocol2. Selecting reference and experimental
populations3. Randomization4. Manipulation or intervention5. Follow-up6. Assessment of outcome
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Protocol
▪ Aims & objectives of the study
▪ Research Question
▪ Selection criteria for study and control groups
▪ Allocation
▪ Treatments applied- when , where, how
▪ Standardization of working procedures, schedules n responsibilities of parties involved
Protocol aims at preventing bias and to reduce the sources of error in the study
Once the protocol is made we need to strictly adhere to itDr. Meena Satia 22
Selecting reference and experimental populations
a) Reference or target population – to which the findings of the trial, if found successful, are expected to be applicable
b) Experimental or study population –
derived from reference population, randomly chosen criteria:
1. Informed consent
2. Representative of the population to which they belong
3. Qualified or eligible for the trial
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Randomization (Fisher)
▪Heart of a control trial
▪Statistical procedure by which participants are allocated into groups k/a study & control groups
▪Its an attempt to eliminate selection bias & allow comparability
▪“Like can be compared with like”
▪Best done by using table of random numbers
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Manipulation
▪ To intervene or manipulate the study group by the deliberate application or withdrawal or reduction of the suspected causal factor as laid in the protocol
▪ It creates an independent variable whose effect is then determined by measuring final outcome, which constitutes dependent variable
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Mienert 1986- requirements for test and control treatments
▪ They must be distinguishable from one another
▪ They must be Medically justifiable
▪ There must be ethical base for use of either treatment
▪ Acceptable to study patients and to physicians administering them
▪ There must be reasonable doubt regarding efficacy of the test treatment
▪ Reason to believe that benefits outweigh the risks of treatment
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Random assignment equalizes the influence of nonspecific processes not integral to the intervention whose impact is being tested. Nonspecific processes might include effects of participating in a study, being assessed, receiving attention, self-monitoring, positive expectations, etcRandom assignment and the use of a control condition ensure that any extraneous variation not due to the intervention is either controlled experimentally or randomized.That allows the study's results to be causally attributed to differences between the intervention and control conditions.
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In sum, the use of an RCT design gives the investigator confidence that differences in outcome between treatment and control were actually caused by the treatment, since random assignment (theoretically) equalizes the groups on all other variables
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Follow Up
▪ Implies examination of the study and control group subjects at defined intervals of time, in a standard manner, with equal intensity, under the same given circumstances, in the same time frame till final assessment of outcome.
▪ Losses to follow-up are inevitable due to deaths, migration or loss of interest k/a attrition
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Data and Safety Monitoring Committee or Board
Early stopping of trial
▪ Appearance of an effect favoring one treatment so strong as to make it unethical to randomize patient to alternative treatment
▪ Occurrence of adverse events at unacceptable rates given expected benefits
▪ Determination that the reasonably expected results are no longer of sufficient value to continue the trial
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Assessment :
▪ In terms of –a) Positive results- reduced incidence, severity, costb) Negative results- side effects, complications , death
Techniques are available to analyse the data as they are collected-- Sequential analysis OR at the end of trial analysis
“Intent to treat” principle
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Bias may arise from the errors of assessment due to human element: 3 sources
1.Subject variation:Bais on the part of the participant who may subjectively feel better once he knows he is in the trial .
2.Observer bias:The investigator measuring the outcome may be influenced if he knows before hand what Rx the patient is taking
3.Bias in evaluation: the researcher may subconsciously give a favourable report of the outcome
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Blinding
▪ Randomisation cannot guard against these sorts of Bias & hence in-order to reduce these problems blinding is adopted, which will ensure that the outcome is assessed objectively It can be done in 3 ways1.Single Blind Trial:Participant is not aware whether he belongs to study /control group
2.Double Blind Trial: Participant /Researcher not aware
3.Triple Blind Trial: Participant /Researcher/Analyser are blinded.
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Clinical Trial: Parallel Group Design
Participants screened for entry criteria
ControlTreatment
Experimental
TreatmentWithout
Outcome
WithOutcome
Without Outcome
With Outcome
TimeScreening Baseline Treatment
Dr. Meena Satia 34
Clinical Trial: Crossover Design
Participants screened for entry criteria
Control Treatment
Experimental Treatment
WithoutOutcome
With Outcome
Without Outcome
With Outcome
Control Treatment
Experimental
TreatmentWithout
Outcome
With Outcome
Without Outcome
With Outcome
Screening Treatment (Phase 1)
{Washout}B/L Treatment (Phase 2)Dr. Meena Satia 35
Advantages of Cross- over design
▪ All patients assured to receive new therapy
▪ Economy of numbers at expense of time
▪ Not suitable if drug cures the disease
▪ If drug effective only in certain stage of disease
▪ Disease course radically changes during trial time
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Internal Validity
Internal validity is the extent to which the results of a study
are true ie the intervention really did cause the change in
behavior.
The change was not the result of some other extraneous
factor, such as differences in assessment procedures
between intervention and control participants.
This describes the technical soundness of a study,
particularly concerned with the control of extraneous
influences that might effect the outcomeDr. Meena Satia 37
External Validity
External validity is the extent to which the results can be generalized to a population of interest.
The population of interest is usually defined as the people the intervention is intended to help
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Validity
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▪ Both are important in a study but they are frequently at odds
with one another in planning and designing a study
▪ Internal validity is considered the basic minimum for
experimental research
▪ To gain internal validity, the researcher attempts to control
everything and eliminate possible extraneous influences
▪ Lends itself to highly controlled, laboratory settings
Dr. Meena Satia
Threats to Internal Validity
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▪ History – events occurring during the experiment that are not part of the treatment
▪ Maturation – biological or psychological processes within participants that may change due to the passing of time, e.g., aging, fatigue, hunger
▪ Testing – the effects of one test upon subsequent administrations of the same test
▪ Instrumentation – changes in testing instruments, raters, or interviewers including lack of agreement within and between observers
Dr. Meena Satia
Threats continued
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▪ Statistical regression – the fact that groups selected on the basis of extreme scores are not as extreme on subsequent testing
▪ Selection bias – identification of comparison groups in other than a random manner
▪ Experimental mortality – loss of participants from comparison groups due to nonrandom reasons
▪ Interaction among factors – factors can operate together to influence experimental results
Dr. Meena Satia
External Validity
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▪ Generalizability of results . . . to what populations, settings, or treatment variables can the results be generalized?
▪ Concerned with real-world applications
▪ What relevance do the findings have beyond the confines of the experiment?
▪ External validity is generally controlled by selecting subjects, treatments, experimental situations, and tests to be representative of some larger population
▪ Random selection is the key to controlling most threats to external validity
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Types of External Validity
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▪ Population Validity ––refers to the extent to which the results can be
generalized from the experimental sample to a defined population
▪ Ecological Validity ––refers to the extent to which the results of an
experiment can be generalized from the set of environmental conditions in the experiment to other environmental conditions
Dr. Meena Satia
Common Sources of Error
▪ Many possible sources of error can cause the results of a research study to be incorrectly interpreted. The following sources of error are more specific threats to the validity of a study than those described previously
▪ Selected examples:–Hawthorne Effect–Placebo Effect–John Henry Effect–Rating Effect–Experimenter Bias Effect
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Hawthorne Effect
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▪ A specific type of reactive effect in which merely being
a research participant in an investigation may affect
behavior
▪ Suggests that, as much as possible, participants should
be unaware they are in an experiment and unaware of
the hypothesized outcome
Dr. Meena Satia
Placebo Effect
▪ Participants may believe that the experimental
treatment is supposed to change them, so they
respond to the treatment with a change in
performance
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John Henry Effect
▪ A threat to internal validity wherein research
participants in the control group try harder just
because they are in the control group
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Types of Randomized controlled trials
▪ Clinical trials
▪ Preventive trials
▪ Risk factor trials
▪ Cessation experiments
▪ Trial of etiological agents
▪ Evaluation of health services
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Clinical Trials
▪ Evaluating therapeutic agents
▪ Beta blockers- CVS mortality in MI patients
▪ Folate supplements to prevent recurrent neural tube defects
▪ Tonsillectomy to prevent recurrent throat infections
▪ Ethical, administrative, technical problems
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Preventive Trials
▪ Vaccines and chemoprophylactic drugs
▪ Whooping cough vaccine 3 manufacturers 10 field trials 1946- UK
▪ 6-18 months
▪ Study group-149 cases/ 3801 vaccinees
▪ Control group-687 cases/ 3757 unvaccinated
▪ Attack rate 1.45/1000 Vs 6.72/ 1000
▪ Risk- benefit & Cost
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Risk factor trials
▪ Single factor/ Multi- factors eg :
▪ Clofibrate to lower cholesterol
▪ 15000 men clofibrate Vs Olive oil, 3 centres in Europe
▪ Edinburgh, Prague, Budapest
▪ 9.6 yrs mean follow up
▪ Reduction in non-fatal cardiac infarction
▪ 25% more deaths due to drug toxicity
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Cessation Experiment
▪ Termination of a habit
▪ Removal of a suspected agent
▪ E.g. Smoking cessation- Lung cancer/ primary prevention of CHD
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Trial of etiological agents
▪ Retro- lental Fibroplasia
▪ 50% oxygen for 28 days Vs Oxygen only for clinical emergency was given to premature babies < 1500 gm in 18 hospitals in the USA
▪ All babies in curtailed oxygen group who developed RLF received some oxygen
▪ No cases in those who never received oxygen
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Evaluation of Health services
▪ Domiciliary / sanatorium treatment for TB
▪ Multi-phasic screening trials in UK
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Non randomized Trials▪
▪ It is not always possible for Ethical ,Administrative or other reasons to resort to RCT in human beings eg
▪ Smoking and lung cancers & induction of cancers by viruses cannot be done in human beings
▪ Crude as compared to RCTs
▪ Useful when disease frequency low , long natural history- cancers
▪ Costs and logistics prohibitive
▪ Some preventive measures can only be applied to groups/ community
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Non-randomized controlled trials
▪ No randomization
▪ Low degree of comparability
▪ Higher chances of spurious results
▪ Control group is predetermined (without random assignment) to be comparable to the study group
▪ Also k/a “quasi experiments”
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Non Randomized Controlled Trials
▪ Rely on participants who -1) volunteer to join the study OR2) are geographically close to the study site OR3) conveniently turn up (at a clinic, school) while the
study is being conducted
▪ Because the study groups are opportunistically rather than randomly composed, study group characteristics (age, sex) may not be balanced before (at baseline) the study begins.
▪ Baseline differences between groups may confound the study’s results.
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Typical confounding variables include age, educational level, motivation, severity of illness, social structure, and income.
▪ study groups in non RCT may differ from one another at baseline, and the study’s findings will be compromised.
▪ They aim to create study groups that are as similar to one another as possible (equivalent) at baseline or before “treatment.”
▪ Among the strategies commonly used to ensure equivalence is one called matching.
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Natural Experiments
▪ Where RCT are not possible in human subjects the epdimiologist seeks to identify natural circumstances that mimic an experiment eg :
▪ Smokers/ Nonsmokers
▪ Migrants
▪ Religious or social groups
▪ Atomic bombing of Japan
▪ Famines/Earthquake 1981 Athens- who studied the effects of Acute stress-CVS mortality)
▪ John Snow :discovery that cholera is a water borne disease Dr. Meena Satia 59
Before and after comparison studies
▪ A Before and after comparison studies Without
▪ B Before and after comparison studies with control
▪ Introduction of new treatment- prior group acts as control eg:
▪ Use of seat belt- fall in accident deaths and injuries
▪ Victoria Vs other States with no statutory compulsion for seat belt.
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Criteria
▪ Before – after incidence data must be available
▪ Introduction or manipulation of only one factor e.g. fluorine in water
▪ Diagnostic criteria constant
▪ Preventive measure over wide area
▪ Several trials needed, reduction in incidence must be large
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Thank you..!!
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Group Activity - Quantitative Research Methods
24-07-2019
1
21-07-2019 11:00 DR. DEEPAK LANGADE 1
Basic workshop onResearch Methodology,
Biostatistics & Principles of GCP
22 – 24 July 2019Pushpanjali, 1st floor Auditorium,
D Y Patil Hospital, Nerul
Jointly organized byDept. of Obs. & Gynaecology
Institutional Ethics Committee (IEC)
RCT EXAMPLES GROUP ACTIVITIES
DR. KAVITHA VIVEK / DR. ANANT PATIL 2
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Group Activity - Quantitative Research Methods
24-07-2019
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Discuss in your group and prepare a research protocolDecide your population and how you would recruit participants in control and intervention groupWhat will be the independent and dependent variables and how will you collect data pertaining to themWhat are the likely biases and how will you overcome themDiscuss ethical, administrative and technical issues relevant to your study.
DR. KAVITHA VIVEK / DR. ANANT PATIL 3
Steps1. Drawing up a protocol2. Selecting reference and experimental populations3. Randomization4. Manipulation or intervention5. Follow-up6. Assessment of outcome
DR. KAVITHA VIVEK / DR. ANANT PATIL 4
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Group Activity - Quantitative Research Methods
24-07-2019
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Group task
DR. KAVITHA VIVEK / DR. ANANT PATIL 5
Group – 1Prepare a protocol to compare the effect of
Atorvastatin Vs Rosuvastatin in reducing cardiac mortality
Group – 2Draw up a protocol to see the efficacy of citrus fruits for the treatment of scurvy
DR. KAVITHA VIVEK / DR. ANANT PATIL 6
Group 3 Comparison of intravenous tramadol and intravenous
clonidine for post-spinal shivering in patients undergoing lower limb
orthopaedic surgeries
Group 4 Evaluation of zinc
supplementation in acute diarrhoea in children
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Group Activity - Quantitative Research Methods
24-07-2019
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Group 1
What would be the Aims & Objectives of the studyReduce the cardiac mortality
How would you do Randomisation-Study group would receive one drug and control group would receive the other
-How would you randomise the participants Coin flip methods Random No table Odd & even No
DR. KAVITHA VIVEK / DR. ANANT PATIL 7
How would you do Manipulation or interventionBy using the drugs like Atorvastatin Vs Rosuvastatin
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Group Activity - Quantitative Research Methods
24-07-2019
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Follow up of patients in the studyBy monitoring the BP and ECG & lipid profile of the patients in
the study What would be the final outcome of the studyTo check the no of patients dying due to MI
DR. KAVITHA VIVEK / DR. ANANT PATIL 9
Group 2
Draw up a protocol to see the efficacy of citrus fruits for the treatment of scurvyQuestion to considerAims & objectives Response to the treatment How would you randomise One group of patients who were given lemons and oranges the other group would be given some placebo
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Group Activity - Quantitative Research Methods
24-07-2019
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What would be the final outcome??Recovered most quickly, suggesting a beneficial effect of
citrus. ...
DR. KAVITHA VIVEK / DR. ANANT PATIL 11
GROUP 3
Comparison of intravenous tramadol and intravenous clonidine for post spinal shivering in patients undergoing lower limb orthopaedic surgeries.
DR. KAVITHA VIVEK / DR. ANANT PATIL 12
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Group Activity - Quantitative Research Methods
24-07-2019
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What will the aims and objectives be?
Compare the efficacy and safety of intravenous tramadol and clonidine in controlling post spinal anaesthesia shivering in patients undergoing lower limb orthopaedic surgeries
DR. KAVITHA VIVEK / DR. ANANT PATIL 13
What will the inclusion criteria be?Patients aged 18–60 years undergoing elective lower limb orthopaedic surgeries who developed Grade III and above level of shivering
Where will the patients be recruited from?Operation theatre
What will the exclusion criteria be?Patients with Grades I and II shivering, patients with cardiac disease (heart blocks, bradyarrhythmias, and left ventricular failure), renal disease, hepatic disease, psychiatric disorder, neuropathies, known history of substance or alcohol abuse
DR. KAVITHA VIVEK / DR. ANANT PATIL 14
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Group Activity - Quantitative Research Methods
24-07-2019
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How will you do randomization?Drawing sequential numbered, sealed envelopes containing a code based on computer generated number list
What will the evaluation parameters?Time taken to stop shivering
Response rate (good if shivering stopped within 15 min)
Recurrence rate (recurrence before the end of surgery)
Side effects such as hypotension, bradycardia, nausea, vomiting, dry mouth, respiratory depression, and deep sedation (Ramsay sedation scale >3).
DR. KAVITHA VIVEK / DR. ANANT PATIL 15
Group 4
Evaluation of zinc supplementation in acute diarrhoea in children
DR. KAVITHA VIVEK / DR. ANANT PATIL 16
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Group Activity - Quantitative Research Methods
24-07-2019
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What will the aims and objectives be?To evaluate efficacy and safety of daily supplementation of zinc plus oral rehydration solution(ORS) in acute diarrhoea among children
DR. KAVITHA VIVEK / DR. ANANT PATIL 17
What will the inclusion criteria be?Children aged 6 months to 59 months with acute diarrhoea
Where will the patients be recruited from?A tertiary hospital in Navi Mumbai
What will the exclusion criteria be?Child with severe malnutrition, intractable vomiting, renal failure, respiratory distress, altered sensorium or any such comorbid condition that precludes the use of oral rehydration solution(ORS), severe dehydration (as per standard national guidelines for diarrheal management) or inability to drink
DR. KAVITHA VIVEK / DR. ANANT PATIL 18
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Group Activity - Quantitative Research Methods
24-07-2019
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Intervention: Group A: ORS plus zinc; Group B: ORS plus placebo
How will you do randomization?A computer based random number generator with randomization schedules in permuted blocks
What will the evaluation parameters?Duration of diarrhoea from the time of onset
Number and proportion of patients with diarrhoea >4 days
Mean length of hospital stay
Severity of diarrhoea: use of unscheduled IV fluids, weight loss at discharge
Mortality rate
Adverse events
DR. KAVITHA VIVEK / DR. ANANT PATIL 19
DR. KAVITHA VIVEK / DR. ANANT PATIL 20
THANK YOU
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 1
Good Clinical Practices An Introduction to the ICH-GCP GuidelinesDR. DEEPAK LANGADEMB, MD, PGDASS (APPLIED STATISTICS)
What is GCP?
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible, accurate and that the rights, integrity and confidentiality of trial subjects are protected.
3 Good Clinical Practices
Part of the International Conference on Harmonization (ICH)
ICH-GCP E6 (R2)
Based on the Declaration of HelsinkiAssures protection of human subjects
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How did it evolve?
The need to harmonizePublic disasters, serious fraud and abuse of human rights.Trials of War criminals-Nuremberg code 1949Thalidomide- Declaration of Helsinki 1964Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
5 Evolution
Declaration of Helsinki, 1964 → 2001ICH GCP guidelines, 1996Ethical Guidelines for Biomedical Research in Human Subjects (ICMR), 2000GCP Guidelines, CDSCO, New Delhi, 2001
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 2
What is GCP ? 7
Assures unified, high standards for designing, conducting, recording and reporting trials
GCP
Why GCP?Protect the rights and safety of subjects involved in trialsTrials are based on good science, are well designed and properly analyzedTrial procedures are properly undertaken and documentedAssures integrity of data submitted to regulatory authoritiesPreserves a record of the trial – Source Document
What if GCP is not followed?
Subjects who take part may be at riskData collected may be unreliableApproval of dangerous and ineffective drugsFailure to obtain approval for useful drugsCostly litigation if patients are harmedInvestigator disqualification
9 Scope of GCP
Applies to clinical data intended to be submitted to regulatory authorities
Also applies to clinical interventions and observational studies
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Stakeholders
CRO
Regulatory Authorities
IRB/IECInvestigator
Investigator Team
11 Declaration of Helsinki
Adapted from the Nuremberg Code by The World Medical Association to address the needs of the biomedical communityFirst published in 1964, revised five time most recently in 2001Lists 31 principlesIs the international standard for the conduct of clinical research
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 3
Key Points: Declaration of Helsinki
Interests of the subjects must always prevail
Protocol must be reviewed by independent committee
Non-therapeutic research
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13Principles of ICH-GCP
Principles of ICH GCP
1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements.
15 Principles of ICH GCP Continued
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject & society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
16
Principles of ICH GCP Continued
3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science & society.
17 Principles of ICH GCP Continued
4. The available non-clinical & clinical information on an investigational product should be adequate to support the proposed clinical trial.
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 4
Principles of ICH GCP Continued
5. Clinical trials should be scientifically sound, and describe in a clear, detailed protocol.
19 Principles of ICH GCP Continued
6. A trial should be conducted in compliance with the protocol that has received prior IRB (or IEC) approval.
20
Principles of ICH GCP Continued
7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
21 Principles of ICH GCP Continued
8. Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective tasks.
22
Principles of ICH GCP Continued
9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.
23 Principles of ICH GCP Continued
10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 5
Principles of ICH GCP Continued
11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory compliance.
25 Principles of ICH GCP Continued
12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
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Principles of ICH GCP Continued
13. Systems with procedures that assure the quality of every aspects of the trial should be implemented.
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Areas addressed in GCP
Areas Addressed in the GCP Guidelines
IRB/ECInvestigator ResponsibilitiesInvestigator’s BrochureClinical Trial ProtocolSponsor ResponsibilitiesEssential Documents
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IEC / IRB
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 6
IRB/IEC Responsibilities
Should safeguard the rights, safety & well being of all trial subjects.Should obtains following Documents:
Protocol & their amendments, Patient Information sheet & consent form, subject recruitment procedures (e.g. advertisements), Investigator's Brochure (IB), available safety information, Payments and compensation available to subjects, Investigator’s current CV and/or other documentation evidencing qualifications, Any other documents that the IRB/IEC may need to fulfil its responsibilities
31 IRB/IEC Responsibilities
Should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year. Review Protocol/ ICD/ recruitment procedures/ IB/paymentsContinuing review for Ongoing Progress/Adverse events
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IRB/IEC Composition
At least 5 membersAt least one non scientific memberAt least one independent memberMaintain list of members and qualificationsOnly independent members to voteQuorum to be present
33 Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
CompositionMeeting Scheduling & conductSpecify that trial starts only after IRB reviewSpecify regarding changes in protocolSpecify prompt reporting of adverse events
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IRB/IEC Records
The IRB/IEC should retain all relevant records for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies). The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists.
35 IRB/IEC Summary
All studies must be approved prior to recruiting participants
IRB must review all documents given to participants
Composition of the IRB
Reporting AEs and Deviations from protocol to the IRB
Maintenance of Records
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Investigator Responsibilities
Investigator Responsibilities
Qualifications & AgreementsUp to date CVCompliance with GCPPermission of monitoring by sponsor & regulatory authoritiesMaintenance of a list of qualified personnel who are delegated study responsibilities
38
Investigator Responsibilities
Adequate ResourcesRecruitmentTimeQualified StaffFacilitiesTraining
39 Investigator Responsibilities
Medical CareA qualified MD (or dentist) responsible for trial-related medical decisionsProvide adequate medical care for AEs or other significant medical conditionInform PCP (Primary Care Physician) about participation in trialMake a reasonable effort to ascertain why participant withdrawals from study
40
Investigator Responsibilities
Communication with IRBWritten & dated approval prior to initiation of trialProvide IRB with copy of Investigator BrochureProvide IRB with all documents subject to it’s review (amendments, consent form if changed, recruitment material, medical record release forms, etc.)
41 Investigator Responsibilities
Compliance with ProtocolInvestigator should sign off on protocolInvestigator should not implement deviations from protocolIf deviations occur, they should be documented and reported at once to the sponsor, the IRB and other regulatory authorities
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 8
Investigator Responsibilities
Investigational ProductAccountabilityStorageUseMaintenance of records of product delivery, inventory, use by subject, product returned to sponsor & any unused product
Dates, quantities, serial numbers, expiration date, unique code
43 Investigator Responsibilities
Informed ConsentReviewed & approved by IRB (all versions)No coercion or unduly influenceNo language of a waiver of legal rightsFully inform participant (or legally authorized representative) of all aspects of the trialWritten in lay languageProvide ample time to review & ask questions
44
Investigator Responsibilities
Informed Consent Continued…Signed & dated by participant, the legally authorized representative, person administering consent, and a witness if applicableAll contents of an informed consentParticipant should be given a copy
45 Investigator Responsibilities
Records & ReportsAccuracy, completeness, legibility & timeliness of data reportedCRF consistent with source documentationChanges to CRF should be dated, initialed & explainedMaintain trial documentsRetention of trial documentsFinancial aspects noted in contractMake available all records for monitor, auditor, IRB, or other regulatory authority
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Investigator Responsibilities
Progress ReportsWritten summary of trial status to the IRBWritten reports to the sponsor or regulatory authority of any changes affecting the trial
Safety MonitoringSAEs should be reported immediatelyAEs should be reported according to sponsor guidelinesSupply sponsor & IRB with requested materials on participant deaths
47 Investigator Responsibilities
Premature Termination or Suspension
Promptly inform trial subjectsAssure appropriate therapy & follow-upInform sponsor, regulatory authorities & IRB
Final ReportingInform IRB of study completion & a summary of the trial’s outcomeProvide sponsor & regulatory authorities with all required reports
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22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 9
IB
Investigator’s Brochure
Defined as a compilation of the clinical and non-clinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects.
