Safety Workshop: Part IClinical Trial Safety and Safety Monitoring

Safety Workshop: Part IClinical Trial Safety and Safety Monitoring

Ling Chin, MD, MPHNIAID/DAIDS/Office of Policy for Clinical Research Operations

Durban, South AfricaMay 13, 2011

Ling Chin, MD, MPHNIAID/DAIDS/Office of Policy for Clinical Research Operations

Durban, South AfricaMay 13, 2011

ObjectivesObjectives

At the conclusion of this workshop, participants will be able to demonstrate an understanding of:

• Clinical research involving human subjects• Current context regarding safety in clinical trials• The concept of safety and safety monitoring and how it

relates to clinical trials research • Protocol requirements pertaining to areas relevant to safety• Key roles and responsibilities related to safety• Safety and adverse event terminology• Expedited reporting of adverse events

2

Objectives - continuedObjectives - continued

• Assuring safety in clinical trials

• The adverse event life cycle

• What makes a well-documented adverse event, including a comprehensive narrative

• How to assess an adverse event case, including causality assessment

3

History of research involving humansHistory of research involving humans

• 1747: Lind: first recorded clinical trial: British Navy surgeon, evaluated 6 different interventions on 12 sailors for the treatment of scurvy

• 1897: Sanarelli: discovered bacillus of yellow fever, produced yellow fever in 5 patients

• 1898: Osler: “To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal”

• 1901: Walter Reed: yellow fever research that included: Self-experimentation, Written agreements with other subjects, Payment in gold, Restriction to adult subjects, Using the phrase “with his full consent”

• 1939-45: Nazi medical war experiments

• 1938-72: Tuskegee Study of Untreated Syphilis in the Negro Male

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1966

International Covenant onCivil and Political Rights.Article on humanexperimentation.Codified and adopted by UNGeneral Assembly.

1964

Declaration of Helsinki.Ethical Principles to guide physicians.By World Medical Association.

1948

Universal Declaration ofHuman Rights.As common standard forhuman rights.By UN General Assembly.

1947

Nuremberg Code.Basic Principles forresearch-Firstinternat'l standard.Judgment by warcrimes tribunal atNuremberg - TheDoctor's Trial.

Timeline

1995

Guidelines forGood ClinicalPractice (GCP)for Trials onPharmaceuticalProducts.Standard fordesign, conduct,monitoring ofclinical studies.By WHO withMember StatesAdopted by ICH.

1982

International EthicalGuidelines forBiomedical ResearchInvolving HumanSubjects.By Council for InternationalOrganizations of MedicalSciences.

1979

Belmont Report.3 Ethical Principles of Respect,Beneficence, Justice.National Commission for theProtection of Human Subjectsof Biomedical and BehavioralResearch.

Timeline

5

History of research involving humansHistory of research involving humans

Regulations: Federally Supported Research Involving Human SubjectsRegulations: Federally Supported Research Involving Human Subjects

45 CFR 46: Protection of Human Research Subjects

• Applies to all research involving human subjects• Institution must provide assurance of compliance, such as a

Federal Wide Assurance (FWA) on file with the Office for Human Research Protection (OHRP)

• FWA provides assurance that research is conducted in accordance with the regulations• Research reviewed and approved by IRB• Subject to continuing review by IRB

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Regulations: Non-Federally Supported Studies Involving Human SubjectsRegulations: Non-Federally Supported Studies Involving Human Subjects

21 CFR 50: Protection of Human Subjects• Clinical investigations regulated by FDA • Requirements for informed consent

• Elements of informed consent• Documentation of informed consent

• Form approved by IRB

21 CFR 56: Institutional Review Boards• Clinical investigations regulated by FDA • Requirements for IRB review

• Membership, functions, review procedures, etc• Criteria for IRB approval

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NIH ResearchNIH Research

• Must comply with regulations pertaining to research involving human subjects, investigations of new drugs, biologics, or devices, or new indications, or use in new populations

• HHS, OHRP

• FDA

• Must adhere to NIH and Institute Policies for clinical research and conduct of clinical trials

• Additional monitoring bodies: Network-specific clinical safety monitors/groups, IRBs, DSMBs

