introduction to clinical protocol

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Introduction to Clinical Protocol

Topics To be Covered What is Protocol Protocol Outline Protocol Design Study Procedure Informed Consent process Subject Confidentially Data Recording GCDMP Data Management Plan Data Capture

Data Quality Assurance Data Validation Query Management Plan Best Practice for CRF Statistical Analysis Data Locking Appendices / Supplements Conclusion


Protocol• A protocol is a document that states the reasoning

behind and structure of a research project

• Protocol also defined as a document that describes the background, rationale, objectives, design, methodology, statistical consideration and organization of trial

• The Study protocol can be viewed as a written agreement between the investigator , the participants and the scientific community


Protocol OutlineA typical protocol has the following elements:

• Title Page• Objectives• Signature Page• Study Design• Background Information and scientific rationale• Study Population


Protocol Design

• Study Procedure• Informed Consent process• Statistical Considerations• Literature References• Subject Confidentiality• Supplements / Appendices


Title Page1. Title pages introduce the document, their title,

precise number, sponsor and author to the reader• Protocol title, protocol identifying number, and

date• Any amendments should also bear the amendment

number and date• The protocol number must clearly indicate the

version number, whether it is final or draft and date of this version


Continue…Elements

Full title should include:

1. Summary study design

2. Medicinal products3. Nature of the

treatment (ex: treatment, prophylaxis and diagnosis)

4. Comparator

5. Placebo6. Indication 7. Patient population8. Setting (ex: in-

patient, outpatient)9. Randomized 10. Double Blind11. Multiple Studies


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2. Name and address of the sponsor and monitor. Sponsor names and list of responsibilities with agreed allocations

3. Name and title of the person authorized to sign the protocol and the protocol amendments for the sponsor. Generally, Chief Investigator for multiple center trials or Principal Investigator for single center trials

4. Name, title, address and telephone number of the sponsor medical expert for the trial


Continue…5. Name and title of the investigator who is responsible for

conducting the trial, and the address and telephone numbers of the trial site

6. Name, title , address and telephone number of the qualified physician who is responsible for all trial site related medical decisions

7. Name and address of the clinical laboratory and other medical and /or technical department and /or institution involved in the trial


Protocol Summary/Synopsis

• This summary should be only one to two pages long

• It should give the reader sufficient information to understand the rationale for the trial, its objective and the methods that will be used to achieve these objectives


Study Objective/Aims• A clinical trial often has both primary and

secondary objective, and these should be identified as such in the protocol

• Ideally, no more than 1 or 2 of each should be included in a clinical trial


Signature Page• Signature page of the healthcare professional in the

trial including contact details of participating site, sponsor and sponsor medical advisor if not already given above.


Content Page

• This helps navigating through the document by large number of different people that will be needed throughout the life of the trial


Study DesignA description of the trial design should include:

1) A description of the design of trial to be conducted ex: double blind, placebo controlled, parallel design

2) A description of the measure taken to minimize/ avoid bias

A) RandomizationB) Blinding


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3) A description of the trial treatment and the dosage and dosage regimen of the IP. Also, include a description of the dosage form, packaging and labeling of the IP

4) The expected duration of subject participation , and description of the sequence and duration of all trial periods, including follow up any.

5) A description of “stopping rile” or “Discontinuation Criteria”


List of Abbreviation• All abbreviations used should be listed and defined

• Accepted international medical abbreviations should be used

• Project specific abbreviations should be standardized with each project


Compliance Statement

• The protocol should include a trial statement with the protocol, GCP and the applicable regulatory requirements


Background Information• Name and description of the investigational product

• A summary of finding from nonclinical studies that potentially have clinical significance and form clinical trials that are relevant to the trial

• Summary of the known and potential risks and benefits, if any, to human subjects

• Description and justification for the route of administration, dosage, dosage regimen and treatment period


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• Description of the population to be studied

• In short, the data in this background information should be able to justify the need for this study


Selection and Withdrawal of Subjects1. Subject Inclusion Criteria

2. Subject Exclusion Criteria

3. Subject Withdrawal Criteria


Treatment of Subjectsi) The treatment to be administered, including the

name of all the products, dose, the dosing schedule, the route/mode of administration and the treatment period

ii) Medication/ treatment permitted and not permitted before and/ or during the trial.

iii) Procedure for monitoring subject compliance


Assessment of Safetyi) Specification of safety parameters

ii) The methods and timing for assessing, recording, and analyzing safety parameters

iii) Procedure for eliciting reports of and recording and reporting adverse event and inter current illnesses


Direct Access to Source Data Document

• Sponsor ensures that it is specified in the protocol or other written agreement that the investigator will permit trial related monitoring, audits, IEC review, and regulatory inspection by providing direct access to source data/documents


Informed Consent• Defined as: a patient is being given adequate

information about a clinical trial; understanding and voluntarily accepting the terms of a clinical trials and agreeing to cooperate in its conduct