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Study Protocol
Clinical Trial Protocol
General InformationBackground InformationTrial Objectives & PurposeTrial DesignSelection & Withdrawal of ParticipantsTreatment of SubjectsAssessment of EfficacyAssessment of Safety
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Clinical Trial Protocol Continued
StatisticsDirect Access to Source DataQuality Assurance & Quality ControlEthicsData Handling & RecordkeepingFinancing & InsurancePublication PolicySupplements
53
Sponsor Responsibilities
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 10
Sponsor Responsibilities
Quality Assurance & Quality ControlProvide written SOPsSecures agreement between all partiesData handling
Contract Research Organization (CRO)Hired by the sponsor to implement trial-related duties
Medical ExpertiseDesignated medical personnel to advise on trial-related medical questions and problems
55 Sponsor Responsibilities contd…
Trial DesignDesigns CRFsPlanning analyses
Trial Management, Data Handling, Recordkeeping, & Independent Data Monitoring Committee (DMC)
Qualified personnel to supervise overall conduct of the studyDMC assesses the progress of the clinical trialMaintain SOPs for electronic data processingInform Investigator of guidelines for record retention
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Sponsor Responsibilities contd…
Investigator SelectionQualifications by training and experience
Allocation of Duties & FunctionsSponsor should define, establish and allocate all trial-related duties and functions
Compensation Insure investigator/institution against claims arising from the trialCoverage for the cost of treatmentCompensation for the subject
Financing
57 Sponsor Responsibilities contd…
Notification/Submission to Regulatory Authorities
Submission of required applications to authorities for review, acceptance, and/or permission to begin trial
Confirmation of Review by IRBShould obtain name & address of institutional IRB, statement that they comply with GCPs and applicable laws and regulationsDocumentation of approval
Information on Investigational ProductsSufficient safety & efficacy data from non-clinical studies are available to support human exposureUpdate Investigator’s Brochure as new info becomes available
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Sponsor Responsibilities contd…
Manufacturing, Packaging, Labeling, & Coding Investigational Products
Manufactured in accordance with GMPsCoded and labeled in a manner that protects blindingPI should be informed of storage informationCoding system for rapid identification of product
Supplying & Handling Investigational ProductsTimely delivery of productMaintenance of records (shipment, receipt, return)System for disposition of unused product
59 Sponsor Responsibilities contd…
Record AccessSponsor should have access to records
Safety InformationOngoing safety evaluation
Adverse Drug Reaction ReportingReport all adverse drug reactions that are serious and unexpectedSubmit all safety updates and DSM reports
MonitoringRights and well being of human subjects are protectedTrial data are accurate and complete
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 11
Sponsor Responsibilities contd…
AuditingEvaluate trial conduct and compliance with protocol, SOPs, GCPs and other regulatory requirements
Non-compliancePremature Termination or Suspension
Promptly notify investigators/institution with reason for the termination
Clinical Trial/Study ReportsMulticenter Trials
Communication is facilitated between all investigators
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Documents
Essential Documents
Before trial
commencement
During conduct
of trial
After completion or termination of
trial
63 Before Commencement
Document Investigator’s Files
Sponsor’sFiles
Investigator’s Brochure
X X
Protocol, Amendments & Consent Form
X X
Recruitment Material
X X
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Document Investigator’s Files
Sponsor’sFiles
Financial Docs X X
Contracts X X
IRB Correspondence
X X
IRB Composition X X (where required)
CV/Resume of investigator
X X
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FilesSponsor’s
Files
Normal Values/ Ranges for tests
X X
Lab accreditation X(where required)
X
Medical Certification
X(where required)
X
Sample of label on study drug
X
Instructions for handling drug
X X
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Dr. Deepak Langade / Dr. Vidita Morepatil 12
Document Investigator’s Files
Sponsor’sFiles
Shipping Records
X X
Certificate of analysis of drug
X
Decoding procedures
X X
Master randomization list
X
Pretrial/Trial initiation monitoring report
X X
67 During the Trial
Document Investigator’s Files
Sponsor’sFiles
Updates to Investigator’s Brochure
X X
Revisions to Regulatory Docs
X X
Dated approvals from the IRB
X X
Updates to normal values
X X
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Document Investigator’s Files
Sponsor’sFiles
Updates to medical/ lab/ technical procedures/tests
X X
Drug shipment information
X X
Certificate of analysis for new batches of drug
X
Monitoring visit reports
X X
Relevant communications
X X
69 Document Investigator’s Files
Sponsor’sFiles
Signed informed consent forms
X
Source documents
X
Signed, dated & complete CRFs
X(Copy)
X(Original)
Documentation of CRF corrections
X(Copy)
X (Original)
Notification of SAEs & related reports
X X
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Document Investigator’s Files
Sponsor’sFiles
Notification by sponsor of safety information
X X
Interim or annual reports to IRB
X X(where required)
Subject screening log
X X(where required)
Subject identification code list
X
Subject enrollment log
X
71 Document Investigator’s Files
Sponsor’sFiles
Investigations product accountability log at site
X X
Signature sheet X X
Record of retained body fluids/tissue samples
X X
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22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 13
Closure/Termination of Trial
Document Investigator’s Files
Sponsor’sFiles
Investigational product accountability log at site
X X
Documentation of product destruction
X(if at site)
X
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FilesSponsor’s
FilesCompleted subject ID code list
X
Audit certificate X
Close out monitoring report
X X
Treatment allocation & decoding documentation
X
Final report to IRB X
Clinical Study Report
X X
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Document Storage
Storage of Essential Documents
OHRP Rule: 3 years following study completionNIH Rule: 3 years from date of submission of final expenditure report FDA Rule: 2 options
2 years following marketing of the drug or,2 years after IND application is withdrawn if drug was not marketed
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Storage of Essential Documents
Sponsor Rule: refer to study protocol
Privacy Rule: Authorizations must be kept for 6 years
Follow rule with the longest time limit!
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Audits
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22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 14
A systematic and independent examination of trial related activities and documents to determine if these activities were:
RecordedAnalyzed & Accurately Reported
According To:ProtocolSOP’sGCP &Regulatory Requirements
What is an Audit? 79 What does an Site Audit involve?
Introductory Meeting to explain the aims and conduct of the audit Interviews with Study Personnel assessing study conduct Review of:
Facilities - Tour of Lab, Housing Area, Pharmacy etcinvestigator documentation on site and at CRORaw Data such as consent formssource documents including patient notesdrug accountabilitytranscription into CRF/EDC
Close-out meeting to discuss the observations/findings, and also any outstanding questionsFollow-up to review the implementation of the proposed Corrective and Preventive Action
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Latest addendum
ICH-GCP E6 (R2) Step-4 version dt. 09 Nov. 2016
GlossaryApplies to all records (paper or electronic)Investigators/SitesSponsor – Quality management & Risk managementMore active monitoring of CRO’sMonitoring Non-compliance
81 Key changes in new version of E6
Vendors and contract staff (whether used by Investigational Sites or Sponsors) must be qualified and managed to ensure the quality of provided work. The delegation and approval of tasks should be put in writing.Source data should be “attributable, legible, contemporaneous, original, accurate, and complete,” with any changes to the original entry documented (audit trail).Trial Master Files should be searchable and retrievable.Electronic systems should be validated, backed up and safeguarded.A risk-based approach to quality management should be implemented and maintained during the entire life cycle of the clinical trial.Development of a risk-based approach to monitoring should be implemented and the rationale for monitoring plan / monitoring approach documented.CAPA methodology should be used for any identified noncompliance.
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e is one IMPORTANT unwritten Rule in Clinical Trial Study,
DOCUMENT IT DOWN ON PAPER…!
If it is not documented, it did not happen!
Close Out Comment: 83 Differences Between Indian GCP & ICH GCP
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 15
Investigator Qualification
IICH – GCP: (4.1.1)
The investigator(s) should be qualified byeducation, training, experience to assumeresponsibility for the proper conduct of the trial,should meet all the qualifications specified by theapplicable regulatory requirement(s)
Indian GCP: (3.3.1)
The investigator should be qualified by education,training and experience to assume responsibilityfor the proper conduct of the study and shouldhave qualifications prescribed by the MedicalCouncil of India (MCI).
85 Investigator & Sponsor SOP’s
ICH – GCP:
Investigator to comply with the protocol (4.5)and leaves the task of monitoring compliance toSOPs to monitors and auditors (5.19.1).
Indian GCP: (3.1.3)
The Sponsor should establish detailed StandardOperating Procedures (SOP’s). The Sponsor andthe Investigator(s) should sign a copy of theProtocol and the SOPs or an alternativedocument to confirm their agreement.
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PI responsibility for data analysis
ICH – GCP: (4.10)
when the trial is completed, the investigator has toprovide the Independent Ethics Committee (IEC)with a summary of the outcome of trial.
Indian GCP: (3.3.8)
The completion of the study should be informed bythe investigator to the institution, the sponsor andthe ethics committee. The investigator should signand forward the data (CRFs, results andinterpretations, analyses and reports, of the studyfrom his / her centre to the sponsor and the ethicscommittee.
87 Essenttial Documents
ICH – GCP: (8.2)Investigator/ SponsorInstitution
Indian GCP: (APPENDIX V)Investigator / InstituteSponsorCROIEC
88
Monitor Responsibilities
ICH – GCP: (5.18..4)Communicating deviations from the protocol,SOPs, GCP, and the applicable regulatoryrequirements to the investigator and takingappropriate action designed to preventrecurrence of the detected deviations.
Indian GCP: (3.2.2)The monitor should promptly inform thesponsor and the ethics committee in case anyunwarranted deviation from the protocol orany transgression of the principles embodiedin GCP is noted.
89 Drug Label
Indian GCP: (2.3.1.6)
In the section on protocol, it ismentioned that drug label shouldinclude name and contact numbers ofinvestigator and name of institution.
This is not a global practice.
This will lead to practical difficulties inglobal trials where the labels areuniform with minor changes made ifrequired by local laws and practice.
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Research Methodology: D Y Patil School of Medicine
22 July 2019
Dr. Deepak Langade / Dr. Vidita Morepatil 16
DDocument Retention
ICH – GCP: (5.18.4)Essential documents should be retained untilat least 2 years after the approval of amarketing application in an ICH region.
Indian GCP: (4.9)Indian GCP mandates that the sponsor shouldmake arrangements for safe and securecustody of all study related documents andmaterial for a period of three years after thecompletion of the study or submission of thedata to the regulatory authority (ies)whichever is later.
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Thank You!QUESTIONS?
Resources
http://www.fda.gov/oc/gcp/guidance.htmhttp://www.clinicaltrials.gov/http://www.fda.gov/oc/ohrt/irbs/websites.htmlhttp://ohrp.osophs.dhhs.gov/http://privacyruleandresearch.nih.gov/
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Dr. Padmaja Samant
Introduction to qualitative methods • Basic terms in qualitative research • Sampling and data collection • Data Collection methods – Focus Groups,
Structured interview, etc. • Triangulation, Mixed Methods research • Data analysis and statistical methods, including
software for qualitative data analysis • Challenges Q
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Scientific research ….asks a question,• uses predetermined tools to answer them,• collects evidence & produces findings that were not determined in advance & •that are applicable beyond the immediate boundaries of the study
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• Additionally, seeks to understand a given problem or topic from the perspectives of the local population it involves.
• Effective in obtaining culturally specific information about their values, opinions, behaviors, and social mileau
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Effective in identifying intangible factors, such as social norms, socioeconomic status, gender roles, ethnicity, and religion, whose role in the research issue may not be readily apparent.
• help us to interpret and better understand the complex reality of a given situation and the implications of quantitative data.
• Typically data should not be generalized to other geographical areas or populations.
• In this sense, qualitative research differs from scientific research
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Quantitative research
• Researcher decides what to study;
• asks specific, narrow questions,
• collects quantifiable data from large number of participants;
• analyzes these numbers using statistics;
• and conducts the inquiry in an unbiased, objective manner.
• Postpositivism – singular reality; objective; deductive
Qualitative research
• Researcher relies on the views of participants;
• asks broad, general questions;
• collects data consisting largely of words (or text) from participants;
• describes and analyzes text for themes; and
• conducts the inquiry in a subjective, biased manner.
• Constructivism – multiple realities; biased; inductive
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Generally involves collecting numerical data that can be subjected to statistical analysis
• Data collection methods Performance Tests Personality Measures Questionnaires
( closed-ended or open-ended but transferred to quan data) Not flexible
involves listening to the participants’ narration and subjecting the data to analytic induction (e.g., finding common themes) •Exploratory in nature •Data collection methods InterviewsOpen-ended questionnairesObservations •Focus Groups•Flexible
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• Only a sample ( a subset) of a population is selected for any given study.
• Research objectives and the characteristics of the study population (size and diversity) determine which and how many people to select.
• most common sampling methods used in qualitative research:
purposive sampling, quota sampling, snowball sampling.
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Purposive sampling
Groups participants according to preselected criteria relevant to a particular research question (ie, HIV-positive women in Capital City). • Sample sizes, may or may not be fixed prior to data
collection, depend on the resources and time available, as well as the study objectives.
• Theoretical saturation (the point in data collection when new data no longer bring additional insights to the research questions).
• Purposive sampling is therefore most successful when data review and analysis are done in conjunction with data collection.
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Quota sampling
• we decide while designing the study how many people with which characteristics to include as participants.
• Characteristics might include age, place of residence, gender, class, profession, marital status, use of a particular contraceptive method, HIV status, etc.
• The criteria allow us to focus on people we think would be most likely to experience, know about, or have insights into the research topic.
• Using recruitment strategies appropriate to the location, culture, and study population –
find people who fit these criteria, until we meet the prescribed quotas.
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• In quota sampling, a population is first segmented into mutually exclusive segments. Then number is decided
• This second step makes the technique non-probability sampling. In quota sampling, there is nonrandom selection – The researcher may use accidental sampling
Quota sampling is useful when• Time is limited, • Tight budget• Sample frame not available • Quota sampling is the non probability version of
stratified sampling
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Snowballing • Also known as chain referral sampling – a type of
purposive sampling.• used to find and recruit hidden populations,
i.e. groups not easily accessible to researchers• Participants or informants with whom contact
has already been made; use their social networks to refer the researcher to other people who could potentially participate in or contribute to the study.
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• A recruitment strategy is a project-specific plan for identifying and enrolling people to participate in a research study.
The plan should specify criteria for • screening potential participants, • the location, and• the approach to be used.
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Determined by • the type and number of data collection activities in
the study and• by the characteristics of the study population. Typically flexible and can be modified if• new topics, research questions, or subpopulations
emerge as important to the study, • initial strategies do not result in the desired
number of recruits or method and / or the chosen population does not answer the research question
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• The criteria for selection can also be changed if certain data collection activities or subpopulations of people prove not to be useful in answering the research questions
• Proposed changes in the recruitment strategy must be submitted to the sponsoring organization, and some will require submission of a protocol amendment for approval by the ethics committees
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Data types Include• in-depth or unstructured interviews,• field notes, unstructured field diaries, personal
documents, • Photographs and so on. • initial stages -large mass of data
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The three most common qualitative methods, •participant observation, •In-depth interviews, and• focus groups. •Participant observation is appropriate for collecting data on naturally occurring behaviors in their usual contexts.•In-depth interviews are optimal for collecting data on individuals personal histories, perspectives, and experiences,particularly when sensitive topics are being explored.•Key informant interviews•Focus groups are effective in eliciting data on the cultural norms of a group and in generating broad overviews of issues of concern to the cultural groups or subgroups represented.
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• CAHPS: Consumer Assessment of Health Plan Study
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Researcher administered survey• The questions are read exactly as they appear on
the survey questionnaire. • Close-ended in the beginning though later open-
ended questions can also be included within a structured interview.
• Standardized order in which questions are asked of survey respondents. Q
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• The participant observer – investigator studies the life of a group by sharing in its activities
• an "insider" viewpoint and the information may be much more rich than that obtained through systematic observation.
• Bias and reactivity.• These difficulties are magnified in participant
observation. Events are interpreted through the single observer's eyes.
• Biases-- in taking extensive notes and writing down one's impressions; one's own views can come in to play.
• Going native --sympathy -> objectivity is lost. • Reactivity -- influencing what is being observed.
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• They are qualitative, in-depth interviews of 15 to 35 people selected for their first-hand knowledge about a topic .
• loosely structured, relying on a list of issues to be discussed. allow a free flow of ideas and information.
• Interviewers frame questions spontaneously, probe for information and takes notes, which are elaborated on later.
When Are Key Informant Interviews Appropriate? • This method is useful in all phases of development
activities— identification, planning, implementation, and evaluation
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• When qualitative, descriptive information is sufficient for decision-making.
• When there is a need to understand motivation, behavior, and perspectives of our customers and partners..
• When a main purpose is to generate recommendations. Key informants can help formulate recommendations that can improve a program’s performance.
• When quantitative data collected through other methods need to be interpreted.
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• An essential element of testing reliability nad validity of survey instruments to know whether or not the items or response options are understood or not and interpreted consistently correctly as desired .
• Feed back interview • Think aloud • Probing why
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• formal informed consent is necessary for all qualitative research methods ( except participant observation) regardless of the sampling method used to identify potential participants and the strategies used to recruit them.
• Whether this informed consent is oral or written depends on a number of project-specific factors and ultimately upon approval by the ethics committee.
• Individual informed consent may be written or oral.• During recruitment, obtaining informed consent for qualitative
research involves clearly explaining the project to potential study participants.
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• Gatekeeping influences the research endeavor in a number of ways: by limiting conditions of entry, by defining the problem area of study, by limiting access to data and respondents, by restricting the scope of analysis, and by retaining prerogatives with respect to publication
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A mixed methods research design is a procedure for collecting, analyzing, and “mixing” both quantitative and qualitative research and methods in a single study to understand a research problem.
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Triangulation• Triangulation. : use of more than one approach to the
investigation of a research question in order to enhance confidence in the ensuing findings.
• Since social research founded on the use of a single research method may suffer from limitations associated with that method or from the specific application of it, triangulation offers the prospect of enhanced confidence.
• Triangulation is one of the several rationales for MULTIMETHOD RESEARCH. The term derives from surveying, where it refers to the use of a series of triangles to map out an area.
• triangulation becomes a device for enhancing the credibility and persuasiveness of a research account
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• The two sets of findings may be inconsistent, but, such an occurrence underlines the problem of relying on just one measure or method.
• Equally, the failure for two sets of results to converge may prompt new lines of inquiry relating to either the methods concerned or the substantive area involved.
• Webb et al.
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• Denzin (1970) distinguished four forms of triangulation: • Data triangulation : gathering data through several
sampling strategies, so that slices of data at different times and social situations, as well as on a variety of people, are gathered.
• Investigator triangulation: use of more than one researcher in the field to gather and interpret data.
• Theoretical triangulation : use of more than one theoretical position in interpreting data.
• Methodological triangulation: use of more than one method for gathering data.
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• Analysis also involves breaking down data into bits and then beating the bits together, so that the data is resolved into its components, and its characteristic elements are revealed. In this sense you can say that we split data processing into two activities, namely,
• Checking and converting the data Generating metadata
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The focus on text—on qualitative data rather than on numbers—is the most important feature of qualitative analysis. The text is most often •transcripts of interviews or notes from participant observation sessions,• pictures or other images that the researcher examines.
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1. Analysis of a text as a way to understand what participants reallythought, felt, or did in some situation or at some point in time. The text becomes a way to get behind the numbers that are recorded in a quantitative analysis to see the richness of real social experience.
2. A hermeneutic perspective on texts—that is, a perspective that views a text as an interpretation that can never
be judged true or false. The text is only one possible interpretation among many.
• From a hermeneutic perspective, a researcher is constructing a reality with his or her interpretations of a text provided by the
subjects of research; other researchers, with different backgrounds, could come to markedly different conclusions.
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Qualitative data analysis tends to be inductive—•The analyst identifies important categories in the data, as well as patterns and relationships, through a process of discovery.• There are often no predefined measures or hypotheses
•Emic focus - Representing a setting with the participantsterms and from their viewpoint.•Etic focus - Representing a setting with the researchersterms and from their viewpoint. Q
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• focus on the interrelated aspects of the setting, group, or person under investigation—
• the case— rather than breaking the whole into separate parts.
• The whole is always understood to be greater than the sum of its parts, and so the social context of events, thoughts, and actions becomes essential for interpretation. Q
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An iterative and reflexive process that begins as data are being collected rather than after data collection has ceased ( the meaning of the text and how it might relate to other issues). This process of reading through the data and interpreting them continues throughout the project. The analyst adjusts the data collection process itself when it begins to appear that additional concepts need to be investigated or new relationships explored. This process is termed progressive focusingIf early questions are not working, if new issues become apparent, the design is changed.
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1. Documentation of the data and the process of data collection2. Organization/categorization of the data into concepts3. Connection of the data to show how one concept may
influence another4. Corroboration/legitimization, by evaluating alternative
explanations, disconfirming evidence, and searching for negative cases
5. Representing the account (reporting the findings)• The data for a qualitative study most often are notes jotted
down in the field or during an interview—from which the original comments, observations, and feelings are reconstructed—or text transcribed from audiotapes.
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The various contacts, interviews, written documents, and whatever it is that preserves a record of what happened all need to be saved and listed.
• Documentation is critical to qualitative research for several reasons:
• It is essential for keeping track of what will be a rapidly growing volume of notes, tapes, and documents;
• it provides a way of developing and outlining the analytic process; and it encourages ongoing conceptualizing and
strategizing about the text.
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• Identifying and refining important concepts is a key part of the iterative process of qualitative research.
• Sometimes, conceptualizing begins with a simple observation that is interpreted directly, pulled apart,and then put back together more meaningfully.
• The focus in this conceptualization is to provide a detailed description of what was observed and a sense of why that was important.
• More often, analytic insights are tested against new observations, the initial statement of problems and
• concepts is refined, the researcher then collects more data, interacts with the data again, and the process continues.
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• Matrix : A form on which can be recorded systematically particular features of multiple cases or instances that a qualitative data analyst needs to examine.
• The matrix condenses data into simple categories, reflects further analysis of the data to identify degree of support, and
• provides a multidimensional summary that will facilitate subsequent, more intensive analysis. Direct quotes still impart some of the flavor of the original text.
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• Examining Relationships and Displaying Data• Examining relationships is the centerpiece of the analytic
process,• It allows the researcher to move from simple description
of the people and settings to explanations of why things happened as they did with those people in that setting.
• The process of examining relationships can be captured in a matrix.
• Matrix shows how different concepts are connected, or perhaps what causes are linked with what effects. Q
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• Need for authenticity ; but no set standards• Individual items of information can be assessed in terms of at
least three criteria (Becker 1958):1. How credible was the informant? 2. Were statements made in response to the researcher s
questions, or were they spontaneous? 3. How does the presence or absence of the researcher or the
researcher s informant influence the actions and statements of other group members?
• Reactivity to being observed can never be ruled out as a possible explanation for some directly observed social phenomenon.
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• Comparing conclusions from a qualitative research project to those other researchers obtained while conducting similar projects can also increase confidence in their authenticity.
• Confidence in the conclusions from a field research is strengthened by an honest and informative accountabout
• how the researcher interacted with subjects in the field, • what problems he or she encountered, • and how these problems were or were not resolved.
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• The first activity comprises a) checking out the completeness and quality of data,
• the relationship between data - interviews, field notes, audio visual recordings etc and
• Anonymisationb) converting data or transferring data to a format that is appropriate for dissemination. • checking out the completeness and quality (in terms of
its physical condition, readability audibility, re- usability)• researcher needs to bring to light any problems relating
to confidentiality, anonymity, reusing, suitability for digitisation, etc.
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• Anonymisation. - confidentiality of the respondent or any other person or entity.
• The level of anonymisation used for a dataset depends on the nature of the study
• Sometimes, it is not easy to disguise the identity of the subjects of research without bringing about an unacceptable distortion to the data. Then, the particular data can hardly be reused for any purpose.
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• The second processing activity of generating metadata
• Contextual information that a researcher obtains during processing, for example
• One may create lists of data giving biographical inputs that would make it easier to identify transcripts
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Preparing i) a data list andii) a catalogue of records. iii) a user guide
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• description, interpretation, explanation, understanding, and possibly, prediction.
• Description provides the basis for analysis, which then lays the base for further description.
• Breaking down our data in order to draw concepts from it, which we then use to classify the data.
• We draw connections between different concepts and these connections form the basis of further description. Ian Dey (1993) presents the following diagram, which succinctly represents the circular processes involved
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Comprehensive descriptions of the phenomenon under study. • “Thin description", merely states facts, •thick description includes information abouta ) the context of an act, social, cultural and historical backdrop b) intentions and meaning attributed by the actor to the action subjective meanings imbued by actors to the way of actionc) the process in which the action is embedded.ie consequences of the action Geertz (1973)
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• Ethnography, netnography ethnomethodology; • qualitative comparative analysis;• narrative analysis;• conversation analysis; • case-oriented understanding; and • grounded theory
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• Describing and classifying serve to produce an account of analysis.