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IRB ReviewIRB Review

• Initial and continuing review• At convened meetings (at intervals appropriate to level

of risk; not less than 1/year)• Majority of members are present; Approval by majority• Approval of Informed Consent• Unanticipated problems involving risks to human

subjects or others• Any instance of serious or continuing non-compliance

with regulations, requirements, or determinations of the IRB

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IRB Review: Approval CriteriaIRB Review: Approval Criteria

• Risks to subjects are minimized:i. By using procedures consistent with sound research

design which do not unnecessarily expose subjects to riskii. Whenever appropriate, by using procedures already

being performed for diagnostic or treatment purposes

• Risks to subjects are reasonable in relation to anticipated benefits, and the importance of the knowledge that may reasonably be expected to result

• Other criteria 45 CFR 46.111 or 21 CFR 56.111

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Safety Monitoring CommitteeSafety Monitoring Committee

Internal process, NOT independent

Members include DAIDS MO, DMC clinical affairs safety associates, Protocol Co-chairs, Protocol Study Physician

Review safety events as study is ongoing

• Review of AEs at stated frequency e.g. monthly

• Assure reportable events are submitted to DAIDS

• Address safety concerns e.g. if safety rules are met (a-priori specification)

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Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)

• Government agencies e.g. NIH and the VA, have required the use of DSMBs in certain trials

• Current FDA regulations, impose no such requirements except under 21 CFR 50.24(a)(7)(iv) for research studies in emergency settings in which Informed Consent is excepted

• Independent group

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• Group of individuals with pertinent expertise; reviews accumulating data from one or more ongoing clinical trials:• Clinicians with expertise in relevant clinical specialties• At least one biostatistician knowledgeable about statistical methods

for clinical trials and sequential analysis of trial data• A medical ethicist, and/or patient advocate• Other scientific areas: toxicologist, clinical pharmacologist,

epidemiologist

• Advises the sponsor:• Continuing safety of trial subjects and those to be recruited• Continuing validity and scientific merit of the trial

• 2 important considerations: Confidentiality, COI.• Knowledge of interim results could influence conduct of the trial

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Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)

PerspectivePerspective

Differing viewpoints on safety requirements:

Impose a burden on investigators

• Cumbersome bureaucratic hindrance

• Holds back pace of science

• Delays availability of new or much needed treatments

Represent only a minimal standard

• What is at least reasonable, practical

• Not what would be most ideal

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• Participants in research are voluntary• Placed their faith in the investigators

• Participation is a gift in the service of the public interest

• Investigators must not betray the public trust• Must conduct trials with ethical and scientific integrity

• Must implement high standards for human subject protections

• Must assure participant well-being and safety at all times

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PerspectivePerspective

Current Safety EnvironmentCurrent Safety Environment

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• Increasing public demands for safety data• Fast track approvals• Post-market events leading to changes in labeling e.g. additonal

precautions, black box warnings

• Food and Drug Administration Amendments Act of 2007 (FDAAA): Provides FDA with additional requirements, authorities, and resources with regard to both pre- and postmarket drug safety

• Global reporting to EMA and regulatory agencies of European Union (EU) member states, other countries throughout the world

• New Final Rule 21 CFR 312.32: focus on signal detection (only submit evidence-based Serious Unexpected Suspected Adverse Reactions), encourage noise reduction (less submission). Sponsor and investigator responsibilities to report.

Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies

Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies

SCHARP

Safety MonitoringSafety Monitoring

Roles and Responsibilities – Site InvestigatorRoles and Responsibilities – Site Investigator

Roles and Responsibilities – Research StaffRoles and Responsibilities – Research Staff

Roles and Responsibilities – Study Clinician/PhysicianRoles and Responsibilities – Study Clinician/Physician

Assurance of Safety and Well-Being:Research vs. Medical RolesAssurance of Safety and Well-Being:Research vs. Medical Roles

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Emergency intervention vs. Non-emergency care• Acute on-site management, as necessary, and per site

SOP• Referral to care when stable

Research provisions vs. Clinical care• Provide interventions permitted by the protocol• Follow protocol specifications for toxicity management • Beyond protocol specifications, refer out for clinical care

Clinical Role vs. Research RoleClinical Role vs. Research Role

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Balancing Both RolesClinical Role: Subject OK Research Role: Study/Data OK

• Is subject in imminent jeopardy?