The following slides are the key concepts to be considered while designing the protocol, which impact the Clinical Data Management

1. Data Recording2. Data Quality Assurance3. Statistical Analysis Plan


Data Handling and Record Keeping

• Indicate how data will be collected. If detailed instructions have been prepared, specify their location (study manual, appendix)

• Discuss the use and management of source documents• Discuss the procedure for correcting errors

1. GCDMP2. Data Management Plan3. Data Capture4. CRF


1. Good Clinical Data Management Practices◦ Provides assistance to clinical data managers in their

implementation of high quality Clinical Data Management processes

◦ Used as a reference tool for clinical data managers◦ Review and approval of new medications or medical

devices◦ Clinical and laboratory information must be collected and

converted to digital form for analysis and reporting purposes

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2. Data Management Plan◦ Record all the most important information on how data

management was carried out for a study◦ The documents are more accurate when written at the start

of the study◦ Provides a focus for identifying the work to be performed,

who will perform the work, and what is to be produced as documentation of the work



2. Data Management PlanContinued…

◦ Touches the elements of the data management process for the study in question

◦ Becomes an approximate table of contents◦ Used as a source document for internal quality assurance

audits



3. Data Capture

Electronic Data Capture◦ EDC systems deliver clinical trial data from the investigation sites to the

sponsor◦ Eliminates the need for double-key data entry◦ Data management planning and implementation are completed even

before data entry is initiated EDC systems are improved for site activities during a

clinical trial



4. Best Practice for CRF A tool used to collect pre- defined data from a subject in a

clinical trial◦ Design the CRF along with protocol◦ Keep questions, prompts and instructions clear and concise◦ Design the CRF to follow the data flow from the perspective of the

person completing it◦ Avoid referential and redundant data points within the CRF◦ Design the CRF with the primary safety and efficacy endpoints in mind◦ Establish and maintain a library of standard forms◦ Make the CRF available for review at the clinical site prior to approval



Describe procedures for assessing subject compliance Discuss source document review• Provide assurance on good clinical practice, quality of data

collection and refer to monitor and their role

1. Data Validation2. Query Management

Data Quality Assurance


1. Data Validation Important role within the drug development program

involving many people, multiple systems, and several data transfers

Automated and manual procedures to detect missing entries, illogical data

Ensures Data accuracy and Completeness Helps to inform Data Managers about data issues in timely

fashion Once data validation is completed it is time for Data

Treatment stage



1. Data ValidationContinued…

Factors affecting the quality of data1. CRF design2. Field Monitoring Guidelines3. Source data verification4. Missing data/ CRF pages5. Data conventions6. Electronic laboratory data



2. Query Management Performance metrics are tracked routinely and analyzed

periodically to ensure maintenance of the highest data management quality standards

All discrepancies are identified automatically by the system that are reviewed by a data manager

These are resolved internally through inspection of the CRF



2. Query ManagementContinued…

Following actions can be taken based on project specific guidelines◦ Closing discrepancy per internal connection◦ Generating a query to the investigator

Creating queries Sending queries Tracking queries Resolving queries Re-quering



2. Query ManagementContinued…

Turning a discrepancy into a query Resolving queries Applying the Resolution Quality assurance and control



It is critical to specify in the protocol the precise definition of the primary variable as it will be used in the statistical analysis.

Oversees the processes that group, summarize, analyze, and otherwise present trial data for clinical interpretation

Statement of the planned sample size Classification of the study variables Information about the timing and purpose of any planned interim

analysis Handling of missing or non- evaluable data


Statistical Analysis Plan

1. Data Locking Once the patient’s data has been collected, the study needs to

be locked in an expeditious manner The list involves many steps:

◦ Collecting final data ◦ Resolving outstanding queries◦ Reconciling against other databases◦ Performing final QC

After these tasks are done, data manager reviews with the clinical group and the study is considered locked- no data will be changed, from the first patient in through to database lock


Statistical Analysis Plan

AppendicesBased on the protocol, relevant appendices as elaborated should be attached:

• Summary of Product characteristics, data sheer for IP

• Measurement tools and their validation

• Pharmacy information, shelf lives, dispensing procedure

• Methods for collecting patient samples, their storage, dispatch and handling conditions


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• Clinical labs and tests• Adverse reaction grading systems for particular

safety parameters• Scoring systems of efficiency parameters• Analysis diagram• Declaration of Helsinki• Patients and parent/legal guardian consent form• Subject information sheet for informed consent• Method of recruitment of patients/subjects to the

trial



Conclusion• Protocol is a blue print for a study. It contains all the information

necessary• Certain Information is required by regulation to be into protocol• The following are the key points that follow Data Management

Protocol:1. Data Recording

• GCDMP• DMP• Data Capture• CRF Practices

2. Quality Assurance• Data Validation• Query Management

3. Statistical Analysis• Data Locking


Thank YouFor queries or questions, please email at [email protected]

introduction to clinical protocol

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study protocol

protocol amendments

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typical protocol

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