• The concepts must be connected together to look for associations between different variables and to see the patterns within the data, so that we can discern regularities and also variation and exceptions.
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• Ethnography The study of a culture or cultures that some group of people shares, using participant observation over an extended period of time.
• Netnography / cyberethnography / virtual ethnography is the use of ethnographic methods to study online communities.
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• The ways in which confidentiality might be breached should be carefully considered before data collection begins and explicit strategies be put in place for protection.
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• the objectivity of a piece of qualitative research is evaluated in terms of the reliability and validity of its observations.
• Reliability - extent to which a measurement procedure yields the same answer however and whenever it is carried out.
• Validity is the extent to which it gives the correct answer.
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The enhancement model • generating hypothesis to be tested by quantitative research,• helping to construct more sophisticated measures of social
phenomena and • explaining unexpected research from quantitative research. The Epistemological Model :• researching parts other research approaches can't reach,• increasing understanding by adding conceptual and
theoretical depth to knowledge, • shifting the balance of power between researchers and
researched and• challenging traditional epidemiological ways of "knowing" the
social world.
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• Sociologists need to establish the usefulness of the data they gather to ensure answers of the following questions.
• How accurate a profile of social life one is able to get • Whether the conclusions reached are representative
enough to be applicable to everyone• Is it possible to repeat the research if others want to
carry it out • and will there be similar results if they did? Q
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• following ideas figure in making data reliable. • consistencye: It is important to obtain consistently similar
responses to the same questions in similar circumstances.
• precision: One has to know how systematic is the form of data that is based on asking people questions about things that they know little about
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Use of open-ended questions and probing –gives participants the opportunity to respond in their own words, rather than forcing them to choose from fixed responses, as quantitative methods do.
Open-ended questions have the ability to evoke responses that are:
• meaningful and culturally salient to the participant
• unanticipated by the researcher• rich and explanatory in nature
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Limitations of Qualitative Research• quality is heavily dependent on the individual skills • easily influenced by personal biases and idiosyncrasies. • Rigor is more difficult to maintain, assess, and demonstrate.• The volume of data makes analysis and interpretation time
consuming.• FGI : Well structured guide, flexible and skilled moderator
required• Not as well understood, accepted as quantitative research
within the scientific community• The researcher's presence during data gathering, often
unavoidable, can affect the subjects' responses. • Issues of anonymity and confidentiality can present problems
when presenting findings• Findings can be more difficult to characterize in a visual way.
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• http://www.referenceworld.com/sage/socialscience/triangulation.pdf
• Claire Anderson Presenting and Evaluating Qualitative Research.Am J Pharm Educ. 2010;74(8):1-7.
• http://www.staff.u-szeged.hu/~magnes/downloads/greetz.pdf
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ETHICS IN MEDICAL RESEARCH
Padmaja Samant: Ethics in Research 2
Session ObjectivesHistoryDefine GCPBrief background to evolution of GCPLandmarksICH GCP Informed ConsentPublication ethics: authorship and plagiarism
Padmaja Samant: Ethics in Research 4
Definition: Good Clinical Practices
(GCP) is an international ethical & scientific quality standard for design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials or studies that involve human subjects.
So that …….Positive (or negative) data can lead to a recommendation to use (or not to use) a treatment.
Objectives of GCP
To protect the rights, safety and welfare of humans participating in research consistent with the principles that have their origin in the Declaration of HelsinkiTo assure the quality, reliability and integrity
of collected dataTo provide standards and guidelines for the
conduct of clinical research
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Evolution of GCP
Nuremberg Code, 1947Declaration of Helsinki, 1964 → 2001ICH GCP guidelines, 1996Ethical Guidelines for Biomedical Research in Human Subjects (ICMR), 2000GCP Guidelines, CDSCO, New Delhi, 2001
Background
The Nuremberg code 1947 In May1946 Dr. Leo Alexander had submitted to the Counsel for War Crimes six points defining legitimate medical research.The trial verdict adopted these points and added an extra four. The ten points constituted the "Nuremberg Code".
The Nuremberg Code and the Declaration of Helsinki are the basis for the regulations issued by the US Dept of health & Human Services governing federally funded human subjects research in the United states.
Voluntary ConsentThe experiment should be such as to yield fruitful results for the good of society.and based on the results ofanimal experimentationAvoid all unnecessary suffering and injury.No experiment should be conducted where there is a prior reason to believe that death or disablity will occur.The degree of risk to be taken should never exceed benefit.Proper preparations should be made and adequate.The experiment should be conducted only by scientifically qualified persons. human subject should be free to withdrawscientist prepared to terminate the experiment at any stage, if likely to result in injury, disability or death .
Declaration of Helsinki
Declaration of Helsinki
Founded in 1947, a central objective of the WMA has been to establish and promote the highest possible standards of ethical behaviour and care by physicians. In pursuit of this goal, it adopted global policy statements on a range of ethical issues related to medical professionalism, patient care, research on human subjects and public health
Declaration of Helsinki (1964)
Well-being of subject takes precedence Respect for persons Protection of subjects health and rights
Special protection for vulnerable populations
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Almost every national scientific community hasacknowledged DH as cornerstone of Ethics inHuman Biomedical ResearchIn Israel, Ethics committees are called HelsinkiCommitteesEven though the Declaration of Helsinki is theresponsibility of the World Medical Association,the document should be considered the propertyof all humanity.“National Forum on the Declaration of Helsinki: Brazilian Perspective”
2008
The Belmont Report 1979
The Belmont Report : written by the National Commission for the Protection of Human Services of Biomedical and Behavioral Research.Prompted in part by problems arising from the
Tuskegee Syphilis study(1932–1972) and based on the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974–1978) work
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS
FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
Background
Need for safe and efficient products for various health problems Drug development is expensive and time consumingNeed for efficient quality systems Global drug marketExistence of national laws and regulations for drug development
ICH - Objective
To provide a unified standard for the EU, Japan & the US to facilitate the mutual acceptance of clinical data by regulatory authorities in these jurisdictionsThe guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).
Should be followed when generating data that are intended to be submitted to regulatory authorities.
ICH GCP: 1996Goals:
Harmonize technical procedures and standards;improve quality of research and products
To provide a unified standard to facilitate the mutual acceptance of clinical data by the regulatory authorities Remove redundancy /duplication in development and review process
In 1997, the FDA endorsed the GCP Guidelines developed by ICH. ICH guidelines have been adopted into law in several countries, but used as guidance for the FDA in the form of GCP
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13 Principles of ICH GCP
Ethics: 1. Ethical conduct of clinical trials 2. Benefits justify risks 3. Rights, safety, and well-being of subjects prevail Protocol and science: 4. Nonclinical and clinical information supports the
trial 5. Compliance with a scientifically sound, detailed
protocol
Responsibilities: 6. IRB/IEC approval prior to initiation 7. Medical care/decisions by qualified physician 8. Each individual is qualified (education,
training, experience) to perform his/her tasksInformed Consent: 9. Freely given from every subject prior to
participation
Data quality and integrity: 10. Accurate reporting, interpretation, and
verification 11. Protects confidentiality of records
Investigational Products 12. Conform to GMP’s and used per protocol Quality Control/Quality Assurance 13. Systems with procedures to ensure quality of
every aspect of the trial
GCP - A Shared Responsibility
Sponsor
Investigator
Regulatory Authority
Ethics Committee
What is an Ethics Committee?• An independent review board or committee comprising of medical
/ scientific and non-medical /non-scientific members, whoseresponsibility is to verify the protection of the rights, safety andwell-being of human subjects involved in a study.
• The independent review provides publicreassurance by objectively, independently and impartially reviewing
and approving the Protocol , the suitability of the investigator(s),facilities, methods and material to be used for obtaining anddocumenting Informed Consent of the study subjects andadequacy of confidentiality safeguards.
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Ethics Committee: Composition as perIndian GCP
Heterogeneous group of at least 5-7 members (up to 15)
Qualified
Experienced in their professional field
Proficient to evaluate both scientific & ethical
aspects (familiar with GCP)
Quorum - 5 members should be present for the
meeting
Multidisciplinary, Independent, Competent
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Ethics Committee: Composition –Schedule Y
Chairperson : Outsider
Member – Secretary Quorum- At least 1 member
basic medical scientistclinicianlegal expert social scientist/philosopher/priestlay person
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All proposals on
biomedical research involving human subjects
must be cleared
by an
Ethics Committee
Ethics Committee: Role
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EC: Type of Studiesprospective / retrospectivepatients / volunteersmodern / alternativedrugs / procedures in physical medicineinterventional/ observational
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Types of studies exempt for Ethics Committee review….
• In vitro drug studies ,Cell lines • Research on educational practices effectiveness of or
comparison among instructional techniques, Curricula, classroom management
Exceptionsa) If direct/ indirect identification involvedb) Direct access poses risk of civil/criminal/financial liability or
psychosocial harm in case of disclosure of information outside research
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EC: Role & Responsibility
Before the study begins
During the study
After the study
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EC: Role & Responsibility
Before the study begins:
Submission of research proposal
Review of proposal
Decision making process
Issuing an approval
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Documents To Be Submitted for ReviewICH-GCP 3.1.2
Trial protocol
Informed consent documents
Subject recruitment procedures (advertisements)
Investigator brochure
Investigator s curriculum vitae & documentation evidencing qualifications and expertise
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Submissions to EC
Information: patient payment/ compensation
Regulatory clearances
Details of sponsors & fund allocation
Any other documents specifically requested by
EC that would add to protection of the rights,
safety and/or well being of the subjects.
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Reviewing Study DocumentsSuitability of protocol
Background & Justification for study
Objective of the study
Study design and methodology
Risks & benefits to the trial subject
Subject safety measures
Confidentiality of subjects and data
Regulatory aspects
Informed Consent Document
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Reviewing Study Documents
ICH GCP: 3.1.3
Competency of the investigator
Qualifications
Experience
Support staff
Available facility
Emergency services
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Suitability of the ICF & Pt. Information sheetInformed Consent Form : Contents
Trial involves research PurposeTreatment options in trial, randomisationTrial procedures & durationSubject’s responsibilities / compensationRisk Vs. benefitsReasonably expected benefits
Contact information RIGHT TO WITHDRAW
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• Review both amount, schedule and mode of payment
• Payment must be prorated (ICH GCP3.1.8)
• Method of how it is prorated (ICH GCP3.1.9)
27/02/11 ,Shatabdi EC-CON 2011, Nashik
Suitability of the ICF & Pt. Information sheet
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EC : Decision makingTo review within a reasonable time
Projects circulated to members
Comments compiled by member secretary
Decisions taken in formal meetings
by consensus
Documents its views in writing
Approval (schedule Y format)
Modifications required prior to approval
DisapprovalPadmaja Samant: Ethics in Research 37
During the study:
Review of amendments ( Protocol, ICD)
Review of Serious Adverse Events
Protocol deviations
Progress (study status)
ICH GCP 3.1.4
Conduct continuing review for each project atleast
once a year
After the study: Study Report
EC: Role & Responsibility
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How an EC functions?
• Documentation requirements• Review procedures• Decision making processes
According to written Standard Operating Procedures
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EC procedures• No subject enrolled prior to approval of the study• Amendment must be approved by EC except when necessary
to eliminate immediate hazard or change is administrative• Specify the investigator to promptly report
deviation/ change in protocolchange increases the riskserious and unexpected ADRnew information that may adversely
affect the safetyEC records: Retain records for atleast 3 years post trial
completionPadmaja Samant: Ethics in Research 40
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...Issues faced by Ethical Committee
Why look into Scientific Aspects?‘Me – too’ studiesEnd points not specifiedNo control armDenial of standard of care
Poor Science = Poor EthicsStudy Participants
Incentives?Management of trial related injury?Informed consent document inadequate
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INFORMED CONSENT
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Bioethics Principles
• Autonomy: Self determination• Beneficence• Non maleficence• Justice
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Why do we need consent?
• Legal and ethical considerations• Way to minimize potential harm• Avoid unfairness and exploitation. • Protect patients' rights.
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Advantages of Consent
• Enhances Doctor Patient relationship.• Gives a frame work for the doctor to act. • It clarifies the objective of treatment.• Patient may cooperate fully with treatment.
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Definition of informed consentInformed consent is: The process of agreeing to take part in a study based
on access to all relevant and easily digestible information about what participation means, in particular, in terms of harms and benefits.
It is not merely a form that is signed but is a process, in which the subject has an understanding of the research and its risks.
Informed consent is essential before enrolling a participant and ongoing once enrolled.
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• It is a process of communication between a patient and physician that results in the patient's authorization or agreement to undergo a specific medical intervention
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Informed Consent must be obtained for all types of human subjects research including; diagnostic, therapeutic, interventional, social and behavioral studies, and for research conducted domestically or abroad.
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Subjects in the study must participate willingly. Vulnerable populations (i.e. prisoners, children, pregnant women, etc.) must receive extra protection.The legal rights of subjects may not be waived and
subjects may not be asked to release or appear to release the investigator, the sponsor, the institution or its agents from liability for negligence.
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The key ethical principles- JusticeResearchers must respect diversity when gaining
informed consent and must take into account factors such as:
Ethnicitygenderdisabilityreligious beliefs culture languagelevel of understanding.
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Who should administer consent
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Some protocols specify the qualifications of the person required to obtain consent. The sponsor is responsible for ensuring that the individual obtaining informed consent is trained to do so.
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Consent should be given by someone with the mental ability to do so
Sufficient information should be given to the participant
If any of these requirements is lacking then the consent is invalidated.
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Coercion
• Undue benefits • Inappropriate compensation• Connection between the consent taker and
participant• Threat of punishment or harm to patient or
loved ones
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The goal of the processTo provide sufficient information so that a participant can make an informed decision about whether or not to enroll in a study or to continue participation. – Autonomy and Justice
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LanguageICD to be written in language easily understood by the participant,it must minimize the possibility of coercion or
undue influence, and the subject must be given sufficient time to consider participation. Translation and Back translation
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Scientific, technical, and medical terms must bedefined or explained in lay terms.It is often recommended that the informed consent
be written at the eighth grade reading level. When enrolling minors in a study, related recruitment materials must reflect the reading level of minors.
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Types of consentImplied informed consent Implied consent may arise when express written and/or verbal consent is not given; for example, when a participant implies their informed consent by returning a completed anonymised questionnaire. In these circumstances the REC will want to be reassured that there is no way that the researcher will be able to identify the participant from their responses.
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Delayed consent usually occurs in emergency situations, when obtaining informed consent might make the study impossible. For example, it may be needed for research undertaken: at the roadside in the event of an accident at a cardiac arrest during the early stages of a patient s emergency
admission to an accident and emergency department.
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Verbal – Verbal consent still contains all elements of written consent, however, the participant is verbally read the elements and verbally agrees to participate.
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Potential participants need to know• The purpose of the research, anticipated uses of
the research • How long their participation will last • Who is involved in the research • The practicalities and procedures involved in
participating, what is expected of them • The possible benefits and risks and, when
appropriate, the alternative therapies
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• How data about them will be managed and used & how long and where it will be stored
• Names, addresses, and telephone numbers of the sponsors of the research;
• That they are free to ask questions and may refuse to participate;
• They may later withdraw from the research, the consequences of such withdrawal;
• Subjects right to confidentiality
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Additional ElementsDepending on the project and the subject population,
the Informed Consent must also contain information on: Certificate of Confidentiality (if any)/limitations of
certification protection Payment for participation (if applicable)Risks to vulnerable subjects, e.g., embryo, fetus,
pregnancyCircumstances for investigator withdrawing the subject
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Additional elements ctd
• Additional costs from participationEarly withdrawal consequencesStatement regarding how significant new findings
will be communicated • Number of subjects participating• Probability of random assignment or placebo
placement• Additional information required by the IRB
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Audiovisual consent
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• In the case of Swasthya Adhikar Manch, Indore & Anr Vs. Ministry of Health and Family Welfare &Ors. the supreme court ordered AV recording of IC process of 5 global trials
• CDSCO vide F. No. GCT/20/SC/Clin./2013 DCG1 dated 19.11.2013 - in all clinical trials, audio-visual recording of the informed consent process of each trial subject, including providing information to the subject and his/her understanding on such consent is required to be done while adhering to the principles of confidentiality.
• Such audio-visual recording and related documentation would be preserved..
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Vulnerable participantsEvery recipient of health care is in some way
vulnerable, but those with more limited ability to act autonomously can also be more vulnerable to the impact of research activity . Are those who are relatively or absolutelyincapable of protecting their own interests.They may have insufficient power, intelligence, education,resources, strength, or other needed attributes to protect their own interestsSituational vulnerability: Natural or manmade disasters
Padmaja Samant: Ethics in Research 67
Pregnant women
Consent of the spouse unless• it is for health needs of the mother• Partner not traceable• Pregnancy due to rape
Padmaja Samant: Ethics in Research 68
ChildrenGaining a child’s views and desires –
use of creative ways of providing information alternative means to express their thoughts.
Children should not receive monetary rewards for participation in research,
Any rewards for participating should benefit the child, not the parents.
In addition, travel costs should be reimbursed for the child and those travelling with them.
Padmaja Samant: Ethics in Research 69
Parental Permission – When children/minors are included in research, the parent/guardian must sign a parental permission consent document. Some situations require permission from at least one parent, while other situations require permission from both parents. Assent – Assent is a child s affirmative agreement to participate in research. If the subject is 7- 17 years of age, assent must be obtained.Appropriate reading level of the youngest subject in the age range and use simple terminology.
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Old people
Padmaja Samant: Ethics in Research 71
Unresponsive peopleUnresponsive patients ( injuries or sedation) can only be
included in research for very specific reasons. Written informed consent to be obtained from a legal
representative.The informed consent given by a LAR should represent that
adult's presumed will.The clinical trial is designed to minimise pain, discomfort, fear
and any other foreseeable risk in relation to the disease and the cognitive abilities of the patient
The risk threshold and the degree of distress are specially defined and constantly monitored
The interests of the patient will always prevail over those of science and society.
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If the patient regains consciousness and capacity, informed consent should be sought as soon as is practical.If the individual refuses consent, all documentation
and data relating them to the study should be destroyed.However in the case of a clinical therapeutic trial, all
documentation must be retained for audit purposes, but it should not be used as part of the research.
Padmaja Samant: Ethics in Research 73
Prisoners & army personnelapproval must be sought from the head of health care within the appropriate statutory bodies. A prisoner s participation will be subject to their informed consent in the normal way, particular attention to the need to avoid coercion.
Parole consideration is not subject to partcipationPrisoner advocate on the IRB Risk is not more than that to nonprisonerArmy: articular attention to the need to avoid coercion.
Padmaja Samant: Ethics in Research 74
Students Power relationships and the risk of coercion.
Padmaja Samant: Ethics in Research 75
Language barrier
• Translator: Name entered in the consent document
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WaiverWaiver of one or more elements of informed consent may be obtained from the IRB for-some research projects that could not practically be
done without an alteration to the required elements or for studies where required elements are not applicable.
• The research involves no more than minimal risk;• The waiver or alteration will not adversely affect the
rights and welfare of the subjects;• Whenever appropriate, the subjects will be provided
with pertinent information after participation.Padmaja Samant: Ethics in Research 77
Rules followed in drafting
• National guidelines• Institutional policies• Ethical guidelines• Sponsor requests
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Authorship
ICMJE criteria for authorship 2004
• Authorship credit should be based on(1) substantial contribution to conception and
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published, with authors meeting all of these three conditions.
Padmaja Samant: Ethics in Research 80
• ICMJE guidelines also state that each author “should have participated sufficiently in the work to take public responsibility for the content
• “Gift” authorship. This is defined as naming, as an author, a person who does not meet authorship criteria
Padmaja Samant: Ethics in Research 81
• A ghost author is defined as a person who is not listed as an author but who made contributions that merited authorship.
• Omitting the name of the true author—for example, the contract researcher—at the time of publication constitutes ghosting.
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Plagiarism
Latin plagere=kidnap, plagiatum= “stealing people”
• Plagiarism is the "wrongful appropriation" and "stealing and publication" of another author's "language, thoughts, ideas, or expressions" and the representation of them as one's own.
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Types of plagiarism• Direct form–Fully or partially copy the text, computer files,
audio or video recordings without mentioning the primary source;
• Mosaic form–Borrowing ideas and opinions from the original source, a few words and phrases without citing the source;
• Self-plagiarism–Reuse own work without specifying the primary (own) sources.
• According to data from WAME - World Association of Medical Editors, precise definition of plagiarism is when are copied six consecutive words in a continuous set of 30 used characters.
Padmaja Samant: Ethics in Research 85
Most common types of plagiarism• CLONE–Submitting someone else's work as his/hers own;• CTRL-C–Copied from a single source, without alterations;• FIND–REPLACE–Changing key words retaining a substantial part of
the content of the primary sources;• REMIX–Paraphrasing multiple sources;• RECYCLE–The use of already published ; own work • HYBRID–Combine perfectly cited sources with the copied without
citation;• MASH UP–Blending the copied material from multiple sources;• ERROR 404–Includes quoting non-existent or inaccurate source;• AGGREGATOR–Include proper citation of sources, but contains
almost nothing of own work;• RE–TWEET– proper citation, with too much text from the original.
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Safeguards to avoid plagiarism Paraphrasing – information read and written with own words.Quote - wording of certain authors and they sentences are always placed in quotes.- Quotation marks should be used if are copied more than six consecutive wordsQuotation or citation and reference Citing own materialAcknowledging ideas taken at conference and formal/informal conversations.
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HPV vaccine trial Andhra Pradesh 2009
Andhra Pradesh government brought out an official order (June 2, 2009) asking the deputy medical and health officer in Bhadrachalam block to issue orders to all the hostel wardens and Ashram schools to sign the consent forms on behalf of the parents.In case of 2,763 girls, consent documents were signed en bloc by teachers, hostel wardens and head masters. This is illegal.In another 1948 cases, illiterate parents were asked to put thumb impressions on documents, which they could not understand."
Padmaja Samant: Ethics in Research 88
• 13,000 girls in A.P.and 10,000 in Gujarat aged 10–14. The trial halted in March 2010 after seven girls who received the vaccines died during the trial.
• A government enquiry concluded that the deaths were unrelated to the vaccines.
• Adverse events were not recorded or reported and even deaths were not promptly reported.
• Vaccines came free from pharma giants Glaxo Smith Kline and Merck Sharp and Dohme.
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DISCUSSION
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THANK YOU
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D Y Patil School of Medicine, Navi Mumbai
Basic Workshop on Research Methodology 1
DR. MRIDULA SOLANKIASSOCIATE PROFESSORDEPARTMENT OF COMMUNITY MEDICINESETH G.S.MEDICAL COLLEGE & KEM HOSPITAL
1Mridula Solanki: Sampling Methods
Learn the concept of sampling.
Develop an understanding about differentsampling methods.
Distinguish between probability & non
probability sampling.
Discuss the relative advantages &
disadvantages of each sampling methods.
2Mridula Solanki: Sampling Methods
• “Scientific research is systematic, controlled,empirical, and critical investigation of naturalphenomena guided by theory and hypotheses aboutthe presumed relations among such phenomena.”– Kerlinger, 1986
• Research is an organized and systematic way of
finding answers to questions.
3Mridula Solanki: Sampling Methods
Problem statement, research questions, purposes,benefits
Theory, assumptions, background literature
Variables and hypotheses
Operational definitions and measurement
Research design and methodology
Instrumentation, sampling
Data analysis
Conclusions, interpretations, recommendations
4Mridula Solanki: Sampling Methods
A Sample is “a smaller (but hopefully representative)collection of units from a population used to determine truthsabout that population”. (Field, 2005)
Sampling is the process of selecting some members of thestudy population to represent the population as a whole.
The Sampling frame is the list from which the potentialrespondents are drawn : e.g.◦ Registrar’s office◦ Class rosters
However, Must assess sampling frame errors like universityversus personal email addresses; changing class rosters; are allstudents in your population of interest represented?
5Mridula Solanki: Sampling Methods
Study of entire population what is called as census is difficultand almost impossible for infinite populations.
Costly, time consuming and not feasible.
Accurate and reliable estimates and inferences possible byproper sampling.
Since size is small in depth study can be done easily
Better supervision hence better data.
There are more risks for making interviewer and other errorsdue to the high volume of persons contacted and the numberof census takers, some of whom may not be well-trained.
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Basic Workshop on Research Methodology 2
Mridula Solanki: Sampling Methods 7
What is your population of interest?To whom do you want to generalize yourresults?
All doctorsSchool childrenIndiansWomen aged 15-45 yearsOtherHRGs
Can you sample the entire population?