• Provide appropriate management commensurate with clinical situation, e.g. toxicity management

• Provide appropriate referral: emergent care or back to regular care

• Follow up with subject status

Not Subject’s Primary Clinician

• Identification of adverse event

• Immediate notification necessary? To whom? [per protocol and safety monitoring plans]

• Complete documentation of adverse event. Follow until resolution/stability including updating records

• Determine if AE meets criteria for SAE

• Adhere to reporting requirements

• Adhere to toxicity management as specified

• Adhere to stopping rules as specified

Therapeutic MisconceptionTherapeutic Misconception

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• Subjects think they are receiving proven interventions, per their usual clinical care, despite participating in a research study• Informed Consent Process must not be trivialized or

relegated to administrative status• Check for understanding• Time for questions, making decision

• Physicians think they can provide interventions, per usual practice• Strict adherence to protocol provisions for care, toxicity

management• Decide if subject can continue in study

Roles and Responsibilities – Study Clinician/PhysicianRoles and Responsibilities – Study Clinician/Physician

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Study product: Per site, per study?

Study status: Safety pause, clinical hold, early termination?

Study product:

Dose held, changed,

or discontinued?

Study participation:

Continue, withdraw?

Action taken with Study product

after AE

Subject Study

Roles and Responsibilities – Study TeamRoles and Responsibilities – Study Team

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Safety: Ensure safety and well being of subjects at all times• Monitor safety across all study sites• Review all safety data at specified intervals• Discuss need for change(s) driven by safety

Data: Ensure data integrity to assess the risks/safety profile of the study intervention• Data capture; especially safety data• Be cognizant of expedited reporting requirements for safety data

Roles and Responsibilities – Study Team vs. Sponsor/RSCRoles and Responsibilities – Study Team vs. Sponsor/RSC

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• Safety monitoring by study team• Acute on-site management and discussion with study team

• Periodic review by study team and monitoring committees• Data generated by Data Management Centers (DMC)

• Expedited reporting to sponsor/RSC• SAE sent to RSC

• RSC is not part of discussions that occur within study/safety monitoring teams regarding the event

• The RSC only has information about the event from the SAE Form; site should include relevant information from study team discussions

• RSC processes event and sends queries to site to obtain additional information

• All follow-up information should be provided to RSC

28Joshua Tree National Park in Southern California

Safety Monitoring EnvironmentSafety Monitoring Environment

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IND Trials: Pre-market Postmarket

OHRP 45 CFR 46 OHRP 45 CFR 46

FDA 21 CFR Part 312 – IND21 CFR 312.32 (IND Safety Reports)21 CFR 312.33 (Annual Reports)21 CFR 812.150 (IDE Reports)

21 CFR Part 314 - NDA

21 CFR 314.80 (Postmarketing)21 CFR 314.98 (Generics)21 CFR 600.80 (Biologics)21 CFR 803 (Medical Devices)

ICH E2A (Oct 1994) ICH E2D (Nov 2003)

NIH Policy NIH Policy

Country/State Regulations Country/State Regulations

IRBs/ECs IRBs/ECs

Sponsor Sponsor

ICH: E Documents on SafetyICH: E Documents on Safety

Clinical Safety

• ICH E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions

• ICH E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

• ICH E2B – Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

• ICH E2C – Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs

• ICH E2D – Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

• ICH E2E – Pharmacovigilance Planning

• ICH E2F – Development Safety Update Report

Good Clinical Practice

• ICH E6 – Good Clinical Practice

30http://www.ich.org/cache/compo/276-254-1.html

Drug Development Model:Safety Data Flow in Clinical TrialsDrug Development Model:Safety Data Flow in Clinical Trials

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Subject Enrolled

AE Reported

Record AE*Yes

SAE?

To Sponsor

Record SAE**

To IRB

To FDA

To other

Follow until Resolutionor Stability

Outcome: Resolved/

Stable?

Update SAE

No

Adverse Event FlowchartAdverse Event Flowchart

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Subject Enrolled

AE Reported

Record AE*Yes

SAE?