8Mridula Solanki: Sampling Methods
3 factors that influence sample representativenessSampling procedure
Sample size
Participation (response)
When might you sample the entire population?When your population is very small
When you have extensive resources
When you don’t expect a very high response
9Mridula Solanki: Sampling Methods 10
SAMPLING BREAKDOWN
Mridula Solanki: Sampling Methods
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Defining the Population
Developing a Sampling Frame
Determining Sample Size
Specifying Sample Method
SELECTING THE SAMPLE
Mridula Solanki: Sampling Methods
The sampling process comprises several stages:◦ Defining the population of concern.◦ Specifying a sampling frame, a set of items or events
possible to measure.◦ Specifying a sampling method for selecting items or
events from the frame.◦ Determining the sample size◦ Implementing the sampling plan◦ Sampling and data collecting◦ Reviewing the sampling process
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Basic Workshop on Research Methodology 3
A population can be defined as including all
people or items with the characteristic one
wishes to understand.
Because there is very rarely enough time or
money to gather information from everyone or
everything in a population, the goal becomes
finding a representative sample (or subset) of
that population.
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Note also that the population from which the sample isdrawn may not be the same as the population aboutwhich we actually want information. Often there is largebut not complete overlap between these two groups dueto frame issues etc .
Sometimes they may be entirely separate - for instance,we might study rats in order to get a betterunderstanding of human health, or we might studyrecords from people born in 2008 in order to makepredictions about people born in 2009.
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A sampling frame is the list of all elements in
the population from which the samples are
drawn.
Sample frames for an entire target population
rarely exists and are too impractical to
construct. (Here cluster sampling is done).
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In the most straightforward case, such as the sentencing of a batchof material from production (acceptance sampling by lots), it ispossible to identify and measure every single item in thepopulation and to include any one of them in our sample. However,in the more general case this is not possible. There is no way toidentify all rats in the set of all rats. Where voting is notcompulsory, there is no way to identify which people will actuallyvote at a forthcoming election (in advance of the election)
As a remedy, we seek a sampling frame which has the propertythat we can identify every single element and include any in oursample .
The sampling frame must be representative of the population
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Sampling methods can be split into two distinct
groups:
1. Probability samples
2. Non-probability samples
17Mridula Solanki: Sampling Methods
Probability Samples
Probability samples offer each respondent an equal
probability or chance at being included in the sample.
They are considered to be:
• Objective
• Empirical
• Scientific
• Quantitative
• Representative
Sampling
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Basic Workshop on Research Methodology 4
A probability sampling scheme is one in which everyunit in the population has a chance (greater than zero) ofbeing selected in the sample,
And this probability can be accurately determined.
When every element in the population does have thesame probability of selection, this is known as an 'equalprobability of selection' (EPS) design. Such designs arealso referred to as 'self-weighting' because all sampled
units are given the same weight.
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Non Probability Samples
A non probability sample relies on the researcher selecting the respondents.
They are considered to be:
• Interpretive
• Subjective
• Not scientific
• Qualitative
• Unrepresentative
Samplling
Mridula Solanki: Sampling Methods 20
Any sampling method where some elements of population have no chance of
selection (these are sometimes referred to as 'out of coverage'/'under covered'),
or where the probability of selection can't be accurately determined. It involves
the selection of elements based on assumptions regarding the population of
interest, which forms the criteria for selection. Hence, because the selection of
elements is non random, non probability sampling does not allow the estimation
of sampling errors..
Example: We visit every household in a given street, and interview the first
person to answer the door. In any household with more than one occupant, this
is a non probability sample, because some people are more likely to answer the
door (e.g. an unemployed person who spends most of their time at home is
more likely to answer than an employed housemate who might be at work when
the interviewer calls) and it's not practical to calculate these probabilities.
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Probability (Random) Samples◦ Simple random sample
◦ Systematic random sample
◦ Stratified random sample
◦ Multistage sample
◦ Multiphase sample
◦ Cluster sample
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Non-Probability Samples◦ Convenience sample
◦ Purposive sample
◦ Quota sample
◦ Snowball Sample
• In addition, non response effects may turn any probabilitydesign into a non probability design if the characteristics ofnon response are not well understood, since non responseeffectively modifies each element's probability of beingsampled.
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• Applicable when population is small, homogeneous &readily available
• All subsets of the frame are given an equal probability.Each element of the frame thus has an equal probabilityof selection.
• It provides for greatest number of possible samples. Thisis done by assigning a number to each unit in thesampling frame.
• A table of random number or lottery system is used todetermine which units are to be selected.
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Basic Workshop on Research Methodology 5
Advantages
Estimates are easy to calculate.
Simple random sampling is always an EPS design, but
not all EPS designs are simple random sampling.
Disadvantages
If sampling frame is large, this method impracticable.
Minority subgroups of interest in population may not be
present in sample in sufficient numbers for study.
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Sampling schemes may be without replacement ('WOR' - noelement can be selected more than once in the same sample)or with replacement ('WR' - an element may appear multipletimes in the one sample).
For example, if we catch fish, measure them, and immediatelyreturn them to the water before continuing with the sample, thisis a WR design, because we might end up catching andmeasuring the same fish more than once. However, if we donot return the fish to the water (e.g. if we eat the fish), thisbecomes a WOR design.
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Systematic sampling relies on arranging the target populationaccording to some ordering scheme and then selecting elements atregular intervals through that ordered list.
Systematic sampling involves a random start and then proceedswith the selection of every kth element from then onwards. In thiscase, k=(population size/sample size).
It is important that the starting point is not automatically the first inthe list, but is instead randomly chosen from within the first to thekth element in the list.
A simple example would be to select every 10th name from thetelephone directory (an 'every 10th' sample, also referred to as'sampling with a skip of 10').
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As described above, systematic sampling is an EPS method, because
all elements have the same probability of selection (in the example
given, one in ten). It is not 'simple random sampling' because different
subsets of the same size have different selection probabilities - e.g. the
set {4,14,24,...,994} has a one-in-ten probability of selection, but the set
{4,13,24,34,...} has zero probability of selection.
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ADVANTAGES:
Sample easy to select
Suitable sampling frame can be identified easily
Sample evenly spread over entire reference population
DISADVANTAGES:
Sample may be biased if hidden periodicity in population
coincides with that of selection.
Difficult to assess precision of estimate from one survey.
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Where population embraces a number of distinct categories,the frame can be organized into separate "strata." Eachstratum is then sampled as an independent sub-population, outof which individual elements can be randomly selected.
Every unit in a stratum has same chance of being selected.
Using same sampling fraction for all strata ensuresproportionate representation in the sample.
Adequate representation of minority subgroups of interest canbe ensured by stratification & varying sampling fractionbetween strata as required.
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Basic Workshop on Research Methodology 6
Finally, since each stratum is treated as an independentpopulation, different sampling approaches can be applied todifferent strata.
Drawbacks to using stratified sampling.
First, sampling frame of entire population has to be preparedseparately for each stratum
Second, when examining multiple criteria, stratifying variablesmay be related to some, but not to others, further complicating thedesign, and potentially reducing the utility of the strata.
Finally, in some cases (such as designs with a large number ofstrata, or those with a specified minimum sample size per group),stratified sampling can potentially require a larger sample thanwould other methods.
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Draw a sample from each stratum
Mridula Solanki: Sampling Methods
Cluster sampling is an example of 'two-stage sampling' .
First stage a sample of areas is chosen;
Second stage a sample of respondents within thoseareas is selected.
Population divided into clusters of homogeneous units,usually based on geographical contiguity.
Sampling units are groups rather than individuals.
A sample of such clusters is then selected.
All units from the selected clusters are studied.
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Advantages :Cuts down on the cost of preparing a sampling frame.
This can reduce travel and other administrative costs.
Disadvantages : Sampling error is higher.
Often used in epidemiologic research for eg to evaluate vaccination coverage in EPI, studies on
HRGs etc..
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Two types of cluster sampling methods.
One-stage sampling. All of the elements within
selected clusters are included in the sample.
Two-stage sampling. A subset of elements within
selected clusters are randomly selected for
inclusion in the sample.
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• Identification of clusters– List all cities, towns, villages & wards of cities with their
population falling in target area under study.
– Calculate cumulative population & divide by 30, this gives
sampling interval.
– Select a random no. less than or equal to sampling interval
having same no. of digits. This forms 1st cluster.
– Random no.+ sampling interval = population of 2nd cluster.
– Second cluster + sampling interval = 3th cluster.
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• Freq c f cluster• I 2000 2000 1• II 3000 5000 2• III 1500 6500• IV 4000 10500 3• V 5000 15500 4, 5• VI 2500 18000 6• VII 2000 20000 7• VIII 3000 23000 8• IX 3500 26500 9• X 4500 31000 10• XI 4000 35000 11, 12• XII 4000 39000 13• XIII 3500 44000 14,15• XIV 2000 46000• XV 3000 49000 16
• XVI 3500 52500 17• XVII 4000 56500 18,19• XVIII 4500 61000 20• XIX 4000 65000 21,22• XX 4000 69000 23• XXI 2000 71000 24• XXII 2000 73000• XXIII 3000 76000 25• XXIV 3000 79000 26• XXV 5000 84000 27,28• XXVI 2000 86000 29• XXVII 1000 87000• XXVIII 1000 88000• XXIX 1000 89000 30• XXX 1000 90000• 90000/30 = 3000 sampling interval
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Although strata and clusters are both non-overlapping subsets ofthe population, they differ in several ways.
All strata are represented in the sample; but only a subset ofclusters are in the sample.
With stratified sampling, the best survey results occur whenelements within strata are internally homogeneous. However,with cluster sampling, the best results occur when elementswithin clusters are internally heterogeneous.
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Complex form of cluster sampling in which two or more
levels of units are embedded one in the other.
First stage, random number of districts chosen in all states.
Followed by random number of talukas, villages.
Then third stage units will be houses.
All ultimate units (houses, for instance) selected at last
step are surveyed.
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This technique, is essentially the process of taking random samples of
preceding random samples.
Not as effective as true random sampling, but probably solves more of
the problems inherent to random sampling.
An effective strategy because it banks on multiple randomizations. As
such, extremely useful.
Multistage sampling used frequently when a complete list of all
members of the population does not exist and is inappropriate.
Moreover, by avoiding the use of all sample units in all selected
clusters, multistage sampling avoids the large, and perhaps
unnecessary costs associated with traditional cluster sampling.
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Part of the information collected from whole sample & part from
subsample.
In Tb survey MT in all cases – Phase I
X –Ray chest in MT +ve cases – Phase II
Sputum examination in X – Ray +ve cases - Phase III
Survey by such procedure is less costly, less laborious & more
purposeful
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A method of assigning participants to groups in which pairs of participantsare first matched on some characteristic and then individually assignedrandomly to groups.
The Procedure for Matched random sampling can be briefed with thefollowing contexts,
Two samples in which the members are clearly paired, or are matchedexplicitly by the researcher. For example, IQ measurements or pairs ofidentical twins.
Those samples in which the same attribute, or variable, is measured twiceon each subject, under different circumstances. Commonly called repeatedmeasures.
Examples include the times of a group of athletes for 1500m before andafter a week of special training; the milk yields of cows before and afterbeing fed a particular diet.
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Basic Workshop on Research Methodology 8
The population is first segmented into mutually exclusive sub-groups, justas in stratified sampling.
Then judgment used to select subjects or units from each segment basedon a specified proportion.
For example, an interviewer may be told to sample 200 females and 300males between the age of 45 and 60.
It is this second step which makes the technique one of non-probabilitysampling.
In quota sampling the selection of the sample is non-random.
For example interviewers might be tempted to interview those who lookmost helpful. The problem is that these samples may be biased becausenot everyone gets a chance of selection. This random element is itsgreatest weakness and quota versus probability has been a matter ofcontroversy for many years
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Conveniencee SSampling• This involves selecting the nearest
and most convenient people toparticipate in the research.
• This method of selection is nnotrepresentative and is considered avery unsatisfactory way to conductresearch.
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Sometimes known as grab or opportunity sampling or accidental orhaphazard sampling.A type of non probability sampling which involves the sample being drawn fromthat part of the population which is close to hand. That is, readily available andconvenient.
The researcher using such a sample cannot scientifically make generalizationsabout the total population from this sample because it would not be representativeenough.
For example, if the interviewer was to conduct a survey at a shopping centerearly in the morning on a given day, the people that he/she could interview wouldbe limited to those given there at that given time, which would not represent theviews of other members of society in such an area, if the survey was to beconducted at different times of day and several times per week.
This type of sampling is however most useful for pilot testing.
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◦ Use results that are easy to get
Mridula Solanki: Sampling Methods
Snowball Sampling• This type of sampling is used when the research is focused
on participants with very specific characteristics such asbeing members of a gang.
• Having identified and contacted one gang member theresearcher asks to be put in touch with any friends orassociates who are also gang members.
• This type of sampling is not representative however isuseful, especially where the groups in the research are notsocially organised i.e. they do not have clubs ormembership lists.
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The researcher chooses the sample based on
who they think would be appropriate for the study.
This is used primarily when there is a limited
number of people that have expertise in the area
being researched
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Method of first selecting a group of participants through a random samplingmethod and then asking that group for the same information again several timesover a period of time.
Therefore, each participant is given same survey or interview at two or more timepoints; each period of data collection called a "wave".
This sampling methodology often chosen for large scale or nation-wide studiesin order to gauge changes in the population with regard to any number ofvariables from chronic illness to job stress to weekly food expenditures.
Panel sampling can also be used to inform researchers about within-personhealth changes due to age or help explain changes in continuous dependentvariables such as spousal interaction.
There have been several proposed methods of analyzing panel sample data,including growth curves.
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THANK YOU
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1
Literature search
Dr. Anant PatilMD Pharmacology
Department of PharmacologyDr DY Patil Medical College, Navi Mumbai
Content
• Why (& when), where and how of literature search
• Effective literature search
• Examples
Content
• Why, where and how of literature search
• Effective literature search
• Examples
“A researcher cannot perform significant research without first understanding the
literature in the field”
Boote and Beile, 2005: 3
Why?
• F• I• N• E• R
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“If you have no destination, you’ll never get there”
Harvey Mackay
Other reasons
• Writing introduction, review of literature and discussion sections in thesis
• Manuscript writing
• Writing systematic reviews and meta-analysis
Content
• Why, where and how of literature search
• Effective literature search
• Examples
Literature search is not just Googling
Sources of literature source
• Textbooks
• Journals (open access, subscription)
• Websites
Databases• PubMed• IndMed• MedInd• Scopus• Index Copernicus• EMBASE• Google Scholar• Cochrane database• Science direct• Springer link• Informa world• IngentaConnect
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• It is free search engine
• MELINE + PubMed Central
• Available since 1996
• United States National Library of Medicine (NLM)
• Has more than 28 million references
• Articles published in >5000 journals
• https://www.ncbi.nlm.nih.gov/pubmed/
PubMed
• Database of articles from journals related to medicine, nursing, pharmacy, dentistry, veterinary medicine and healthcare
• Over 26 million records
• Temporal coverage: since 1946
MEDLINE
• Selected peer reviewed medical journals published from India
• About 100 journals indexed from 1985 onwards
• MedIND: Full text articles of selected Indian medical journals indexed in IndMED or PubMed
• http://indmed.nic.in/
IndMED and MedIND Embase
• 1947 onwards
• Over 32 million records, including MEDLINE articles
• Over 8,500 journals
• https://www.elsevier.com/en-in/solutions/embase-biomedical-research
• Elsevier’s database
• Available since 2004
• About 69 million articles
• About 36,377 titles
• https://www.scopus.com/
Scopus
• International indexation database of scientific journals
• Registered scientific journals: 44,929
• http://en.indexcopernicus.com/
Index Copernicus
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Content
• Why, where and how of literature search
• Effective literature search
• Examples
Principles for effective search
• Planning: Understanding the research framework/paradigm
• Identify key search terms
• Preliminary research followed by focused research
Steps
• Research problem
• Resources
• Principles for effective literature search
How do we approach?
• Basic information
• Research related information
• Meta-analysis/guidelines
How do we approach?
• Basic information: Textbook, handbook, manuals
• Research related information: Journals, clinical trial registries
• Meta-analysis/guidelines: Cochrane database, association’s websites, journals
http://library.downstate.edu/EBM2/2100.htm
In vitro researchAnimal research
Ideas, Editorial, Opinion
Case reportsCase series
Case control study
Cohort study
RCT
Meta-analysis
Evidence pyramid
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Which is the most commonly searched database for scientific/medical
literature?
PubMed gives different types of articles
Content
• Why, where and how of literature search
• Effective literature search
• Examples
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How to get best results with minimum efforts?
Search/key word
1
Tagging
2
Methods of PubMed search
PubMed search by words
1. Your choice of word
2. MeSH
3. Specific word search in the article
4. Combination of words
PubMed search by words
1. Your choice of word (e.g. diabetes)
2. MeSH (diabetes mellitus)
3. Specific word search in the article (title, abstract, journal name, author name etc)
4. Combination of words (e.g. Diabetes AND India)
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1. MeSH terms
2. Synonyms
3. Filters
4. Boolean operators
Content
• Why, where and how of literature search
• Effective literature search
• Examples
Type 2 diabetes in elderly patients Type 2 diabetes in elderly patients
Who tags what?
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Short forms for search words in…
Area of search
[Ti] Title
[tiab] Title plus abstract
[Jour] Journal name
[Au] Author
[MeSH] Mesh terms
[page] Page number
[pdat] [dp] Year
Title
Author Journal
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Combining terms
• Renal disease in diabetes
Combining terms
Do not use words like “of”, “in”, “with” etc.
• Prevalence of renal disease in diabetes
• Renal disease in patients with diabetes
Use “Boolean” terms
• Boolean logic
• George Boole (British-born Irish mathematician)
• Relationships between search terms
“Boolean” terms
Command Purpose
AND
OR
NOT
Boolean operators
Command Purpose
AND Articles that include all search terms/keywords
OR Articles that include any of the search terms
NOT Excludes articles that include specific keyword
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What does it mean?
Boolean operator Searchresult
Why?
1 Diabetes X2 Diabetes AND hypertension3 Diabetes OR hypertension4 Diabetes NOT hypertension
What does it mean?
Boolean operator Searchresult
Why?
1 Diabetes X2 Diabetes AND hypertension < X Both terms3 Diabetes OR hypertension4 Diabetes NOT hypertension
What does it mean?
Boolean operator Searchresult
Why?
1 Diabetes X2 Diabetes AND hypertension < X Both terms3 Diabetes OR hypertension > X At least one term4 Diabetes NOT hypertension
What does it mean?
Boolean operator Searchresult
Why?
1 Diabetes X2 Diabetes AND hypertension < X Both terms3 Diabetes OR hypertension > X At least one term4 Diabetes NOT hypertension < X Diabetes but not
hypertension
What does it mean?Boolean operator Search
resultWhy?
1 Diabetes X2 Diabetes AND hypertension < X Both terms3 Diabetes OR hypertension > X At least one term4 Diabetes NOT hypertension < X Diabetes but not
hypertension
DM HTBoth
Specific search
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Articles published by Anant Patil in“Perspectives in Clinical Research”
Which search words will I put in PubMed?
Patil[Au] AND Perspect Clin Res[jour]
How would the result look like?
Enalapril in diabetes as well as hypertension
Search words
• Diabetes OR hypertension AND enalapril
Diabetes OR hypertension AND enalapril…anywhere in the article
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Diabetes OR hypertension AND enalapril
Diabetes OR hypertension AND enalapril…in the title or abstract
Diabetes[tiab] OR hypertension[tiab] AND enalapril[tiab]
Diabetes OR hypertension AND enalapril…only in the title
Diabetes[ti] OR hypertension[ti] AND enalapril[ti]
MeSH
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MeSH
• Medical Subject Headings
• Standard terms to describe the article
Where do we get the MeSH term?
Articles on diabetes published in 2017
Boolean search
Diabetes[MeSH] AND 2017[dp]Diabetes[MeSH] AND 2017[pdat]
Diabetic nephropathy
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Diabetic nephropathy
Diabetic nephropathy
Treatment of gastroesophageal reflux disease in children
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Finding incomplete reference
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Patil Indian J Endocrinol Metab2014
Patil Indian J Endocrinol Metab2014
Advanced search
Diabetic retinopathy
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More customization for search
Customize your search
Getting correct reference style
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We are done with…
• Why, where and how of literature search
• Effective literature search
• Examples
Summary
• Research problem
• Resources
• Principles for effective literature search
• Use correct Boolean terms
• Advanced search helps to get you specific articles
Thank you
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Group ActivityLiterature search
Dr. Anant PatilMD Pharmacology
Department of PharmacologyDr DY Patil Medical College, Navi Mumbai
Exercise 1You attended a lecture in a conference on the topic
“Heart failure in pre-diabetes” and one of the slides of the speaker had following reference
“Nielsen R, et al 2018”
Search the article in PubMed
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2
Exercise 1
J Nucl Cardiol. 2018 Feb;25(1):169-176. doi: 10.1007/s12350-016-0622-0. Epub 2016 Jul 29.Heart failure patients with prediabetes and newly diagnosed diabetes display abnormalities in myocardial metabolism.
Nielsen R1, Jorsal A2,3, Iversen P4, Tolbod L4, Bouchelouche K4, Sørensen J4, Harms HJ4, Flyvbjerg A3, Bøtker HE2,3, Wiggers H2.Author information
Abstract
You attended a lecture in a conference on the topic “Heart failure in pre-diabetes” and one of the slides
of the speaker had following reference
“Nielsen R, et al 2018”
Search the article in PubMed
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Exercise 2
• Search articles related to diabetes authored by Dr. Mohan which are published in 2017 and 2018
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Exercise 3
• Search clinical trials related to gastroesophageal reflux disease published in 2017 and 2018
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Exercise 4
• Search clinical trials related to zinc in pediatric diarrhea published between 2016 to 2018
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Thank you
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24-07-2019
1
Pratap L JadhavAssistant Professor Statistics & Demography
Department of Community MedicineSeth G.S. Medical College & K.E.M. Hospital
Data Primary DataSecondary Data
Data Qualitative DataQuantitative Data
Data Discrete dataContinuous Data
STATISTICAL DATA
DATA
QUANTITATIVE
CONTINUOUS DISCRETE
QUALITATIVE
DISCRETE
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Measurement Scales for Statistical Data
Measurement scales
Nominal
Ordinal
Interval
Ratio
Sr no Name of variable Type of data Measurement scale
1 Diagnosis of patients admitting in psychiatry ward
2 Range of motion of elbow joint
3 APGAR score
4 Temperature
5 Religion
6 Haemoglobin level of IV year medical students
7 Pain measured on Vas
8 Grades of anaemia
9 IQ score
10 Birth weight
Data Representation
Contingency table
Frequency distribution Table
Graphical presentation
Contingency TableA group of 3579 person was protected against post-traumatic tetanus. Of the 1546 who were given Benzathine penicillin intramuscularly, 578 had punctured wounds, 271 had lacerated or contused wounds and 306 had incised wounds. Of the 962 with other type of injuries, 561 received A.T.S. which was administered to 767 with punctured wounds and 381 with incised wounds. Present the information in tabular form.
Contingency table
Type of wound
Treatment mode
Total
Benzathinepenicillin
ATS
Punctured wounds 578 767 1345
Lacerated wounds 271 314 585
Incised wounds 306 381 687
Other type of injuries
391 571 962
Total 1546 2033 3519
578
271
306
391
0 100 200 300 400 500 600 700
Punctured wounds
Lacerated wounds
Incised wounds
Other type of injuries
Punctured wounds Lacerated wounds Incised wounds Other type of injuriesBenzathine penicillin 578 271 306 391
Simple Bar diagram
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Frequency distribution Table Hemoglobin values in grams percentage of 100 first MBBBS first term Medical students are given below.
11.4 12.4 12.8 13.0 12.0 11.0 12.9 12.4 11.5 11.2
11.3 10.8 12.4 12.7 11.5 13.0 12.8 11.0 10.5 12.4
13.2 11.9 11.4 12.7 12.8 12.5 12.1 13.0 11.8 12.3
11.8 12.2 12.3 12.4 12.1 12.4 12.9 13.0 11.0 11.5
12.9 13.2 13.1 12.0 12.5 12.8 13.4 12.5 12.2 10.9
11.3 11.5 12.1 10.8 13.9 13.5 13.2 11.8 12.8 12.5
12.0 11.5 11.9 11.8 11.7 11.6 12.2 11.9 11.3 10.6
10.5 12.0 13.1 10.9 13.8 13.6 11.5 11.9 10.8 10.1
12.3 12.6 13.9 10.1 10.9 11.1 10.9 11.8 12.5 12.7
11.8 11.9 11.4 11.9 12.0 13.4 12.2 13.6 12.3 13.4
Frequency distribution tableClass interval Frequency Relative
frequency
< Cumulative frequency
> Cumulative frequency
10.0 – 10.5 2 0.02 2 100
10.5 - 11.0 10 0.10 12 98
11.0 – 11.5 11 0.11 23 88
11.5 – 12.0 20 0.20 43 77
12.0 – 12.5 22 0.22 65 57
12.5 – 13.0 17 0.17 82 35
13.0 – 13.5 12 0.12 94 18
13.5 – 14.0 6 0.06 100 06
Graphical presentation for Quantitative data
HistogramFrequency polygon Line diagramOgive curveScatter diagram Box plot
Graphical presentation for Qualitative data
Bar diagram a) Simple bar diagramb) Multiple bar Diagramc) Subdivided bar diagram
Pie diagram
578
271
306
391
0 100 200 300 400 500 600 700
Punctured wounds
Lacerated wounds
Incised wounds
Other type of injuries
Punctured wounds Lacerated wounds Incised wounds Other type of injuriesBenzathine penicillin 578 271 306 391
Simple Bar diagram
0
100
200
300
400
500
600
700
800
Benzathine penicillin ATS
578
767
271
314306
381391
571
freq
uenc
y
Axis Title
Multiple Bar Diagram
Punctured wounds Lacerated wounds Incised wounds Other type of injuries
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Subdivided Bar diagram
0
500
1000
1500
2000
2500
Benzathine penicillin ATS
578767
271
314306
381391
571
freq
uenc
y
Mode of treatment
Other type of injuries
Incised wounds
Lacerated wounds
Punctured wounds
57837%
27118%
30620%
39125%
Pie Diagram showing Frequency Distribution for type of Wounds
Punctured wounds Lacerated wounds
Incised wounds Other type of injuries
0
5
10
15
20
25
10 10.5 11 11.5 12 12.5 13 13.5
2
1011
20
22
17
12
6
freq
uenc
y
Hemoglobin Level
Histogram showing frequency Distribution for hemoglobin levels
02
12
23
43
65
82
94
100
0
20
40
60
80
100
120
10 10.5 11 11.5 12 12.5 13 13.5 14
cum
ulat
ive
freq
uen
cyOgive Curve or cumulative frequency curve
0
2
1011
20
22
17
12
6
00
5
10
15
20
25
10 10.5 11 11.5 12 12.5 13 13.5 14 14.5
freq
uenc
y
FREQUENCY POLYGON
y = 0.6286x + 21.124R² = 0.9429
81.5
82
82.5
83
83.5
84
84.5
85
85.5
96 97 98 99 100 101 102 103
Pul
se ra
te
Temperature 0 F
Scatter diagram
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Research Methodology 23 July 2019
D Y Patil University School of Medicine 1
Inferential Statistics
PRATAP L . JADHAVAssistant Professor Statistics & DemographySeth G.S. Medical College & K.E.M. Hospital
STATISTICAL DATA
DATA
QUANTITATIVE
CONTINUOUS DISCRETE
QUALITATIVE
DISCRETE
Measurement Scales for Statistical Data
Measurement scales
Nominal
Ordinal
Interval
Ratio
Summary values
Summary value Population Sample
Mean μStandard Deviation σ S
Variance
Proportion P p Complementary proportion Q q
Standard Error P = {x1, x2, x3,……….xn} = μ σ РS1= {x1, x2, x3, …….,x50} = p1S2= {x1, x2, x3, …….,x100} = p2S3= {x1, x2, x3, …….,x60} = p3...Sn= {x1, x2, x3, …….,x40} = pn
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Inferential StatisticsInferential statistics provides the procedure to draw inference about the conditions which exist in a large population. For e.g.- to test the efficacy of a new hypertensive drug in which the physician will have only a limited number of hypertensive patients with whom to work.The methods of inferential statistics are those of making inference from a sample about a large population, from which the sample is drawn.
Inferential statisticsInferential statistics has two aspects
Estimation of population valueTesting of hypothesis
Purpose of Estimation To provide an estimate of a population parameter.In theory, the parameter value could be computed if a measurement could be obtained from every subject in the population. In practice, that is too expensive, and sometimes operationally impossible
To give an idea of the precision of the estimate and reliability of the estimation procedure
This is possible only if the estimate is obtained from a “probabilistic sample”. In probabilistic sampling every subject in the population has a known probability of being selected .
The sample mean is the natural estimator of the population mean. We will use the mean of a sample (statistic) as an estimate of the mean of the population (parameter).
The difference between the sample mean and the population mean is called “sampling error” of the estimation.
Estimation SEM SEPSEDMSEDP
Estimating with Confidence
That chance (95%) is what gives the researcher “confidence” in the method. He will present his sample mean as an estimate of the population mean in the form
Sample mean ± 1 SEM Covers 68.27 % Samples Sample mean ± 2 SEM Covers 95.45 % Samples Sample mean ± 3 SEM Covers 99.73 % Samples
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Confidence interval (CI)
Indicates the ammount of random error in the estimateCan be calculated for any ‚ “test statistic e.g.: means, proportions,
ORs, RRs "
e.g. CI for means95% CI = x – 1.96 SE up to x + 1.96 SE
1 - αα/2 α/2
Lower limit upper limitof 95% CI of 95% CI
= 5%
s
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Intervals for large samples with different confidence level
Important Note
This procedure is valid when the sample is large (n≥ 30) and it is small with respect to the population (no more than 5% of it)
Confidence interval for a Population MeanSuppose a researchers wish to estimate the mean of some normally distributed population.They draw a sample of size n from the population and compute sample mean ( )which they use point estimate of μAlthough this estimator of μ possesses all qualities of good estimator, we know that random sampling inherently involves chance, sample mean can not be expected to be equal to μIt would be much more meaningful, therefore, to estimate μby interval that somehow communicates information regarding to the probable magnitude of population mean μ
Confidence interval for a Population mean
In particular, when sampling is from normal distribution with known variance, an interval estimate of population mean μ may be expressed as
Population estimate range =
At different level of significance we can estimate interval for μ using following properties
Sample mean ± 1 SEM Covers 68.26 % Samples meansSample mean ± 2 SEM Covers 95.45 % Samples meansSample mean ± 3 SEM Covers 99.73 % Samples meansSample mean ± 1.96 SEM Covers 95 % Samples meansSample mean ± 2.58 SEM Covers 99 % Samples means
Confidence interval for a Population meanIn a situation such as, that the population variance as well as population mean is unknown then confidence interval for population mean is given by statistics
Range =
When we construct a confidence interval for a population mean, we must decide whether to use value of Z or value of t as the reliability factor To make an appropriate choice we must consider sample size, whether the sampled population is normally distributed, and whether the population variance is known.
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Confidence interval for the difference between Two Population Means
Sometimes there arise a case in which we are interested in estimating the difference between two population mean The confidence interval for difference between two population mean If the population variances are known the CI of difference given by
Confidence interval for the difference between Two Population Means
From examination of confidence interval for the difference between Population means provides information that is helpful in deciding whether or not it is likely that the two population means are equal.When constructed interval does not include zero (0) we say that interval provides evidence that the two population means are not equal.When interval includes zero, we say that the population means may be equal.
Confidence interval for the difference between Two Population Means
A research team is interested in the difference between serum uric acid levels in patients with and without Down’s syndrome. In a large hospital for a treatment of mentally retarded, a sample of 12 individual with Down’s syndrome yielded a mean of 4.5 mg / 100 ml. In a general hospital a sample of 15 normal individual of the same age and sex were found to have a mean value of 3.4 mg/100 ml. If it is reasonable to assume, that the two populations of values are normally distributed with variance equal to 1 & 1.5. Find the 95 % CI for difference between two population mean
Confidence interval for the difference between Two Population Means
For a point estimate of we use= (4.5 – 3.4 )= 1.1 reliability coefficient is
corresponding to .95 is 1.96 so the value of
SEDM= .4282 so 95 % CI is given by= 1.1 ± 1.96 ( 0.4282)= 1.1 ± 0.84 = ( 0.26 , 1.94)Since the interval does not include zero, we conclude that the two population means are not equal
Confidence interval for the difference between Two Population Means
When population variances are unknown and we wish to estimate the difference between two population mean with a confidence interval, we can use a t distribution as a source of reliability factorAssuming that the two sampled populations are normally distributed.With regard to the population variance we distinguish between two conditions a) Population variances are equalb) Population variances are not equal
Confidence interval for the difference between Two Population Means
The confidence interval is given by
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Confidence interval for a Population ProportionMany questions of interest to the health worker relate to population proportionsWhat proportion of patients who received a particular type of treatment?What proportion of some population has certain disease?What proportion of the population are immune to certain disease?To estimate population proportion we proceed in the same manner as when estimating a population mean
Confidence interval for a Population proportionCI for population proportion is given by
Where p = probability of occurrence and q = (1- p )
n= no of observation in a given sample
Confidence interval for the difference between two population proportion
The magnitude of the difference between two population proportion is often of interest We may want to compare two age groups, or two diagnostic groups with respect to the proportion possessing some characteristic of interestCI for (p1-p2) is given by
Confidence interval for the difference between two population proportion
Testing of Hypotheses.Hypothesis is usually considered as the principal instrument in research.In fact many experiments are carried out with the deliberate object of testing of hypotheses.Decision makers often face situations wherein they are interested in testing hypotheses on the basis of available information and then take decisions on the basis of such testing.
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Testing of Hypotheses.In social since, where direct knowledge of population parameter(s) is rare, hypothesis testing is often used strategy for deciding whether a sample data offer such support for a hypothesis that generalization can be madeThus hypothesis testing enables us to make the probability statement about population parameter.The hypothesis may not be prove absolutely, but it is accepted if it is withstood a critical testing.
What is a Hypothesis?Hypothesis is a formal question that researcher tend to resolve.Hypothesis may be defined as proposition or a set of proposition set forth as an explanation for the occurrence of some specified group of phenomena.E.g.:- students who receive counseling will show greater in creativity than students not receiving A hypothesis states what we are looking for and it is a proposition which can be put to a test to determine its validity.
Characteristics of good HypothesisHypothesis should be clear and precise.Hypothesis should be capable of being tested.Hypothesis should state relationship between variablesHypothesis should be limited in scope and must be specific.Hypothesis should be consistent with most known facts.Hypothesis should be amenable to testing within reasonable time.
Basic concepts concerning testing of HypothesesNull hypothesis and Alternative hypothesis :-
Null hypothesis (H0)- If we have to compare method A with method B about it superiority and if we proceed on the assumption that methods are equally good then this assumption is termed as Null Hypothesis.As against this, we may think that the method A is superior or method B is inferior, we are then stating what is termed as Alternative Hypothesis (H1).
Basic concepts concerning testing of Hypotheses
In simple word Null hypothesis is simple statement of no difference stating no difference in population parameter and sample statistics.Alternative hypothesis is usually the one which one wishes to prove and the null hypothesis is one wishes to disprove.Thus null hypothesis represents the hypothesis we are trying to reject and alternative hypothesis presents all other possibilities.
Basic concepts concerning testing of Hypotheses
Level of significance:- it is always some percentage (usually 5 % ) which should be chosen with great care, thought and reason.In case we take LS 5 % implies that H0 will be rejected when the sampling result has less than 0.05 probability of occurrence if H0 is true Level of significance is the maximum probability of rejecting null hypothesis when it is true.Level of significance determined in advance before testing of hypothesis.
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Basic concepts concerning testing of HypothesesDecision rule or test of hypothesis:-Given a hypothesis H0 and H1, we make a rule which is known as Decision rule according to which we accept or reject Ho. E.g.:- if Ho- is that a certain lot is good (there are very few defective items in it ) against H1- that the lot is not good ( there are too many defective items in it )then we must decide the number of items to be tested and the criterion for accepting or rejecting the hypothesis.
Basic concepts concerning testing of Hypotheses
Type-I and Type-II error:-There are basically two types of errors we can make.We may reject H0 when it is true is called as type-I error. Type one error means rejection of hypothesis which should have been accepted. Type –I error can also be called α (alpha) error or level of significance of test.If we accept H0 when it is false is called Type-II error. it means accepting the hypothesis which should have been rejected and also called β (beta) error.
Errors in testing of Hypothesis
Your Statistical Decision
True state of null hypothesis
H0 True(example: the drug doesn’t
work)
H0 False(example: the drug works)
Reject H0(ex: you conclude that the drug works) Type I error (α) Correct
Do not reject H0(ex: you conclude that there is insufficient evidence that the drug works)
Correct Type II Error (β)
Steps involve in testing of hypothesesMaking formal statement i.e. Null Hypothesis and Alternative HypothesisSelection of level of significanceDeciding distribution to be used Calculation of critical ratioInference on the critical ratio.Final Conclusion
Testing of hypothesis or tests of significanceThere are different types of problems for which tests of significance are use to drawing results.Different types of problem needs different tests but basis of all the tests and steps involve in procedures are the same. The common types of problems are:
Compare sample mean with population meanCompare two sample meansCompare sample proportion with population proportion Compare two sample proportions
Parametric test of significance The statistical methods of inference which make certain assumption about the population from which the samples are drawn.e.g.: assumption may be that populations are normally distributed, have the same variance etc. The statistical techniques which make assumption about the parameter are called parametric techniques.
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Non-parametric or Distribution free test of significance
More recently large no of techniques of inference have been develop which do not make any assumption about population parameter or their distribution
Parametric Vs Nonparametric BASIS FOR
COMPARISON PARAMETRIC TEST NONPARAMETRIC TEST
Meaning A statistical test, in which specific assumptions are made about the population parameter is known as parametric test.
A statistical test used in the case of non-metric independent variables, is called non-parametric test.
Basis of test statistic
Distribution Arbitrary
Measurement level Interval or ratio Nominal or ordinal
Measure of central tendency
Mean Median
Information about population
Completely known Unavailable
Applicability Variables Variables and Attributes
Correlation test Pearson Spearman
Parametric tests of significance
The most commonly used test of significance areZ- Testt-test F test One way ANOVA & Two way ANOVARepeated measure ANOVA
Non-parametric or Distribution freetest of significance
Chi-square testWilcoxon’s Signed rank testMann Whitney U- TestKruskal -wallis testMedian test Freidman ANOVA testFisher exact testMc Nemar testSpearman rank correlation
Correlation & Regression
Types of correlation Correlation coefficient (r )Regression Types of regression
simple Multiple Logistic
Which test should I use?
Outcome Variable
Are the observations independent or correlated?
Assumptionsindependent correlated
Continuous(e.g. pain scale, cognitive function)
TtestANOVALinear correlationLinear regression
Paired t testRepeated-measures ANOVAMixed models/GEE modeling
Outcome is normally distributed (important for small samples).Outcome and predictor have a linear relationship.
Binary or categorical(e.g. fracture yes/no)
Relative risksChi-square test Logistic regression
McNemar’s testConditional logistic regression
Sufficient numbers in each cell (>=5)
Time-to-event(e.g. time to fracture)
Kaplan-Meier statisticsCox regression
n/a Cox regression assumes proportional hazards between groups
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Continuous outcome (means)
Outcome Variable
Are the observations independent or correlated?
Alternatives if the normality assumption is violated (and small sample size):independent correlated
Continuous(e.g. height ,weight
Ttest: compares means between two independent groups
ANOVA: compares means between more than two independent groups
Pearson’s correlation coefficient (linear correlation): shows linear correlation between two continuous variables
Linear regression: multivariate regression technique used when the outcome is continuous; gives slopes
Paired t-test: compares means between two related groups (e.g., the same subjects before and after)
Repeated-measures ANOVA: compares changes over time in the means of two or more groups (repeated measurements)
Mixed models/GEE* modeling: multivariate regression techniques to compare changes over time between two or more groups; gives rate of change over time
*Generalized estimating equations
Non-parametric statistics
Wilcoxon sign-rank test: non-parametric alternative to the paired ttest
Wilcoxon sum-rank test (=Mann-Whitney U test): non-parametric alternative to the ttest
Kruskal-Wallis test: non-parametric alternative to ANOVA
Spearman rank correlation coefficient: non-parametric alternative to Pearson’s correlation coefficient
Binary or categorical outcomes
Outcome Variable
Are the observations correlated? Alternative to the chi-square test if sparse cells:independent correlated
Binary or categorical(e.g. fracture, yes/no)
Chi-square test: compares proportions between more than two groups
Relative risks: odds ratios or risk ratios
Logistic regression: multivariate techniqueused when outcome is binary; gives multivariate-adjusted odds ratios
McNemar’s chi-square test: compares binary outcome between correlated groups (e.g., before and after)
Conditional logistic regression: multivariate regression technique for a binary outcome when groups are correlated (e.g., matched data)
GEE* modeling: multivariate regression technique for a binary outcome when groups are correlated (e.g., repeated measures)*Generalized estimating equations
Fisher’s exact test: compares proportions between independent groups when there are sparse data (some cells <5).
McNemar’s exact test: compares proportions between correlated groups when there are sparse data (some cells <5).
Time-to-event outcome (survival data)
Outcome Variable
Are the observation groups independent or correlated? Modifications to Cox regression if proportional-hazards is violated:independent correlated
Time-to-event (e.g., time to fracture)
Kaplan-Meier statistics: estimates survival functions for each group (usually displayed graphically); compares survival functions with log-rank test
Cox regression: Multivariate technique for time-to-event data; gives multivariate-adjusted hazard ratios
n/a (already over time)
Time-dependent predictors or time-dependent hazard ratios (tricky!)
P- VALUE VS CI Which approach should be used?
Researchers have become polarized on this issue. Some statistician favor only hypothesis testing approach and some epidemiologist favors only confidence interval approach.CI are always based on the observed or estimated effect and convey useful information regarding the direction of effect and precision of the estimate .Hence more descriptive and useful than p- values, especially while interpreting and reporting of Negative studies.
P- VALUE VS CI Which approach should be used?P-values tell precisely how significant the results are.However, Statistically significant results need not always be clinically important.Further the non significant results (p < 0.05) does not necessarily imply that there is no effect in the population It means that the effect observed in the sample is small compared with what could have occurred by chance alone Both P- values and CIs provides complementary information and both should be reported, where possible
THANK YOU !THANK YOU !
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For the following examples identify the appropriate test of significance (Parametric or Nonparametric) and prepare Null and Alternative Hypothesis.
Lebranchu et al. conducted a study in which the subjects were 9 patients with common variable immunodeficiency (CVI) and 12 normal controls among the data collected were the following on CD4+ T cell per cubic mm of peripheral blood. May we conclude, on the basis of this data the CVI patients have a reduced level of CD4 + cells?
CVI Patients
623 437 370 300 330 527 290 730 1000
controls 710 1260 717 590 930 995 630 977 530 710 1275 825
The following table shows the duration of endurance of pain by eleven mice before and after administration of drug (adrenaline 0.04 mg/20 gm body-weight). Is there sufficient evidence in the data to say that the drug increases the duration of endurance of pain?
Before drug 15 12 14 16 20 22 20 18 17 17 19 After drug 21 20 17 22 20 20 20 19 18 24 19
In a study of cerebrovascular disease the patient from three socioeconomic back-ground were thoroughly investigated. One characteristics measured was diastolic blood pressure in mm/Hg. Is there is any reason to believe that three groups differ with respect to this characteristic? Sr. no
Group-A
Group-B Group-C
1 100 92 81 2 103 97 102 3 89 88 86 4 78 84 83 5 105 90 99 6 --- 95 --- Total obs.
05 06 05
In a survey on hearing level of school children with normal hearing it was found that in the frequency 500 cycle/ second , 62 children tested in the soundproof room had a mean hearing threshold of 15.5 decibels with SD of 6.5. In a sample of 76 comparable children who were tested in the fields had a mean threshold of 20 decibels with SD of 7.1. Test, if there is any difference between the hearing levels recorded in sound-proof room and in the field.
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Thirty percent of children enrolled in particular school are known to have been fully immunised. In a class 7th c of this school, there are 56 pupils. At-least how many of these would be fully immunised at 95% confidence interval.
An experiment was conducted to test the efficacy of chloromycetin in checking typhoid. In the certain hospital chloromycetin was given to 285 out of 392 patients suffering from typhoid. The numbers of typhoid cases were as follows: test the effectiveness of Chloromycetin in checking typhoid
Use of Drug Typhoid No Typhoid Total Chloromycetin 35 250 285 No Chloromycetin 50 57 107 Total 85 307 392
An IQ test was administrated to 5 persons before and after they were trained. Test whether there is any improvement in IQ after the training program.
Sr no 1 2 3 4 5 IQ before Training 110 120 123 132 125 IQ after Training 120 118 125 136 130
Systolic blood pressure (SBP) measured in mm of Hg and Pulse Rate/ min was measured
for 10 individuals as follows: Estimate pulse rate for SBP = 130
SBP 120 140 128 142 110 148 132 126 158 100 PR/MIN 70 78 72 74 66 76 80 68 84 60
A survey was carried out in a state amongst the doctors belonging to Rural Health service
cadre (500 Doctors) and among the medical education directorate cadre (300 teaching doctors). They were asked a question, “would it be acceptable to you, if the government proposes to hire all the doctors on a fixed period contractual basis?” The doctors were to answer either as ‘Acceptable’ or ‘Not Acceptable’. There was not third category ‘Undecided’. For the following data test an appropriate hypothesis.
Doctors Acceptable Not Acceptable Total Rural cadre 195 305 500 Teaching cadre 140 160 300 Total 335 465 800
Research Methodology 23 July 2019
21-07-2019 11:00 DR. DEEPAK LANGADE 1
Basic workshop onResearch Methodology, Biostatistics &
Principles of GCP
22 – 24 July 2019Pushpanjali, 1st floor Auditorium,
D Y Patil Hospital, Nerul
Jointly organized byDept. of Obs. & Gynaecology
Institutional Ethics Committee (IEC)
Determination of Sample Size
Dr. Deepak Langade
7/24/2019 5:25 PM Sample Size Estimation 2
Objectives
List the factors influencing the sample size
Appreciate importance of incorrect sample size in research
Calculate the sample size using appropriate formulae
7/24/2019 5:25 PM Sample Size Estimation 3
Factors affecting sample size
Size of populationResources – subjects, financial, manpowerStudy Design – Crossover / Parallel / Paired Method of Sampling – random, stratifiedDegree of difference ( ) to be detectedMargin of Error (ME)Variability (S.D.) – pilot study, historical
7/24/2019 5:25 PM Sample Size Estimation 4
Factors affecting sample size
Degree of Accuracy (or errors)- Type I error (alpha) p<0.05- Type II error (beta) less than 0.2 (20%)- Power of the test (1 – β): more than 0.8 (80%)Statistical FormulaeDropout rate, non-compliance to Rx
7/24/2019 5:25 PM Sample Size Estimation 5
Correct ( ) decisions and Types of Errors (X) in hypothesis testing
X
X
Difference exists (H1) No Difference (H0)
Difference exists (H1)
No Difference
Do not reject (H0)
TRUE Situation
CONCLUSION hypothesis test
(Power or 1-beta)
Type II error or
Beta error
Type I error or
Alpha error
7/24/2019 5:25 PM Sample Size Estimation 6
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Research Methodology 23 July 2019
Approach to sample sizeDetermine the expected difference
Find out the Standard deviations of both groups
Set alpha error to be tolerated viz. P = 0.05
Decide the power of the study desired viz. 80%, beta error 0.2
Select the appropriate formula
Calculate the sample size using the formula
Give allowance for drop-out rate
Give allowance for non-compliance of treatment if possible7/24/2019 5:25 PM Sample Size Estimation 7
Incorrect sample size
Wrong conclusions
Poor quality research (Errors) Type II error can be minimized by increasing the sample size
Waste of resources
Loss of money
Ethical problems
Delay in completion
7/24/2019 5:25 PM Sample Size Estimation 8
Formulae for Sample Size
7/24/2019 5:25 PM Sample Size Estimation 9
Comparison of means (two groups)
Alpha=0.05,
Beta=0.2, (power 80%)
Between group comparison (Unpaired)
n = 16 X (S.D./M1-M2)2
Within group comparison (Paired)n = 8 X (S.D. of differences/M1-M2)2
7/24/2019 5:25 PM Sample Size Estimation 10
2
2/2
2
difference)Z(2 Z
n
Formula for difference in means
Sample size in each group (assumes equal sized groups)
Represents the desired power (typically .84 for 80% power).
Represents the desired level of statistical significance (typically 1.96).
Standard deviation of the outcome variable Effect Size (the
difference in means)7/24/2019 5:25 PM Sample Size Estimation 11
Comparison of percentages (two groups)
Alpha=0.05,
Beta=0.2, (power 80%)
n = 8 X p1q1 + p2q2
---------------(p1-p2)2
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Research Methodology 23 July 2019
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2/2
)(p)Z)(1)((2
pZpp
n
Formula for difference in proportions
Sample size in each group (assumes equal sized groups)
Represents the desired power (typically .84 for 80% power).
Represents the desired level of statistical significance (typically 1.96).