To Sponsor

Record SAE**

To IRB

To FDA

To other

Follow until Resolutionor Stability

Outcome: Resolved/

Stable?

Update SAE

No

Adverse EventAdverse Event

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* Protocol specifications for AE• When to collect e.g., study visit• Method of collection e.g., in person, telephone call• What to collect e.g., all AEs, only certain AEs by body system,

only certain AEs by severity• What forms to use e.g. AE CRF, study CRFs

** Protocol specifications for SAE• Criteria• Expedited time frames• Reporting form (e.g. SAE)

Documentation Differences Between AE CRF and SAE FormDocumentation Differences Between AE CRF and SAE Form

Record on SAE Form (includes narrative)

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Record in source document

Record on AE case report form

Yes

Attach additional documentation

Does AE meet SAE criteria?

Documentation Differences Between AE CRF and SAE Form: Data ElementsDocumentation Differences Between AE CRF and SAE Form: Data Elements

AE CRF Data Elements

• AE• Start Date• Stop Date / Continuing• Is it SAE?• Severity• Relatedness• Action taken with Study Agent • Outcome (study participation)

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SAE Form Data Elements

• Participant Identifiers• Study Agent details• Narrative• Past medical history• Relevant labs, tests, procedures• Concomitant meds• Outcome of SAE• Other supporting information

Safety Data from Clinical TrialsSafety Data from Clinical Trials

Obligations to report safety data (IND or Non-IND studies):•Data for non-expedited reporting:

• Recorded on AE CRF, goes to clinical trial database

•Data for expedited reporting:• Recorded on AE CRF and then an SAE type form• Goes to safety database (unless a linked system)

• IND timelines: 24o to sponsor, 7/15 days to FDA, EMEA

• Post-marketing timelines: depends on sponsor, 15 days to FDA, EMEA

•Annual/Periodic Reports :• Need safety data from clinical and safety database• Must be reconciled

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Stretch Break

Stretch Break

Adverse EventAdverse Event

ICH E2A: Any untoward medical occurrence in a patient or clinical

investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

21 CFR 312.32 Sep, 2011Any untoward medical occurrence associated with the

use of a drug in humans, whether or not considered drug related.

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Adverse Event TermAdverse Event Term

• The AE should best describe what the subject says (i.e. verbatim description)

• Can be extracted from medical records

• Can incorporate medical assessment (including a diagnosis if available)

• The more accurate the AE term, the more accurate the safety database. The AE terms will be coded using a standard dictionary, e.g. Medical Dictionary for Regulatory Activities (MedDRA); this is NOT site responsibility

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AE Term - ExamplesAE Term - Examples

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• If “anaphylactic reaction” is associated with “rash, dyspnea, hypotension, and laryngospasm,” report primary AE as “anaphylactic reaction.”

• If “myocardial infarction” is associated with “chest pain, dyspnea, diaphoresis, ECG changes and jaundice,” report “myocardial infarction” and “jaundice” as separate primary AEs.

Serious Adverse Event (SAE)Serious Adverse Event (SAE)

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:•Results in death, •Is life-threatening • Requires inpatient hospitalization or prolongation of existing

hospitalization• A persistent or significant incapacity or substantial disruption of the

ability to conduct normal life functions, or a congenital anomaly/birth defect

•Is a congenital anomaly/birth defect•Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition

41(ICH E2A, New Final Rule)

Suspected Adverse ReactionAdverse ReactionSuspected Adverse ReactionAdverse Reaction

21 CFR 312.32 Sep, 2011 Suspected Adverse Reaction: Any adverse event for

which there is a reasonable possibility that the drug caused the adverse event.

Adverse Reaction: Any adverse event caused by a drug

Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction

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The Universe of Adverse EventsThe Universe of Adverse Events

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Adverse Events

Suspected Adverse

Reactions

Adverse Reactions

Adverse Event vs. Event OutcomeAdverse Event vs. Event Outcome

Hospitalization

• Hospitalization is a consequence and is not usually considered an AE.

• Example: If the subject was hospitalized due to congestive heart failure, “congestive heart failure” is the primary AE and hospitalization is the outcome.

• If the only information available is that the study subject was hospitalized, “hospitalization” can be reported.