A measure of variability (similar to standard deviation)
Effect Size (the difference in proportions)
7/24/2019 5:25 PM Sample Size Estimation 13
Comparison of one mean only
Alpha=0.05,
Beta=0.2, (power 80%)
n = 8 X (S.D./M1-M0)2
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Sample Size Example
Effect on sleep
7/24/2019 5:25 PM Sample Size Estimation 15
Sleep Aid Example : 1 Sample
Study the effect of new sleep aid1 sample testParameter – Sleep time after taking the medication for one weekTwo-sided test, α = 0.05, power = 90%Difference = 1 (4 hours of sleep to 5)Standard deviation = 2 hr
7/24/2019 5:25 PM Sample Size Estimation 16
Sleep Aid Example
1 sample test2-sided test, α = 0.05, 1-β = 90%σ = 2hr (standard deviation)δ = 1 hr (difference of interest)
2 2 2 21 / 2 1
2 2
( ) (1.960 1.282) 2 42.04 431
Z Zn
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Effect of Difference
Change difference of interest from 1hr to 2 hrn goes from 43 to 11
2 2
2(1.960 1.282) 2 10.51 11
2n
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Research Methodology 23 July 2019
Effect of Power
Change power from 90% to 80%n goes from 11 to 8(Small sample: start thinking about using the t distribution)
2 2
2(1.960 0.841) 2 7.85 8
2n
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Effect of S.D.
Change the standard deviation from 2 to 3n goes from 8 to 18
2 2
2(1.960 0.841) 3 17.65 18
2n
7/24/2019 5:25 PM Sample Size Estimation 20
Sleep Aid Example: 2 Sample
2 2 2 21 / 2 1
2 2
2( ) 2(1.960 1.282) 2 84.1 85 170 total!1
Z Zn
Original design (2-sided test, α = 0.05, 1-β = 90%, σ = 2hr, δ = 1 hr)Two sample randomized parallel designNeeded 43 in the one-sample designIn 2-sample need twice that, in each group!4 times as many people are needed in this design
7/24/2019 5:25 PM Sample Size Estimation 21
Conclusion
2 21 / 2 1
2
4 ( )2
Z ZN
Changes in the detectable difference have HUGE impacts on sample size20 point difference → 25 patients/group 10 point difference → 100 patients/group 5 point difference → 400 patients/groupChanges in α, β, σ, number of samples, if it is a 1- or 2-sided test can all have a large impact on your sample size calculation
7/24/2019 5:25 PM Sample Size Estimation 22
Group Activity
7/24/2019 5:25 PM Sample Size Estimation 23
Group Task 1 - Question
The cure rate of disease is 20% with a known drug treatment. It is claimed that yoga is better than the drug and a trial is to be conducted find out the truth. It is decided that a even 10% increase in cure rate would be clinically important.
The alpha and beta were set at 0.05 and 0.2.
The results will be analysed using Chi Square test.
How many patients would be required for the trial?
7/24/2019 5:25 PM Sample Size Estimation 24
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Research Methodology 23 July 2019
Task 1 - Answer
Aim – To see whether yoga is better than standard drug Rx in curing the pt.Analysis type- comparison of proportion Parameters- cure rate 20% vs 30%No. of groups – 2 p1=20 q1=80, p2=30 q2=70Set alpha=0.05, beta=0.2, Power=0.8Statistical formula to be used
n = p1q1 + p2q2 X 8(p1-p2)2 Ans. 296
7/24/2019 5:25 PM Sample Size Estimation 25
Group Task No. 2 - Question
The mean(+SD) hospital stay of patients after a conventional surgical procedure (CP) is 12.3 ( 4.8) days. A modified procedure (MP) is to be tried to reduce the hospital stay.
Their hospital stay will be compared using unpaired t test at p<0.05 with power of 80%.
The minimum clinically important difference in the duration of hospital stay is expected to be 3.
Calculate the sample size for each group ?
7/24/2019 5:25 PM Sample Size Estimation 26
Task 2 - Answer
Aim – To see whether modified procedure reduces the hospital stay as compared to conventional procAnalysis type- comparison of mean, unpaired dataParameters- duration of hospital stay 12.3 vs 9.3 No. of groups-2Given M1=12.3, M2=9.3, SD= 4.8 Set alpha=0.05, beta=0.2, Power=0.8Statistical formula to be used
n = 16 X (S.D./M1-M2)2
Ans 40.967/24/2019 5:25 PM Sample Size Estimation 27
Group Task 3 - Question
The mean fruit juice consumption in the population is 5 oz./day.
Dennison and colleagues wanted to know whether mean juice consumption in 2 year old children is different from 5 oz./day – either more or less by1 oz/day.
SD is 3 oz/day.
Calculate the sample size required ?
7/24/2019 5:25 PM Sample Size Estimation 28
Task 3 - Answer
Aim – To see whether fruit juice consumption differs by 1 from the population (Normal standard) mean of 5oz./dayAnalysis type- comparison of mean, paired dataParameters- fruit juice/day 5 vs 6 or 4 No. of groups-1Given M1= 4 or 6, M0=5, SD= 3
Set alpha=0.05, beta=0.2, Power=0.8Statistical formula to be used
n = 8 X (S.D./M1-M0)2
Ans 727/24/2019 5:25 PM Sample Size Estimation 29
Hands – on
SamplePower (IBM SPSS)NCSS PASSMedcalcStataSASStatisticaGraphpad
7/24/2019 5:25 PM Sample Size Estimation 30
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Research Methodology 23 July 2019
Exercise-1
A survey estimated that 20% of all people aged 16 to 20 from UP drove under the influence alcohol.A similar survey is planned for Maharashtra. They want a 95% confidence interval to have a margin of error of 0.04.
Find the necessary sample size if they expect to find results similar to those in the UP.
7/24/2019 5:25 PM Sample Size Estimation 31
One proportion
P = 20%Margin of error (difference) = 4%Z-score
1.645 90%1.96 95%2.58 99%
N = 384.27/24/2019 5:25 PM Sample Size Estimation 32
Exercise-2
A researcher wants to assess the mean change in blood sugar with a oral antidiabetic drug. An earlier study reported a mean and standard deviation of 140 mg% and 100 mg%.
How many patients should be included for a 95% C.I. to have a margin of error of 20?
7/24/2019 5:25 PM Sample Size Estimation 33
One mean
S = 100Margin of error (difference) = 20t = 1.96 for 95% confidence (t-distribution)
N = 199
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In reality, the SD is now 10. Using the sample size you used above, would the margin of error for a 95% C.I. be -
<20, 20, or >20
Margin of error decreased to 10in same proportion of SD
7/24/2019 5:25 PM Sample Size Estimation 35
Thank You !
7/24/2019 5:25 PM Sample Size Estimation 36
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For the following data identify the study design and using appropriate formula calculate minimum sample size required for given studies
1) A local health department wishes to estimate the prevalence of tuberculosis among children under five years of age in the locality. How many children should be included in the sample so that the prevalence may be estimated to within 5 % points of the true value with 95 % CI if it is known that the true rate is unlikely to exceed 20%?
2) In a pilot survey in a developing country, an epidemiologist compared a sample of 50 adults suffering from a certain neurological disease with a sample of 50 comparable control subjects who were free of the disease. Thirty of the subjects with the disease and 25 of the control were involved in fishing related occupations. If the proportion of the population involved in fishing related occupation in the entire population is similar to that observed in pilot survey. How many subject should be included in a larger study in each of the two group if the epidemiologist whishes to be 90% CI detecting the true difference between the two group at the 5 % LS
3) A health department nutritionist, wishing to conduct a survey among population
of teen age girls to determine their average protein intake, he would like an interval about 10 unit wide ie he would like his estimate to be within 5 unit of the true value in either direction at 5 % LS. From the past experience he feels that the population standard deviation is probably about 20 gms.
4) Suppose we want to test the hypothesis that, mothers with low economic status
deliver babies whose birth weights are lower than normal. To test this hypothesis a list of birth weights from 100 consecutive, full term, live-born deliveries from the maternity ward of a hospital in low SES area is obtained. The mean birth weight is found to be 2.4 kg with SD = 0.24 kg suppose we know from nationwide survey based on millions of deliveries that the mean birth weight is 2.8 kg with standard dev of 0.35 kg
5) In a hypothetical disease the fatality rate is 40%. A new remedy is available and preliminary experiments suggest that it reduces the fatality rate to 35 % it is decided to carry a careful clinical trial with an equal no of patients in each group. What is the smallest number that must be included in each group if the drop of 5% in the fatality rate is to be statistically significant at 95% confidence limit.
6) An epidemiologist is planning the study to investigate the probability that the certain lung disease is linked with exposure to a recently identified air pollutant. What sample size should be needed in each of the two groups exposed and non-exposed, if epidemiologist wishes to estimate the relative risk within 50 % of the true value (which is believed to be approximately = 2 ) with 95 % confidence. The disease is present in 20 % of people who are not expose to the air pollutant.
7) Given that Westoff and Bumpass (1973) approximately 30% women of childbearing age will have exposure to OC within three months of conception P0 = 30 % or 0.3 Alpha (α) = 0.05 Beta (β) = 0.10 RR = 3 Calculate sample size for given study
For RCT with Equal Allocation
2
12
2
( * (2(p*q) )c c t t
c t
Z z p q p qnc
p p
Sample size for continuous outcome measure
2 2
12
2
( ) ( )t c
c t
z znc
(Case control ) P0 = RR = Alpha = Beta =
21 1 0 01
22
1 0
( * (2(p*q) )Z z p q p qn
p p
01
0
( *R)[1 (R 1)]
ppp
Cohart study RR= P(e) / P(c)
2
2[(1 ) (1 ) / ]
log (1 )e e c c
e
z p p p pn
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Questionnaire Designing
Nima Rege
:Questionnaire Designing: Nima Rege
Session ObjectivesAt the end of this session, participants will be able to:
Select questionnaire as a tool for collecting information
Enumerate types of questions
Describe care to be taken while wording questions
Select appropriate response format
Appreciate importance formatting a questionnaire
State importance of pretesting a questionnaire
Describe strategies to increase response rate3:Questionnaire Designing: Nima Rege
Questionnaire
Is a tool/Instrument to collect data systematically
when survey is selected as a method of
obtaining information
4:Questionnaire Designing: Nima Rege
Survey
Method to obtain information
- for a specific purpose
- from or related to a specific population
- that is analyzable to meet the purpose.
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Survey types
Interview
Individual- Face to face- Telephonic
Focus group
Mail surveyGroup administeredDrop off surveyElectronic survey
e-mailonline
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Self-completion
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Questionnaire is NOT the method of choice
when little is known about the subject
:Questionnaire Designing: Nima Rege 8
1. Decide the information required- Research question
2. Define the target respondents3. Choose the method(s) of reaching your target
respondents4. Decide on question content5. Develop the question wording6. Put questions into a meaningful order and format7. Check the length of the questionnaire8. Pre-test the questionnaire9. Develop the final survey form
Questionnaire designing steps
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Questions and questionnaire are
vital to successful survey.
:Questionnaire Designing: Nima Rege
How to get 'right' questions?
10
Thinking of a question is not a problem; coming up with right question is.
Questions
:Questionnaire Designing: Nima Rege
'Right' questions
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List variablesSources include patients/subjects (focus groups, key informant interviews), clinical observation, your prior research, and expert opinion
Literature search: theory or conceptual framework, published work of others
Borrow from other instruments
Solicit input from peers:Questionnaire Designing: Nima Rege 1212
Questionnaire Design
Introduction
Instructions
Questions
Closing
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INTRODUCTION
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INTRODUCTIONMention the purpose of the questionnaire Provide reason for selection of participantsInform what the participants are supposed to do and request for timeExplain how the information obtained will be usedAssure research ethics: right of non- acceptance, anonymity, confidentialityWhere and when to return, whom to contact for queriesPromise sharing of resultsAcknowledge participant's co-operationUse language appropriate for participants selectedGive researcher's details
Establishes rapport
:Questionnaire Designing: Nima Rege 14
INSTRUCTIONS
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INSTRUCTIONS
DirectionsWhat the respondents are supposed to do?
Transitional statementsTo signal that a new topic is about to begin
To start new pages
To break up the monotony of a long series of questions
In this next section of the survey, we'd like to ask youabout your personal relationships. Remember, we do
not want you to answer any questions if you are
uncomfortable doing so.
:Questionnaire Designing: Nima Rege 16
Questions
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Question design
Type
Wording
Response format
Placement and Sequence
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Types of QuestionsOpen ended
Closed endedTwo option responses
Single best response
With multiple answers
Ordered responses –rating scales
Ranking
Filter questions
Partially closed ended:Questionnaire Designing: Nima Rege 20
Have you used computer for graphical presentation?
Yes No
If yes, How often?DailyNot daily but at least twice a weekNot twice weekly, but at least 4 times a monthLess than 4 times a monthNever used till now
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Types of QuestionsPlease indicate your level of agreement/disagreement with the following statements by circling the number that best describes your opinion (PLEASE NOTE: 5=Strongly Agree; 1=Strongly Disagree)
Strongly Agree Agree Neutral Disagree Strongly
Disagree
Some professors are much more interesting than others
5 4 3 2 1
Lengthy lectures can be tiring
5 4 3 2 1
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Question Wording
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Question Wording
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SimpleSpecific Avoid jargon, abbreviationUnambiguousAvoid biasAvoid unnecessary repetitive, leading questionsCareful phrasing:Questionnaire Designing: Nima Rege 24
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Phrasing Questions1. Use clear wording
“Often? Sometimes? Regularly?”
2. Be specific
"In general, how good is your health?"
Would you say your health, in general, is-------
3. Avoid making assumptions
How many children do you have?
Do you have children?
4. Include all necessary information
Do you agree or disagree with the assessment
strategy mentioned in vision 2015?:Questionnaire Designing: Nima Rege 25
5. Double-Barreled Questions Do you think the patients should visit OPD regularly and contact doctors telephonically time to time?How satisfied are you with your treatment and the advice about diet?
6. Double NegativeWould you say that your doctor is not inattentive?
7. Casting Too Big of a NetIs Gynaecology department efficient ?
8. Sensitivity
Funneling questions to introduce sensitive topics 26:Questionnaire Designing: Nima Rege
9. Avoid “deceptively short” questions or those with high respondent burden- complex tables - rank ordering- mental calculations- “check all that apply”
10. Language as understandable by the target participants
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Recently a survey was conducted by the United Nationsusing a sample from several different countries. Thequestion asked was:
" Would you please give your opinion about the foodshortage in the rest of the world?"
The survey was a huge failure. Why?• In Africa they did not know what 'food' meant.• In Western Europe, they did not know what 'shortage'
meant.• In Eastern Europe they did not know what 'opinion'
meant.• In South America they did not know what 'please'
meant.• And in the U.S., they did not know what 'the rest of the
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I can’t decide whether to have ticks in boxes, crosses, circling or underlining
Response format
:Questionnaire Designing: Nima Rege 30Anchored or categorized VAS :Questionnaire Designing: Nima Rege
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31Checklist :Questionnaire Designing: Nima Rege
Broad or General Questions
Narrow or Specific Questions
The Funnel Approach to Ordering Questions
:Questionnaire Designing: Nima Rege 32
Questions: Placement
Group questions on one topicGroup similar type of question based on response formatPlace instructions where needed, not just at the beginning
:Questionnaire Designing: Nima Rege 33 34
• Simple, friendly, closed ended, easy to respond and should convey the theme of the survey
Early Questions
• Target questionsMiddle
Questions
• Optional questions like related to demographic data
• Sensitive questions on difficult or uncomfortable aspects
• open ended questions
Late Questions
:Questionnaire Designing: Nima Rege
Have you copied other students' MCQ answers in a degree exam?
By the way, do you happen to have copied other students' answers in a degree exam?Please tick one or more of the following items which correspond to how you have answered degree examination questions in the past.As we all know, most medical students have copied other students' answers in degree exams. Do you happen to be one of them?Give a scenarioComment and have you done or would you consider doing the above? 35:Questionnaire Designing: Nima Rege
CLOSING
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Questionnaire Design
Introduction
Instructions
Questions
Closing
Length of the questionnaire and time required for answering : keep that is absolutely necessary (2-4 pages)
:Questionnaire Designing: Nima Rege
The Golden Rule
Be sensitive to the needs of the respondent
Do unto your respondents as you
would have them do unto you!
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Visual designAttractive, uncluttered formatConsider light pastel colorsAvoid excessively small or unusual fontsNumber and carefully align (vertically) questions and response optionsAvoid loose pages; booklet format if possible.Avoid splitting questions across columns/pages.Minimize the number and abruptness of format changes; use transitional sentences.
39:Questionnaire Designing: Nima Rege
Response rate:50% to 90% is preferable but this may be unrealistic.
Telephone, mail and computer methods may result in much lower response.
Questionnaires don’t reach!
3–8% of items in any questionnaire are usually left blank.
Response rate for Survey
:Questionnaire Designing: Nima Rege 40
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1) Advance personalized invitation
2) Make the participants feel that they are
stakeholder in the study
3) Stamped, addressed, return envelope
4) Follow-up reminders
5) Incentives or prizes in return for completion
Strategies to increase response rate
:Questionnaire Designing: Nima Rege
Pretesting of Questionnaire
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Essential step!
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Pretesting of Questionnaire
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Participants fail to respond because they
Don’t understand questions Can’t complete the questionnaire Get bored or offended by questionsDislike how the questionnaire looks
:Questionnaire Designing: Nima Rege
Pretesting of Questionnaire
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Purpose
To maximize the proportion of subjects answering
questionnaire - that is, the response rate.
To obtain accurate relevant information
:Questionnaire Designing: Nima Rege
Pretesting of Questionnaire
45
Questions that a pretest should answer:
Does a question measure what it is intended to measure?
Do respondents understand all the words?
Are questions interpreted similarly by all respondents?
Are the answers respondents can choose from correct?
Does any aspect of the questionnaire suggest bias on the part of the researcher?
:Questionnaire Designing: Nima Rege 45
DetermineValidity: How well the test measures what it supposed to measure?
Reliability : Whether the test produces stable and consistent results
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Validity and reliabilityConstruct validity : Literature review to verify concepts and assumptionsContent validity : Expert judgment, other documents, keep some open questionsConcurrent validity: Compare responses with validated questionnaire
Back up with other evidencesPredictive validity: Predicting performanceFace validity: Whether questions ‘look’ right? Reliability: Test-retest reliability
Inter-rater reliabilityInternal consistency
Cronbach's coefficient 47:Questionnaire Designing: Nima Rege
Pretesting
Feedback on questions, response format and impression created by the questionnaire
Try tabulation and analysis procedures
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Revise
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Online survey programsHere are two online products for survey design and data collection:
SurveyMonkey: www.surveymonkey.comQuestionPro: www.questionpro.com
:Questionnaire Designing: Nima Rege 50
Critical appraisal checklist for a questionnaire study
BMJ. 2004 May 29; 328(7451):1312–1315
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ReferencesCrawford IM. Questionnaire Design. Chapter 4. In, Marketing
Research and Information Systems. By Food and agricultural
Organization of United States. 1997 http:/www.fao.org
Taylor-Powell E. Questionnaire Design: asking questions with
purpose. In, Programme Development and Evaluation.
Cooperative Extension Publications. University of
Wisconsins. 1998; 1-17.
Boynton PM. Selecting, designing and developing your
questionnaire. BMJ 2004;328: 1312-1315
http:/ www statcan.gc.ca51:Questionnaire Designing: Nima Rege 52
Additional resourcesLinks to useful articles/guidelines on sampling
and survey methods:http://gsociology.icaap.org/methods/surveys.htmhttp://gsociology.icaap.org/methods/sampling.htmlhttp://gsociology.icaap.org/methods/
ICAAP is The International Consortium for the Advancement of Academic PublicationICAAP is supported by Athabasca University
:Questionnaire Designing: Nima Rege
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Thank You !:Questionnaire Designing: Nima Rege
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Synopsis Submission Process: Research Methodology
7/24/2019
Dr. VaishalI thakare 1
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCHD. Y. Patil School of Medicine
SUBMISSION OF RESEARCH PROPOSAL
Dr Vaishali Thakare
Member Secretary -IECBH
Institutional Ethics Committee :
• As per New clinical trial rules & regulations –
March 2019
• Two different registered ethics committee
– 1. IEC for Clinical trial
– 2. IEC for Biomedical & health
research – ACADEMIC
– ICMR guidelines
Plagiarism check
Institutional Ethics Committee (IEC)
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
IEC for Clinical trial “New drug” means,1. A drug
Active pharmaceutical ingredient Phyto-pharmaceuticalNot been used in the country to any significant extent
2. A drug approved Modified or New indicationNew route of administrationNew dosage New dosage form
3. A fixed dose combination of two or more drugs To be combined for the first time in a fixed ratioRatio of ingredients in an approved combination - To be changed
4. Any drug approved Modified or sustained release form of a drug Novel drug delivery system
5. Vaccine
Academic clinical trialA clinical trial of a drug
already approved for a certain claim Initiated by any investigatorAcademic or research institution
For a New indication New route of administration New dose New dosage form
The results of such a trial Intended to be used only for academic or research purposes Not for seeking approval for marketing or commercial purpose
Biomedical and health research • Research Studies on
– Basic, applied and operational research – Clinical research
• Designed primarily – To increase scientific knowledge – about diseases and conditions– Their detection and cause – Evolving strategies for – health promotion &Prevention– Amelioration of disease and rehabilitation
• Does not include clinical trial as defined in clause
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Synopsis Submission Process: Research Methodology
7/24/2019
Dr. VaishalI thakare 2
IEC – Institutional Ethics CommitteeAll research proposals from Biomedical, social and behavioural
scienceInvolving
• Human participants• Their biological material & Data
To be reviewed & approved – Appropriately constituted EC To safeguard
Dignity , rights, safety and well-being - Research participants.
Approval Prior to their initiationContinuing - Ensure ethical complianceEC - Competent and independent in its functioning
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
MEMBERS Contact number Email ID
•Dr Hemlata Iyer 9820391401 [email protected]
•Chairperson•Dr.Vaishali Thakare 9869366927 [email protected]
•Member Secretary•Dr. Sharmila Patil 8850635503 [email protected]
•Dr. Abhay Chowdhary 9869009050 [email protected]
•Dr.Anant Patil 9920449433 [email protected]
•Dr. Ketan Vagholkar 9821341290 [email protected]
•Dr Sangita Sawant 9321214832 [email protected]
•Dr. Rochna Bakshi 9323272151 [email protected]
•Dr. Baishali Bhattacharya 9820268795 [email protected]
•Dr. DeepaliVidhate 9869687771 [email protected]
•Dr. Balasaheb Khadbade 9967294847 [email protected]
•Usha More 8108236868 [email protected]
•Tanmay Sinnarkar 9820466919 [email protected]
•Lakshmi Patro 9833632967 [email protected]
•Rajesh Dhoke 9320925899 [email protected]
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
• Modification & Innovation of submission process
• PG admission – 2019-2020
• Process of submission – Online
• LMS – Platform
• Portal is created
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
Process Of Synopsis / Research Proposal Submission For IEC Approval
Go to http://mydy.dypatil.edu
Dash board will come IECBH – Assignments 1. Form 2. Annexures
Download the form & annexures
Complete the form & annexuresapllicable to you and complete
Approval of the HOD & Guide Is mandatory
Upload the approved form & completed annexures back
Submit 1 hard copy to IECBH Pharmacology department
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
Circular for uploading (8/8/19- 10/8/19)
Completion of uploading of Proposal and AnnexureApproved by HOD and Guide (15/8/19)
Submission to IECBH (20/8/19)
Department Of Pharmacology - Ms. Poonam and Mr. Bahadur
Proposal for discussion
Submitted through website, approved by HOD and guide, hardcopies submitted to IECBH
Tentative dates for IEC meeting (22/8/19)
Pre-clinical and para-clinical (22/8/19 and (23/8/19)
Medicine and allied (24/8/19 to 27/8/19)
Surgery and allied (28/8/19 - 31/8/19)
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
If no changes – 20 days
Email communication in – 2weekChanges – Chairperson/Secretary
Resubmission – 2 weeks Communication 2 weeks
Submission of approved protocol – HOD & Guide
HARD COPY -IECBH Meeting in 3 days
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
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Synopsis Submission Process: Research Methodology
7/24/2019
Dr. VaishalI thakare 3
• Information required for
• Online submission of
• Synopsis/Research proposal
• Registration of your thesis – Mandatory
• CTRI - Separate portal – Thesis / Dissertation
• http://ctri.nic.in/Clinicaltrials/news.php?lid=17
INSTITUTIONAL ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH D. Y. Patil School of Medicine
Scientific title of the study Carry maximum information about the study In a few word(within 12-15 words) -seven elements
study setting, location, or both
Patients, organism, event, or relationship studied;
Intervention, treatment, or exposure;
Comparator or control group(s);
Outcomes or end points;
Study design, and sometimes
Duration of the study
Ex : 1. Evaluation of safety & efficacy if ITRA Vs Terbinafine
2. “Prospective randomized open lable clinical trial in Dermatology outpatient department
of tertiary care teaching hospital to evaluate the efficacy & safety of Itraconazole Vs
Terbinafine in resistant cases of various types of cutaneous dermatophytosis “
2.Principle investigator –
Name, Department, Designation, Email ID, Contact No.
3.Name of the guide & Co- Guide ( If it is) –
Details as above
4.Contact Person
5.FundingYes No
Self Organization – Govt. Non govt
6.Sponsor
7.Study site : Hospital , Additional site, School, Other sites
8.Health condition /Problem studied
Diabetic, Hypertensive, Post menopausal, Breast cancer, Peptic ulcer, Psoriasis,
Depression
9.Study population –
Healthy volunteers -
Diseased ( specify details – Stage, Duration etc)
• Type of the study –• Observational -• Simply Observing – collecting the data
• May be about intervention - Routinely practiced intervention
• “Comparative study to evaluate safety & efficacy of intrathecal lignocaine(2%) &
Bupivacaine in a patient undergoing caesarean section”
• Longitudinal – Following over a period of time ( Exposure & outcome – different time)
• Prospective - From exposure – Outcome
• Smoking to Lung cancer
• Retrospective - Outcome – Exposure
• Lung cancer to Smoking
• Cross-sectional - Same time (Snap shot picture)
• Ex: Random sample of schools across London may be used to assess the prevalence of
asthma among 12-14 year olds.
• Interventional
– Drug – Pharmacological Name , Dose, duration, Frequency,
– Who will bear the cost, what is to be done with once the trial is
over
– Lifestyle modification – Diet , Exercise
– Operative procedure – Standard of care, Newly introduced
– Other
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Synopsis Submission Process: Research Methodology
7/24/2019
Dr. VaishalI thakare 4
Study arm
o Single arm
o Double arm/Multiple arm
Parallel group - Running parallel
Cross over
Randomized - Method of randomization
Computer generated chart/Table
Flipping of coin
Nonrandomized
Control/Comparator group
Placebo - Ethical issues – explained
Standard drug/Method
Other
Blinding
Open label
Complete study design
• Inclusion criteria
• Exclusion criteria
• Primary outcome
• Secondary outcome
• Sample size
• Too large – resources waste
• Too small – No inference
• Method of sampling
• Calculation
• Phase of trial
• Material & method
– Groups
– Enrollment
– Data collection method
– Estimated duration
– Study procedure
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Synopsis Submission Process: Research Methodology
7/24/2019
Dr. VaishalI thakare 5
• Statistical details
– Test
– Level of significance
• Brief summary
• References : Vancouver style only
• Recent one – Last 5 years
• Please upload the following annexureMandatory• Informed consent form
– Download the format – English – Hindi, Marathi,English– Translation form
• Case record sheet/Patient proforma• Patient information Sheet –
– Download the format – English– Hindi,Marathi,English
IF APPLICABLE
1. Other –Questionnaires - Validation is MUST
2. Waiver of consent form
3. Checklist for Research Involving Pregnant Women & Foetus
4. Checklist for Research Involving Cognitively Impaired Adults
5. Checklist for Research Involving Students, Employees or Residents6. Checklist for Genetic Research
• Group activity• 1. Metformin + Glipizide Vs Metformin + Sitagliptin
In Type 2 DM• 2. Standard vs modified nailing & plating method
for open reduction of # forearm bones• 3. Observational study to analyze prescribing
pattern in dermatology department• 4. Evaluation of efficacy of misoprostol
Versus Dinoprostone Gel For Induction of Labour
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Basic workshop onResearch methodology, Biostatistics &
Principles of GCP22 – 24 July 2019
Venue: Pushpanjali, 3rd floor Auditorium, D Y Patil Hospital, Nerul
Jointly organized by
Dept. of Obs. & GynaecologyInstitutional Ethics Committee (IEC)
7/23/2019 9:53:39 AM I.E.C. - GCP WORKSHOP 1
Regulations in Clinical Research DR. DEEPPAK LANGADE M B B S , M D , P G D A SS ( A P P L I E D S TAT I S T I C S )
PROF. & HEAD, PHARMACOLOGYSECRETARY, INNSTITUTIONAL ETHICS COMMITTEE ( IEC)CHAIRRMAN, IAECCHAIRRMAN, PHAARMACOVIGILANCE COMMITTTEE
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 3
Drugs & Cosmetics Act 1940, and Drugs & Cosmetic Rules 1945
Regulatory body in India
Central Drugs Standard Control
Organisation(CDSCO)
Drug Marketing Approval
Import of Drugs
Clinical Trials for New drugs
Drug Safety in India (Pharmacovigilance)
Materiovigilance
Haemovigilance
Drugs Controller General (I)
(Centre)
FDA (State)
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 4
Schedule ‘Y’CDSCO & DTAB in 2005
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 5 7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 6
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New Drugs and Clinical Trials Rules, 2019
G.S.R. 104(E) 02ND FEB. 2018
G.S.R. 227(E) 19TH MARCH 2019
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 7
New Drugs and Clinical Trials Rules, 2019
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 8
• Preliminary & DefinitionsChapter-I• Authorities & OfficersChapter-II• EC for Clinical Trial, BA and BE studiesChapter-III• EC for Biomedical and Health ResearchChapter-IV• CompensationChapter-VI• MiscellaneousChapter-XIII
Chapter - I
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 9
Rules shall come in to force from the date of
their publication in the Official Gazette
Except Chapter IV which shall come in to force after 180
days
Biomedical and Health ResearchResearch including studies, designed primarily to increase scientific knowledge about diseases and conditions (physical or socio-behavioral); their detection and cause; and evolving strategies for health promotion, prevention, or amelioration of disease and rehabilitation but does not include clinical trial as defined in clause (j) of Rule 2.
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 10
Academic Clinical Trial
7/23/2019 9:53:40 AM
A clinical trial of a drug already approved for a certain claim and initiated by any investigator, academic or research institution for a new indication or new route of administration or new dose or new dosage form, where the results of such a trial are intended to be used only for academic or research purposes not for seeking approval of the regulatory authority of any country for marketing or commercial purpose
DR. DEEPAK LANGADE 11
New Drug(i) a drug, including API or phytopharmaceutical drug, which has not been used in the country to any significant extent, and has not been approved as safe and efficacious by the Central Licencing Authority with respect to its claims; or
(ii) a approved drug with modified or new claims including indication, route of administration, dosage and dosage form; or
(iii) a FDC of two or more drugs; or(iv) a modified or sustained release form of a drug or novel drug delivery system; or(v) a vaccine, r-DNA derived product, living modified organism, monoclonal antibody, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug;
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 12
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The new drugs shall continue to be new drugs ..for a period of FOUR years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 13
Clinical trialAny systematic study of a new drug or Investigational New Drug (IND) in human subjects to generate data for discovering or verifying its,-
i. clinical or;ii. pharmacological including pharmacodynamics,
pharmacokinetics or;iii. adverse effects,with the objective of determining the safety, efficacy or tolerance of such new drug or investigational new drug;
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 14
Orphan Drug
7/23/2019 9:53:40 AM
A drug intended to treat a condition which affects not more than five lakh persons in India
DR. DEEPAK LANGADE 15
Institutional Ethics Committee (IEC)
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 16
EC FOR CLINICAL TRIAL, BIOAVAILABILITY AND
BIOEQUIVALENCE STUDY
• To review and oversee the conduct of research for New Drugs and BA/BE Studies
EC BIOMEDICAL & HEALTH RESEARCH
• To review and oversee the conduct of such research as detailed in National Ethical Guidelines for Biomedical and Health Research Involving Human Participants
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 17
Composition of IECMinimum 7 members from: medical, non-medical, scientific and non-scientific areas …
At-least ….
(i) one lay person;
(ii) one woman member;
(iii) one legal expert;
(iv) one independent member from other related field - social scientist
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 18
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Rules
New Drugs & Clinical Trials Rules, 2019, Good Clinical Practice (GCP) Guidelines, and other regulatory requirements to Safeguard the rights, safety and well-being of study subjects,
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 19
Role of IEC
All proposals on research involving human subjects must be reviewed and approved by an Ethics Committee (EC)
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 20
Functions of Ethics CommitteeNEW DRUGS & CLINICAL TRIALS RULES 2019
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 22
(i) review and accord approval to a clinical trial or BA/BE study
protocol and other related documents,
Oversee the conduct of clinical trial to safeguard the rights, safety
and wellbeing of trial subjects in accordance with these rules,
GCP Guidelines and other applicable regulations;
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 23
(ii) make at appropriate intervals, an ongoing review of the
clinical trials for which it has accorded approval and such
review may be based on periodic study progress reports
furnished by the investigators or
monitoring and internal audit reports furnished by the sponsor or
by visiting the study sites;
(iii) indicate the reasons that weighed with it while rejecting or
asking for a change or notification in the protocol in writing and a
copy of such reasons shall also be made available to the Central
Licencing Authority;
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 24
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(iv) where any Serious Adverse Event (SAE) occurs to a study
subject,
the Ethics Committee shall analyse the relevant documents
pertaining to such event and forward its report to the DCGI and
comply with the provisions of Chapter VI;
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 25
(v) where at any stage of a clinical trial, it comes to a conclusion
that the trial is likely to compromise the right, safety or well-being
of the trial subject,
the IEC may order discontinuation or suspension of the study
and the same shall be intimated to the head of the institution and
the DCGI;
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 26
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 27
(vi) allow any officer authorised by the Central Licencing Authority to enter, with or without prior notice, to inspect the premises, any record, or any documents related to clinical trial, furnish information to any query raised by such authorised person, in relation to the conduct of clinical trial and to verify compliance with the requirements of these rules, Good Clinical Practices Guidelines and other applicable regulations for safeguarding the rights, safety and well-being of trial subjects;
7/23/2019 9:53:40 AM I.E.C. - GCP WORKSHOP 28
(vii) comply with the requirements or conditions in addition
to the requirements specified under the Act and these rules
as may be specified by the Central Licencing Authority with
the approval of the Central Government,
to safeguard the rights of subjects.
Vulnerable subjects
7/23/2019 9:53:40 AM DR. DEEPAK LANGADE 29
STUDENTS EMPLOYEES CHILDREN ELDERLY MENTALLY CHALLENGED
Sources of funding
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 30
ICMR - Indian Council of Medical Research
Department of Biotechnology
Department of Science and Technology
CSIR - Council for Scientific and Industrial Research
Pharmaceutical Industry
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Collaboration outside India
Additional approval from the Health Ministry Screening Committee, a committee that works out of ICMR
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 31
CompensationTRIAL RELATED INJURY
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 32
Chapter - VI
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 33
Rule 39. Compensation in case of injury or death in clinical trial or bioavailability or bioequivalence study of new drug or investigational new drug.
Where any death of a trial subject occurs during a clinical trial or bioavailability or bioequivalence study, the legal heir of the trial subject shall be provided financial compensation by the sponsor or its representative who has obtained permission
Compensation: 7th Schedule
7/23/2019 9:53:41 AM
DeathCompensation = (B x F x R) / 99.37Where,B = Base amount (i.e. 8 lacs)F = Factor depending on the age of the trial subject as per Annexure 1 (based on Workmen Compensation Act)R = Risk Factor depending on the seriousness and severity of the disease, presence of co-morbidity and duration of disease of the trial subject at the time of enrolment in the clinical trial between a scale of 0.5 to 4.0
DR. DEEPAK LANGADE 34
(1) 0.5 terminally ill patient (expected survival not more than (NMT) 6 months)
(2) 1.0 Patient with high risk (expected survival between 6 to 24months)
(3) 2.0 Patient with moderate risk
(4) 3.0 Patient with mild risk
(5) 4.0 Healthy Volunteers or trial subject of no risk.
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 35
High mortality
However, in case of patients whose expected mortality is 90% or more within 30 days, a fixed amount of Rs. 2 lacs should be given.
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Permanent disability
Compensation = (C x D x 90) / (100 x 100)
Where :D = Percentage disability the trial subject has suffered.C = Quantum of Compensation which would have been due for payment to the trial subject's nominees) in case of death of the trial subject.
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Congenital anomaly or birth defect
Lump sum amount - Fixed deposit or alike, which shall bring a monthly interest amount equivalent to half of minimum wage of the unskilled worker (in Delhi). The quantum of compensation in such cases of SAE shall be half of the base amount as per formula for determining the compensation for SAE resulting into death.The medical management of the child as long as required shall be provided over and above the financial compensation.
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Insurance
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Other Guidelines
•Good Clinical PracticesGCP•Good Manufacturing PracticesGMP•Good Laboratory PracticesGLP•Good Documentation PracticesGDP
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 40
Thank You
7/23/2019 9:53:41 AM DR. DEEPAK LANGADE 41
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Research Methodology Workshop 24-07-2019
Dr. Varsha Vyas 1
ROLE AND RESPONSIBILITIES OF PRINCIPAL INVESTIGATOR [PI]
Dr Varsha Vyas Professor in Anaesthesia
Principal Investigator[PI]
The PI has primary responsibility for achieving the success of the research
Varsha Vyas 3
ELIGIBILITY of PI
• Preferably from an post-graduate medical institute or specialty/super-specialty hospital.
• Adequate training and experience in his/her specialty.
• Interested in conducting the study.• Up-to-date Resume/CV should be
submitted to IEC.• Familiar with the use of investigational
product and should comply with norms of GCP and the applicable regulations.
Varsha Vyas 4
Responsibilities of PI
Varsha Vyas 5
Adequate Resources
Adequate medical care of the subjects
Communication with IRB/IEC
Protocol compliance
Accountability of trial supplies
Randomization procedure & un-blinding
Written informed consent
Master file (Maintenance of Records)
Progress of trial
Reporting of Adverse drug reactions (Safety Reporting)
Premature study termination
Final report
ADEQUATE RESOURCES
• Have adequate number of staff to assist in conduct of study.
• Should have adequate facilities for the conduct of study.
• Should be able to recruit required number of subjects for study.
• Should have sufficient time to properly conduct and complete the study.
• Should permit monitoring and auditing by sponsor.• Maintain a list of qualified persons (Investigating
team) to whom study related duties are assigned.• Should inform all persons assisting in the study about
the protocol, investigational product and study related duties
Varsha Vyas 6
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Research Methodology Workshop 24-07-2019
Dr. Varsha Vyas 2
Role of PI
Varsha Vyas 7
Delegate responsibilities to team.
Team memebrs should be qualified and trained.
Supervising entire study activities.
MEDICAL CARE OF SUBJECTS
• Responsible for all study related medical decisions
• Ensure adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values related to the study.
MEDICAL CARE OF TRIAL SUBJECTS
PI should inform a subject when medical care is needed for intercurrent illness of which the investigator becomes aware
Varsha Vyas 9
MEDICAL CARE OF SUBJECTS
Varsha Vyas 10
The PI should inform the subject’s primary physician about the subject’s participation in the study if the subject agrees to the primary physician being informed.
If the subject is withdrawing prematurely from a trial, the PI should ascertain the reason(s), while fully respecting the subject’s rights
Communication with IRB/IEC
Varsha Vyas 11
PI should apply to the IEC for approval of the study.
Documents for IRB/IEC approval:• Study protocol• Investigator’s brochure• Screening & case report forms• Subject recruitment procedures• Details of the tests to be performed• References and literature supporting the• need & design of the study • Informed consent forms• Patient Information Sheet
Communication with IRB/IEC
• PI should initiate a study only after obtaining a written and dated approval to conduct the study from IEC.
• PI should provide all updated documents subject to review.
• If the protocol has to be amended, the proposed protocol amendment should be submitted as soon as possible to:
(a) IRB/IEC for review and approval.(b) The sponsor for agreement.(c) The regulatory authorities.
Varsha Vyas 12
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Research Methodology Workshop 24-07-2019
Dr. Varsha Vyas 3
COMPLIANCE WITH PROTOCOL
Varsha Vyas 13
Should conduct the trial in compliance with the protocol approved by the
IEC
Should not implement any
deviation from the protocol without
approval from IEC
IPINVESTIGATIONAL
PRODUCT
• Accountability of study medication.
• Maintain all records for medication.
• Medicine should be stored as specified by the law.
• Medication should be used in accordance with the approved protocol.
• Correct use of investigational products is explained to each subject.
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Randomization Procedures & Unbinding
• Follow the randomization procedures as per the protocol.
• Ensure that the blinding is broken (Unblinding) only in accordance with the study protocol.
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Informed Written Consent• Written informed consent should be
obtained from each and every patient before participating in the study.
• Informed Consent Forms (ICF) should also be approved by the IEC.
• Consent should be obtained in compliance with GCP and ethical principles laid out in Declaration of Helsinki.
• Participation in the trial should be voluntary and neither the PI nor the trial staff should force the subject to participate in the study.
Varsha Vyas 16
Informed Consent Process• PI should inform to the
subject all pertinent aspects of the study.
• Language should be non-technical and understandable to the subject (Vernacular).
• Should not contain any language that causes the subject to waive any legal rights or appears to release the PI, institution or sponsor from liability for negligence.
• PI should provide ample time and opportunity to the subject to decide whether to participate in the study or not.
Varsha Vyas 17
Informed Consent Process
• If the subject is illiterate, a legally acceptable representative or an impartial witness should be present during discussion.
• In such case the consent form should be signed by the person present during the discussion.
• The informed consent should also be signed by the person who conducted discussion with time and date.
• The informed consent discussion and the written informed consent form should include explanations to all aspects of the study.
• The subject should receive a copy of the signed and dated written informed consent form prior to participation in study.
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Research Methodology Workshop 24-07-2019
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Informed Consent Process
Varsha Vyas 19
In emergency - Consent of subject’s legally acceptable representative should
be taken.
In case of children - Legally Acceptable Representative [LAR]
Contents of Informed Consent
• That the study involves research• Purpose of the study• Trial treatments and the probability of random assignment• Procedures to be followed• Subjects responsibilities• Aspects of the study that are ‘experimental’• Anticipated risks and inconveniences to the subject or
nursing infant• Expected benefits• Alternative modalities of treatment available to the subject• Compensation and/or treatment available to the subject in
case of study related injuryVarsha Vyas 20
Contents of Informed Consent
• Anticipated expenses to the subject due to participating in the study
• That the subjects participation is entirely voluntary, and that the subject can withdraw from the study at any time, without penalty or loss of benefits to which the subject is otherwise entitled
• Records identifying the subject will be kept confidential• Information about the persons to be contacted in case of
study related injury• Foreseeable circumstances or reasons under which the
subjects participation may be terminated• Expected duration of the subjects participation in the study• Approximate number of subjects involved in the studyVarsha Vyas 21
Records & Documents
• The PI/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects.
• Source data should be attributable, legible, contemporaneous, original, accurate, and complete.
Varsha Vyas 22
Correction of records
• Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit study)
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Records to be maintained
• Screening forms• Patient screening log• Patient information sheets & ICF• Adverse event forms• Communication records• Updated record of the study
medication• All original records of the subjects
(laboratory, clinical, ECG, X-ray, Scan, USG, Doppler etc.)
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Safety reportingAll SAE should be reported immediately to the concerned authority.
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Final Study Reports
• Upon completion of the trial, the PI should inform the IEC with study summary.
• The final report to be prepared.• PI should sign the final report.
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Questions ??Varsha Vyas
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Research Methodology: D Y Patil University School of Medicine
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How to write and appraise an original scientific paper
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Objectives• Types of publication• Primacy of research question• Structure of a scientific paper
TitleSummary / AbstractIntroductionMethodologyResultsDiscussion
• Critical appraisal (check list)Research Methodology: D Y Patil
University School of Medicine3
Types of Publication
• 2 Primary Types
(A) Original Research Articles(B) Reviews
(Other than original research)
Research Methodology: D Y Patil University School of Medicine
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Types of Publications
• Original article • Short communication• Case report • Review • Editorial • Letter/• Correspondence·
• Technical note • Pictorial essay • Commentary • Non- scientific
material • Others
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Original Research Article• Report of a study written by the researchers
who actually did the study.• The researchers describe their
– hypothesis– the purpose of the study – the research methods.– Interpretation of results – Discussion of possible implications.
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Original Research Article• Most important and common• Provides new information based on original
research. • Supported by in-depth statistical analysis of
the data provided in the results. • Structure IMRAD
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Primacy of the research question• Central organizing principle of the paper
• Key attributes:1. specificity2. originality or novelty3. relevance to a broad scientific community
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Formal structure of scientific journals and types of Scientific papersDavid Sharp
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7 RULES
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Rule #1-
Create time blocks in your daily schedule for writing
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Rule #2• Create a outline and discuss it with your
mentors or peers
• Outline (level1):-What is the topic of my paper?-Why is this topic important?-How could I formulate my hypothesis?-What are the necessary outcomes to bemeasured?
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The Basic Structure(SIMRAD)
TitleSummary (Structured Abstract)Introduction (What Question was asked?)Methods (How was it Studied?)Results (What was Found?)Analysis (How data was analysed?)Discussion (What Do the Findings mean?)
Figures, Tables, References, AcknowledgementsResearch Methodology: D Y Patil
University School of Medicine13
Structure of a PaperScientific writing follows a rigid structure –A paper can be read at several levels:
• Some • refer to the title • only the title and abstract • the paper for a deeper understanding
• Hence each section should be complete, accurate and self explanatory
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• Start writing as rough drafts
• Do not get tempted to edit your writing during the first draft
• Revise later, followed by feedback from colleagues.
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Rule #3
Material and methods
• Most important part of the manuscript
• Flaws in this section are most common reasons for rejection of an article
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To describe the study in sufficient detail so that other competent researchers canrepeat the study
what was done?which type of study – its locationwhat is the duration?how was it done?how will the data be analyzed?
Main Purpose
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When should you write material and methods ?
• Before start of the study
• After completion of study, material and methods are written first during manuscript preparation.
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Grammar
• Avoid complex sentence structure
• Use simple and clear English
• Passive voice
• Past tense
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Use of past tense and passive voice
I incubated the sample at 37 C for 3 days
The sample was incubated at 37 C for 3 days .
We used ANOVA to compare the means.
ANOVA was used to compare the means.
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Describe the method used
Describe the materials used
Describe the research methodology
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1 . Materials • Patients /volunteers/subjects/ animals• Drugs , chemicals, reagents, plant extract• Cell lines, tissue cultures, immune sera, culture
medias, etc• Kits • Questionnaires• Instruments• Softwares
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Material - Animal studies
• Species, Strain• Number of animals• Age• Gender• Weight • Physiological or pathological status• Diet • Housing conditions • Name of the supplier• Ethics committee approval
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Material - Clinical study
• Subjects - patients , volunteers• Approval from ethics committee• Informed consent• Source of the population• How were they recruited ? • Exclusion and inclusion criteria• Sample size and randomization in detail• Relation between control and study group – whether
matching was done ?
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Material - Drugs / chemicals
• Generic name• Chemical name of non standard drugs• Suppliers name• Dose and dosage form• Route of administration• Schedule of administration
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Material cont..
Plant extract
• Species • Part of the plant • Plant identification by a botanist• Method of extraction
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Material cont..
Questionnaire• Validated or pretested questionnaireInstruments (in case of animal studies) -
•model details• manufacturer• city of manufacture• any modification • illustrations if required
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2. Methods • Study design• Study location • Masking / blinding • Exact methodology of the study • Approved method• If the method is new, all details must be provided
/ any modifications• Questions such as “how” or “how much” must be answered
and not left to be puzzled over
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Task - 1
• "135 microliters of sample one was diluted with 330 microliters of buffer to make the protein concentration 2 mg/ml.“
• samples were diluted to a final concentration of 2 mg/ml protein;"
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Task - 2
• First pour agar into six petri plates. Then inoculate the plates with the bacteria. Then put the plates into the incubator . . .
• Six petri plates were prepared with agar and inoculated with the bacteria. The plates were incubated for ten hours.
DO NOT write this section as though it were directions in a laboratory exercise book.
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3. Evaluation method • Number of observers• Independent/consensus assessments• Time period between readings• Any grading system/ measurement of parameters • Any specially designed form• Follow ups – duration of follow up
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Statistical methods • How is the data expressed ?• Which test ? • Why – for which data ?
The data was expressed as Mean One way ANOVA was used to compare the mean
weight gain in the five groups.
• Significance level• Any software used with version
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• Enough information must be given so that the experiments could be reproduced by a competent colleague
• Be meticulous and accurate in describing material and methods. Do not change the voice within one paragraph
Materials and methods (in short)
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# Rule 4
Be clear , concise and objective in describing your results
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The ResultsText
TablesFigures
StatisticsResearch Methodology: D Y Patil
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ResultsProvide the answers to..
What was found?
Usually expected results
REPORT unexpected findingsREPORT negative findings
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Data Vs Results• Data – Factual findings – Eg. Numbers
– Raw data (Eg: B.P.)– Summarised (Eg: Mean and S.D.)– Transformed (Eg: Percentage of baseline)– Reader is forced to draw their own conclusions
• Results: What do the data mean?• The authors clearly state what is their interpretation
of the dataResearch Methodology: D Y Patil
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Text• Describe study groups, participants
• How was your sample representative of the study population
• Were the groups comparable (Baseline characteristics)
• Characteristics of the subjects
• How many completed study, lost follow up or withdraw from study Research Methodology: D Y Patil
University School of Medicine39
TextEach parameter (Efficacy & safety)–
• One parameter per paragraph
• Logical sequence as methods
• Most important to least important
• Delineate topic and message clearly
• Avoid repetition Research Methodology: D Y Patil University School of Medicine
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Text - IncludeDescriptive data e.g. no. of patients meeting- inclusion criteria, died and lost to follow up.