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HospitalizationHospitalization

Hospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited time frame, such as:• Admission for treatment of a pre-existing condition (can include

target disease) not associated with the development of a new AE or with a worsening of the pre-existing condition

• Diagnostic admission (e.g. for work-up of persistent existing condition such as pre-treatment lab abnormality)

• Protocol-specified admission (e.g. procedure required by study protocol)

• Administrative admission (e.g. for yearly physical exam)

• Social admission (e.g. study subject has no place to sleep)

• Elective admission (e.g. elective surgery)

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SeveritySeverity

• Describes the intensity of the event

• Events are graded on a severity scale

• Mild, Moderate, Severe• Numeric Scale e.g. 1 to 5

• Severity grading must match the clinical picture

• Presenting AE is Grade 1• AE progressed to SAE (hospitalization)• The expedited report should have the grade of the SAE, not

the AE

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Seriousness is NOT the same as SeveritySeriousness is NOT the same as Severity

Action Taken with DrugAction Taken with Drug

• Action Taken with Drug: • Withdrawn• Dose reduced• Dose increased• Dose not changed• Unknown• Not applicable > ICH E2B (R3)

• Refer to protocol

• Refer to DAERS

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OutcomeOutcome

• Outcome of reaction/event at the time of last observation • Recovered/resolved• Recovering/resolving• Not recovered/not resolved• Recovered/resolved with sequelae• Fatal• Unknown > ICH E2B (R3)

• Outcome of subject in study• Remains in Study• Withdrawn• Lost to follow-up• Death

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Unexpected Adverse EventUnexpected Adverse Event

21 CFR 312.32 Sep, 2011

• Considered unexpected if not listed in the IB or is not listed in the specificity or severity that has been observed; …… or is not consistent with the risk information described in the general investigational plan….

• Hepatic necrosis vs. elevated hepatic enzymes (↑ severity)

• Cerebral thromboembolism vs. cerebral vascular accidents (specificity)

• Also… mentioned as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned with the particular drug under investigation

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CausalityCausality

21 CFR 312.32 Sep, 2011• For the purposes of IND safety reporting, “reasonable possibility”

means that there is evidence to suggest a causal relationship between the drug and the adverse event

ICH E2A• Conveys that a “causal relationship” between the study product and

the adverse event is “at least a reasonable possibility”• Facts (evidence) exist to suggest the relationship• Information on SAEs generally incomplete when first received• Follow-up information actively pursued

• Judged by:• Reporting health professional• Sponsor

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Examples of Reasonable PossibilityExamples of Reasonable Possibility

Individual occurrence a single occurrence of an event that is uncommon

and known to be strongly associated with drug exposure

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Angiodema Anaphylaxis

Hepatic InjuryBlood Dyscrasias

Stevens-Johnson Syndrome

Rhabdomyolysis

Examples of Reasonable PossibilityExamples of Reasonable Possibility

One or more occurrences a single occurrence, or a small number of

occurrences, of an event: • (i) is not commonly associated with drug exposure

• (ii) is otherwise uncommon in the population exposed to the drug;

esp. if the event occurs in association with other factors strongly suggesting causation (e.g., strong temporal association, event recurs on rechallenge)

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Tendon Rupture

Heart Valve Lesions in young adults

Intussusception in healthy infants

Examples of Reasonable PossibilityExamples of Reasonable Possibility

Aggregate analysis of specific events an analysis of events observed in a clinical trial that

indicates those events occur more frequently in the drug treatment group than in a control group, e.g.i. known consequences of underlying disease

ii. events common in study pop independent of drug therapy

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i. non-acute death in a cancer trial

ii. acute MI in a long-duration trial with an elderly population with cancer

Determination of CausalityDetermination of Causality

• Standard determinations include:

• Is there [Drug Exposure] and [Temporal Association]?

• Is there [Dechallenge/Rechallenge] or [Dose Adjustments]?

• Any known association per [Investigator’s Brochure] or [Package Insert]?

• Is there [Biological Plausibility]?

• Any other possible [Etiology]?