Statistical significance
Highlight important data from tables & figures
Negative association, unexpected outcome and their statistical significance at the end
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Table
Eye catching, preferred by readersAccommodates MORE extensive and exact data compared to graphs & illustrationsMORE efficient in summarizing results than text
If a table does not convey anything more than the ABSENCE of a statistically significant difference between
two experimental groups –
Table is NOT requiredResearch Methodology: D Y Patil
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Age wise Prevalence of Anemia
Age (Years) Prevalence of Anemia(%)<8 33.3
9-10 38.510-11 48.511-12 49.812-13 52.913-14 50.214-15 51.215-16 49.316-17 47.817-18 49.218+ 37Total 50.1
Multicentric Study on Adolescent Girls (Gujarat, Mumbai, Delhi)N=150
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Figures
• Better visual impact than Tables in
showing
trends,amounts, frequencies relationship in data
GraphsPhotos
Technical Diagrams
Maps
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#Rule 5:Introduction• Be clear in describing the benefit of the paper• Should be brief (250-600 words)
Interest the reader in your Introduction by signalling all its elements and stressing on its novelty and significance
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Introduction• Structure your introduction using the 3 way
approach:
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Discussion
• Typically should move from specific to general (opposite of introduction)
• In some journals, is followed by a Conclusions section
• In some short papers, is called “Comment” rather than “Discussion”
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DISCUSSION• The Discussion is harder to define than other sections.
Thus, it is usually the hardest section to write.
– Many manuscripts are rejected by journal editors because of a faulty Discussion, even though the data of the paper might be both valid and interesting.
– Many if not , most discussion sections are too long and verbose.
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Structure for Discussion (Steps) of scientific papers.
• Statement of principal findings.
• Meaning of the study finding : Possible mechanisms & implications for clinicians or policymakers.
• Strengths & weaknesses in relation to other studies, discussing particularly any differences in results.
• Unanswered questions & future research.
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Limitations : Part of discussion
– For example: small sample size, short follow-up, incomplete data, possible sources of bias, problems with experimental procedures
– Better to mention limitations yourself than for peer reviewers and readers to think that you’re unaware of them
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Word choice
• Avoid prove.
• Use show, demonstrate, indicate, support, suggest, imply, appear.
• Hedging terms such as may be, might be, could be, probably, possibly may be used as needed, but avoid using too many hedges in one sentence.Research Methodology: D Y Patil
University School of Medicine55
Verb Tenses (active!):
Past, when referring to study details, results, analyses, and background research:
• We found that • They lost more weight than• Subjects may have experienced
Present, when talking about what the data suggest … The greater weight loss suggests The explanation for this difference is not clear. Potential explanations include
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# Rule 6:
Present the implications of principle findings, relationships and generalizations in a concise and convincing tone
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How frequently do editors encounter manuscript problems?
Seldom Occasionally Frequently
Poorly written, excessive jargon
Inadequate/inappropriate presentation
Poor description of design
Excessive zeal and self promotion
Rationale confused, contradictory
Essential data omitted, ignored
Boring
Important work of others ignored
Byrne DW, Publishing Medical Research Papers, Williams and Wilkins, 1998
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Conclusions• After the Discussion section the main conclusions
of the study are summarized.
How to write it• Nothing new is presented here. Each conclusion is based
on previously discussed information.• Each conclusion is brief.• The focus is on importance, validity of results, limitations of
the study.
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# Rule 7
Revise your paper at macrostructure and microstructure level.
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Title• Content of title - Title and short describing subtitle
AuthorsCorresponding authorAffiliation
• When is the best time to choose a title? – After you finish the paper– Must accurately reflect the paper s content and emphasis
• The title must:– Brief & grammatically correct – Complete AND be able to stand alone.
• A good title should be able to let the reader knows content of the paper.
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Oral progesterogen in threatened miscarriage
Efficacy of dydrogesterone versus standard care in threatened miscarriage in an Indian population: a prospective randomized double blind study
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Exactly what are you planning to do?
PICOTP - who are the patients or what’s the problem?
disease or conditionstage, severitydemographic characteristics (age, gender, etc.)
I - what is the intervention or exposure?type of intervention or exposuredose, duration, timing, route, etc.
C – what is the comparison group?risk or treatmentplacebo or other active treatment
O - what is the outcome or endpoint?frequency, risk, benefit, harmdichotomous or continuoustype: mortality, morbidity, quality of life, etc.
T – what time limit ?Research Methodology: D Y Patil
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Key words
• Number – 3-10
• Should select in such a way – that reflect the content of your article
• Necessary for retrieval of published data
• Characteristics – 1) Patient type2) Interventions3) Comparison4) Outcome
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Summary /Abstract• Earlier – Abstracts was short, uninformative, written at the
end
• Now they are at the start of an article.
• Longer, structured or unstructured
• Busy reader – read only abstract and decide
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Abstract• Start with a statement describing the
purpose/problem of the research• Show theoretical/experimental plans used for the
research• Summarize principle findings• Indicate major conclusions• No data evaluation, no references, table, figures• Length: 80 to 300 words (Optimal_1 paragraph)• It should be able to stand on its own and published
separately.• Write it last! Research Methodology: D Y Patil
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• http://www.consort-statement.org/(Schulz KF, Altman DG, Moher D, the CONSORT Group(2010) CONSORT 2010 Statement: updated guidelines forreporting parallel group randomised trials. BMJ 340:c332. )• Amor S, Baker D. Checklist for reporting and reviewing studies
of experimental animal models of multiple sclerosis and related disorders. Multiple sclerosis and related disorders 1. (2012) 111-115
• https://www.nc3rs.org.uk/arrive-guidelines (Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research. PLoS Biol 8(6): e1000412. doi:10.1371/journal.pbio.1000412 )
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887790/
Adv Biomed Res. 2018; 7: 55.
Levofloxacin-containing versus Clarithromycin-containing Therapy for Helicobacter pylori Eradication: A Prospective Randomized Controlled Clinical Trial Vahid Sebghatollahi, Maryam Soheilipour, Mahsa Khodadoostan, Alireza Shavakhi,1 and Ahmad Shavakhi
Background: This study evaluated the clinical efficacy and tolerability of a 14-day course of bismuth-based quadruple therapy including tinidazole and levofloxacin in compare to a 14-day bismuth-based quadruple therapy including clarithromycin as first-line treatment for Helicobacter pylori infection in Iranian adults.
Go to:
Materials and Methods: The study was a prospective, parallel group, randomized controlled, clinical trial that conducted on 150 patients with H. pylori infection. Patients were randomly assigned to the two groups as follows: first group received pantoprazole 40 mg, bismuth subcitrate 240 mg, amoxicillin 1 g, and clarithromycin 500 mg (PBAC group), and other group received pantoprazole 40 mg, bismuth subcitrate 240 mg, amoxicillin 1 g, tinidazole 500 mg for 7 days, followed by levofloxacin 500 mg for the second 7 days (PBATL group). Main outcomes were eradication rate, tolerance of treatment, and dyspepsia severity.
Go to:
Results: The eradication rates for PBAC regimen was 81.1% (95% confidence interval [CI]: 71.9–90.2) and for PBATL regimen was 70.8% (95% CI: 60.1–81.6), which was not significantly different (P = 0.147). Tolerance of treatment was similar between groups. The median of severity of dyspeptic after treatment in PBAC group was 10 [9–14.75], which was similar to PBATL group 10 [9–13.5] (P = 0.690).
Go to:
Conclusion: There is no significant difference between PBAC and PBATL regimen, and efficacy was similar in both groups. The overall rate of treatment failure suggests that up to 18%–30% of patients will fail bismuth-based quadruple therapy and require retreatment for the infection.
Keywords: Clarithromycin, Helicobacter pylori, levofloxacin, tinidazole
Introduction
2
Helicobacter pylorus has been linked conclusively to various disorders of the upper gastrointestinal tract, including peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer.[1,2] Approximately over half of the world's population is reported to have H. pylori infection and depending on the population studied, infects 7% to 87% of adults.[3,4] A global systematic review shows that approximately 4.4 billion people in the world were estimated to be infected with for H. pylori in 2015. This infection is more common in developing countries, and in Asia, 54.7% reported to be positive for H. pylori. In Iran, analyses of reports show that 59% of people were infected by H. pylori.[5]
Choosing a treatment for H. pylori eradication depends on different factors, such as the local availability of antimicrobial agents, the pattern of primary antibiotic resistance, and the therapeutic cost.[3] The most commonly recommended for first-line treatment of H. pylori included 7- to 14-day triple therapy with a proton-pump inhibitor (PPI), amoxicillin, and clarithromycin with cure rates of 80%–90%.[6,7] These rates were reported for many years ago, and studies from different parts of the world have raised some important concerns about the current success of this regimen, especially with regard to increasing clarithromycin resistance.[8,9] Thus, bismuth-containing quadruple therapy is recommended as first-line treatment for the eradication of H. pylori infection in regions with a high clarithromycin resistance rate. In Iran with increasing in clarithromycin resistance rate, bismuth-containing quadruple therapy has been strongly recommended.
Levofloxacin and tinidazole have been shown to be effective for the treatment of H. pylori infection, and some studies have also shown that these drugs are effective as the first-line treatment for H. pylorieradication.[10,11,12] The optimal duration for H. pylori eradication therapy is controversial, with recommendations ranging from 7 to 14 days whereas the duration of therapy with the pattern of H. pyloriantibiotic resistance, and the patients’ compliance is known as the main factors in the success rate of eradication regimens.[13] In regard to the high resistance to metronidazole and clarithromycin in patients infected by H. pylori in Iran and controversial findings on the therapy, the present study was designed to investigate effective treatment duration for 14-day bismuth-based quadruple therapy including tinidazole (for 7 days), followed by levofloxacin (for 7 days) in compare to 14-day bismuth-based quadruple therapy including clarithromycin by comparing eradication rate, compliance, and adverse event rate between the regimens as first-line treatment for H. pylori eradication.
Go to:
Materials and Methods The study was a prospective, parallel group, randomized controlled, clinical trial that conducted on 150 patients, referrals to the gastroenterology clinics of Isfahan University of Medical Sciences (IUMS) from February to November 2016. Ethical approval was obtained from the Research Ethics Committee of IUMS before recruitment.
One hundred fifty consecutive patients were included in the study according to the following inclusion criteria: (1) patients in both genders with age 18 and over and (2) patients with peptic ulcer disease. H. pylori infection was confirmed by serologic and gastric tissue. The participants with known gastrointestinal malignancy, MALT lymphoma, Zollinger–Ellison syndrome, immunodeficiency disorders, liver or renal diseases, clinical conditions that need antibiotic therapy, history of gastric surgery, and history of H. pylorieradication or using PPI, antibiotic, or probiotics within 4 weeks before the study and pregnant women were not included in the study. The exclusion criteria were serious side effects that require immediate
3
discontinuation of therapy. Furthermore, patients who did not use their study medications regularly were excluded from the study.
All eligible patients were voluntary and gave written informed consent to participate in the study. The sampling method was consecutive, and randomization was performed by generating a random list of patient allocations before the start of intervention, by Random Allocation Software.
Enrolled patients were randomly assigned to one of the two equal groups. Group I (PBAC) had 75 patients who received treatment regimen included pantoprazole 40 mg, bismuth subcitrate 240 mg, amoxicillin 1 g, and clarithromycin 500 mg; all given twice daily (q12 h) for 14 days. Group II (PBATL) had 75 patients who received treatment regimen included pantoprazole 40 mg, bismuth subcitrate 240 mg, amoxicillin 1 g, twice/day for 14 days, tinidazole 500 mg twice daily for the first 7 days, followed by levofloxacin 500 mg daily for the second 7 days.
Collected data included age, sex, dyspepsia symptoms, medicinal effects of each regimen (bad taste, nausea, bloating, diarrhea, constipation, skin rash, and epigastric pain); intolerance of treatment which was assessed at the end of treatment as none, mild, moderate, and severe; and eradication rate. To assess the eradication rate of H. pylori in studied patients, 13C urea breath test with 94% of sensitivity and 95% of specificity, respectively, was use 1 month after the end of treatments.[14] Dyspepsia severity was evaluated by the short-form leeds dyspepsia questionnaire (SFLDQ), which evaluates frequency and interference of four symptoms including epigastric pain/discomfort, retrosternal burning, regurgitation, and nausea. The total score of the SFLDQ ranges from 0 to 32 and was completed by patients in both groups at baseline and after treatment.[15]
Statistical analyses were done using SPSS software for Windows (SPSS, Inc., Chicago, IL, USA, version 24). Descriptive data are reported as mean ± standard deviation, median (IQR), or number (percent) as appropriate. Independent sample t-test, Chi-square test, Mann–Whitney U-test, Wilcoxon signed-rank test, and analysis of covariance (ANCOVA) were used as appropriate. All hypothesis testing was two tailed, and level of significance was considered to be <0.05 in all tests.
Go to:
Results One hundred sixty patients were reviewed to selected eligible patients; ten patients did not enter (nine refused informed consent and one was not eligible). One hundred fifty eligible patients randomly allocated into two intervention groups. Four patients were lost during follow-up period. Finally, 74 patients in PBAC group and 72 patients in PBATL group completed the study and analyzed [Figure 1].
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Figure 1
Flow diagram of patient's recruitment
The mean age of studied participants was 47.3 ± 12.8 years; 44.5% (65 patients) were male and 55.5% (81 patients) were female. Other demographics and clinical characteristics of the participants by treatment regimens are shown in Table 1.
Table 1
Demographic and clinical characteristics of studied population by intervention groups
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As shown in Table 2, there has been significant reduction in the LDQ score in both regimens. The result of ANCOVA was not found any difference between groups.
Table 2
The summary results of both frequency and severity of dyspeptic symptoms based on Leeds dyspepsia questionnaire score according to treatment regimens
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There was no significant difference of H. pylori eradication rates between the studied regimens. The eradication rate for PBAC regimen was 81.1% (95% confidence interval [CI]: 71.9–90.2) and for PBATL regimen was 70.8% (95% CI: 60.1–81.6) (P = 0.147).
In this study, overall HP eradication rate was significantly associated with age. The whole observations indicate that younger patients had a significantly better response [Table 3 and Figure 2]. However, there was no significant difference between the regimens by age for the H. pylori eradication rates (P > 0.05).
Table 3
Helicobacter pylori eradication in studied population by age group
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Figure 2
Overall Helicobacter pylori eradication in studied population by age group
Go to:
Discussion In this study, PBAC regimen included 14-day treatment with bismuth, amoxicillin, clarithromycin, and pantoprazole which was associated with higher rates of H. pylori eradication in compare to PBATL regimen included 14-day treatment with bismuth, amoxicillin, tinidazole (followed by levofloxacin in the second 7 days), and pantoprazole. Eradication rate for PBAC regimen was 81.1% and for PBATL regimen was 70.8%, which did not significantly differ between groups. There is no significantly different for adverse event between groups, and both studied regimens were well tolerated based on patients’ reports in two studied groups. The rates of eradication in our studied regimens were low, and according to Graham classified efficacy of H. pylori treatment,[15,16] success rate in PBATL regimen is poor and for PBAC regimen is unacceptable. The lower rate of eradication in our study might be related to the prevalence of antibiotic resistant of H. pylori strains in our studied patients, where we did not assess pretreatment antibiotic resistant in these patients.
In a meta-analysis, it is reported that sequential therapy was superior to a 7-day standard triple therapy regimen, but when compared with a longer duration of standard triple therapy, the difference disappeared.[17] In the other studies, the duration of sequential therapy has been assessed to determine whether longer therapy will help improve the eradication rates of H. pylori infection. In Warrington et al. study, it is shown that regardless of the treatment duration, sequential regimens are not better than standard triple therapy. In this study, the eradication rate was 83.7% in the standard triple therapy, 80.0% in the 10-day sequential therapy, and 79.1% in the 14-day sequential therapy regimen.[18] In a large study by Liou et al., it is suggested that longer therapy with a sequential regimen would provide better eradication rates. In these study for 10- and 14-day of sequential therapy, the eradication rate of 90.7% and 87.0% is reported, respectively, and in a 14-day standard triple therapy group,
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the eradication rate was 82.3%.[19] In Ergül et al.'s study, eradication rate of 90.7% is reported for a 14-day bismuth-containing quadruple therapy as first-line therapy.[20] Su et al. in their study showed an eradication rate of 80.2% and 89.7% for 1-week two regimens of bismuth-based quadruple-containing clarithromycin or levofloxacin, respectively.[21] One study in Iranian patients reported 82.3% of eradication rate of H. pylori for quadruple therapy after 2 weeks.[22] In another report from Iran, after 10-day quadruple therapy, eradication rate was 84.0%.[23] In the Mousavi et al. study, 14 days of bismuth-based quadruple regimen had eradication rate of 75.7%.[24] Aminian et al. reported 85.7% of H. pylori eradication rate after 4 days of bismuth-based quadruple with metronidazole.[25] In a randomized clinical trial, Metanat et al. evaluated 10- and 14-day nonbismuth-based quadruple regimen for H. pylori treatment and reported eradication rate 83.5% and 92.8% for studied regimens, respectively.[26] In the present study, in both bismuth-based quadruple therapy, eradication rates were lower than reported previously (81.1% for PBAC regimen and 70.8% for PBATL regimen). The prevalence of antibiotic resistance, differences in the studied regimens, and does of drugs might be explain the differences between study findings.
In the present study, the eradication rate was decreased with increase in age group; patients in older age group had a lower rate of eradication though this difference was not statistically significant. In other study, in Iran, it is reported that patients’ age and gender are associated with H. pylori eradication rate.[22] Another study reported that occupation, gender, and protocol compliance were positively associated with H. pylori eradication rate.[27] Silva et al. report a significant association between age and H. pylorieradication rate but did not report a significant difference between patients’ characteristics and eradication rate.[28]
The present study has some limitations. First is the lack of any analysis of antibiotic resistance relative to the eradication rates and treatment regimens, whereas antibiotic resistance is known as the most important cause of treatment failure. Second, this trial was not a double-blind placebo-controlled trial in which the detection bias was minimized. Third, this study was a single-center study and its results need to be externally validated.
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Conclusion This randomized trial showed that a 14-day bismuth-based quadruple regimen-containing amoxicillin, tinidazole (followed by levofloxacin in the second 7 days), and pantoprazole is statistically effective as well as 14-day bismuth-based quadruple regimen-containing amoxicillin, clarithromycin, and pantoprazole in the eradication of H. pylori infection, and there is no significant difference between PBAC and PBATL regimens. The overall rate of treatment failure suggests that up to 18%–30% of patients will fail bismuth-based quadruple therapy and require retreatment for the infection. More studies are needed to draw meaningful conclusions for optimal duration of H. pylori eradication regimens.
Financial support and sponsorship
This study was supported by a grant from Isfahan University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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Acknowledgments This study was supported by a grant from Isfahan University of Medical Sciences.
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14. Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection – The maastricht IV/florence consensus report. Gut. 2012;61:646–64.[PubMed]
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Basic Workshop on RESEARCH METHODOLOGY 2019 Name: ……..………………………. (optional)
1
Pre / Post - TEST No. ITEM (Please tick appropriate) 1. In the FINER criteria for assessing the research question “I” stands for
A. Innovative B. Interesting
C. Inspiring D. Inclination
2. The authority to whom permission for conducting a clinical is to be asked for in India is A. Director, Indian Council of Medical Research B. Director General Health Services C. Drug Controller General of India D. Chairman, Medical Council of India
3. Among the following types of studies which one can be a “Hypothesis generating study?” A. Clinical trial
B. Case control study C. Cohort study D. Cross sectional study
4. Sampling frame is nothing but describing the A. Sampling method B. Procedure of calculating sample size
C. Population itself D. Inclusion & exclusion criteria
5. Making estimate about dependent variable from the independent variable for values beyond the observed range of independent variable is:
A. Interpolation B. Extrapolation
C. External validation D. Internal validation
6. The drawback/s of the open-ended question is/ are A. Likely hood of blanks B. Time consuming for coding C. Neither A nor B D. Both A & B
7. Harvard and Vancouver are the names for styles of A. Questionnaires B. Protocol writing C. Reference citation D. Sampling
Basic Workshop on RESEARCH METHODOLOGY 2019 Name: ……..………………………. (optional)
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No. ITEM (Please tick appropriate) 8. Focus group discussion is a tool/ method used for
A. Qualitative research B. Quantitative research C. Questionnaire designing D. Sampling
9. Ability of a test to detect disease in those who have it is its A. Sensitivity
B. Specificity C. Predictive power of positive test D. Predictive power of positive test
10. In Likert type of questions (in questionnaire) respondent is asked to indicate: A. How much he/she agrees with the statement B. Which of the statements he/she agrees C. Rank order of the statement D. Correct/ false answers.
11. One type of medical research in which informed consent may not be required and may not be feasible is
A. Survey B. Case control study C. Cohort study D. None of the above
12. For testing the hypothesis about disease causation of a rare disease, the epidemiological study of first choice is
A: Cross sectional study B: Case control study
C: Cohort study D: Experimental study
13. The theoretical range of sensitivity of a screening test when compared with gold standard is A: Zero to one B: Minus 1 to plus 1 C: Zero to infinity
D: 1 to 100
14. For testing etiological hypothesis for a disease wherein you want to test more than one cause (risk factor) the epidemiological study of choice will be
A: Cross sectional study B: Case control study
C: Cohort study D: Experimental study
Basic Workshop on RESEARCH METHODOLOGY 2019 Name: ……..………………………. (optional)
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No. ITEM (Please tick appropriate)
15. When information in qualitative study is validated by collecting it from more than one source, it is called
A. Duplication B. Triangulation
C. Confirmation D. None of the above
16. In questionnaire, the type of questions that do not have a preset answer and respondent is provided with a blank space for response are called:
A. Close ended questions B. Open ended questions
C. Likert type of questions D. Babbie format style questions
17. In a class, students’ height does not show much variation. For this variable the population will be considered as
A: Homogenous B: Heterogenous C: Dynamic D: Static
18. Data of 1000 patients is grouped into 3 groups as per severity of anemia: mild, moderate and severe and is presented in tabular form. What is the scale of measurement here?
A. Nominal B. Ordinal
C. Interval D. Ratio
19. In a hospital, due to turnover, patients stay for a brief period only. As such the age/sex structure of patients shows variation over time. Thus, for these variables this will be
A: A homogenous population B: A heterogenous population C: A dynamic population D: A static population
20. In statistics, the word "Parameter" refers to A: The constant that describe population characteristic B: The constant that describe sample's characteristic C: A property of normal curve D: A measure of variation used in advanced statistics
Basic Workshop on RESEARCH METHODOLOGY 2019 Name: ……..………………………. (optional)
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No. ITEM (Please tick appropriate) 21. Median is almost equal to ……….. percentile.
A: 25 th B: 50 th
C: 80 th D: 90 th
22. In clinical trial "Reference Population" is the population A: To which the results of the study are applicable B: Which actually participates in the trial C: Which receives new drug being tested D: None of the above
23. As per ICMR guidelines, the responsibility of screening of the research proposals coming to institutional ethics committee is assigned to:
A. Chairman B. Secretary
C. Medical expert in the group D. Legal expert in the group
24. You are planning a clinical trial and you want to search if similar trials are planned anywhere in world. The best and authentic source for this information is:
A. World Health Organization: www.who.int/clinical trials B. Pubmed: www.ncbi.nlm.nih.gov/pubmed/clinicaltrials C: US National Institute of Health www.clinicaltrials.gov D: Google: www.google.com/ clinical trials
25. Assigning alphabetical/ numerical identifiers to responses from respondents in a questionnaire is:
A. Data editing B. Data reduction
C. Data coding D. Data embedding
26. Triangulation is a method of - A. Data collection B. Data presentation
C. Data validation D. Data analysis
27. In clinical trial "Study Population" refers to the population - A: To which the results of the study are applicable B: Which is eligible to participate in the trial C: Which receives new drug being tested D: None of the above
Basic Workshop on RESEARCH METHODOLOGY 2019 Name: ……..………………………. (optional)
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No. ITEM (Please tick appropriate)
28. According to ICMR guidelines a new drug is defined as - A. a new chemical entity (NCE); B. a drug which has been approved for a certain indication, by a certain route, in a certain
dosage regimen, but which is now proposed to be used for another indication, by another route, or in another dosage regimen
C. Both A & B D. Neither A nor B
29. A table in which first column represents labels (names) of groups and second column represents the number corresponding to each group is
A: Simple table B: Frequency distribution table C: Master table D: Two by two table
30. When testing the association of one cause (Risk factor) with two or more diseases (or outcomes) is the objective of the study, the epidemiological study of first choice is
A: Descriptive study B: Case control study
C: Cohort study D: Experimental study