• [More on this during case discussion on causality]

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• Comprehensive, stand-alone “medical story”• Written in logical time sequence• Include key information from supplementary records• Include relevant autopsy or post-mortem findings

• Summarize all relevant clinical and related information, including:• Study subject characteristics• Therapy details• Medical history• Clinical course of the event(s)• Diagnosis (workup, relevant tests/procedures, lab results)• Other information that supports or refutes an AE

NarrativeNarrative

56> ICH E2D

Narrative TemplateNarrative Template

• This is a [Age] year old [Race] [Male/Female] in [Study] who reported [Primary AE] on [Date of AE]. Enrolled into study on [Date Enrolled], Study medication was started on [Date], which is [Study Day _/ Week _], taken for [Duration]. The event occurred during the [Treatment/Follow-up Phase].

• If fetus: provide [Gestational Age], (or mother’s LMP), at time of event. Also, [Gestational Age/Trimester] at first drug exposure and duration of exposure. If birth, provide details of [Infant Status] at birth. If hospital stay is complicated, provide details of hospital stay.

• Provide details of the [AE] in chronological order, along with other [Signs/Symptoms]. Provide details of [Physical Exam], along with all relevant [Procedures] and [Lab Results].

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Narrative TemplateNarrative Template

• Provide details of [Treatment] and [Treatment Rationale] on basis of [Findings/Test Result(s)]. Describe [Treatment Response].

• If hospitalization, provide [Dates Hospitalization], describe relevant [Hospital Course], [Diagnostic Work-up], [Procedures/Tests and Results], [Treatment], [Treatment Response].

• Provide [Discharge Diagnosis], and any [Follow-up Information]. List [Discharge Meds].

• Provide pertinent [Past Medical Hx], [Family Hx], [Concomitant Meds], [Alcohol/Tobacco/Substance Use] and any previous similar [AEs].

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Review and Assessment of SAEReview and Assessment of SAE

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• Assemble all information available and use medical judgment

• Standard for each AE:• Select [Seriousness Criteria]

• Grade [Severity] per DAIDS Toxicity Table

• Specify [Actions Taken on Study Product]

• Specify [Outcome of SAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit

• Is it [Expected]?

• Is it [Related]?

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• Sponsor role: (ICH E2D)• Information about the case should be collected from the

healthcare professionals who are directly involved in the study subject’s care

• Clearly identified evaluations by the sponsor are considered appropriate and are required by some regulatory authorities

• Opportunity to render another opinion; may be in disagreement with; and/or provide another alternative to the diagnosis/assessment given by initial reporter

• Sponsor makes an assessment of causality (attribution) just as the PI makes an assessment of causality (attribution)

• If causality (attribution) is different between the sponsor and the investigator, both assessments are reported

Clinical Case EvaluationClinical Case Evaluation

Site Assessment

• Site advantage: access to subject; may elicit further info, perform PE, obtain tests, labs, records

• Information from self-report (may lack validation)

• Know subject• Judgment stands• Open to dialog with

sponsor61

Sponsor Assessment

• Information limited to that provided by site• Information on product will be more

extensive than site• May initiate queries to site: incur time and

delay• Constraint: must comply to regulatory

reporting timelines • MO level: Serious? Unexpected?

Related?• SPT level: consultative role for MOs• Open to dialog with site

Site vs. Sponsor AssessmentSite vs. Sponsor Assessment

Questions?

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Appendix

63

1947: Nuremberg Code: Ten Directives for Human Experimentation1947: Nuremberg Code: Ten Directives for Human Experimentation

1. Voluntary consent of the human subject is absolutely essential:

2. The experiment must yield generalizable knowledge that could not be obtained in any other way and is not random and unnecessary in nature

3. Animal experimentation should precede human experimentation

4. All unnecessary physical and mental suffering and injury should be avoided

5. No experiment should be conducted if there is reason to believe that death or disabling injury will occur

6. The degree of risk to subjects should never exceed the humanitarian importance of the problem

7. Risks … should be minimized through proper preparations 8. Experiments … conducted by scientifically qualified investigators 9. Subjects … at liberty to withdraw from experiments 10. Investigators must be ready to end the experiment at any stage if there is

cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject

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1948: Universal Declaration of Human Rights1948: Universal Declaration of Human Rights

The UN General Assembly proclaims THIS UNIVERSAL DECLARATION OF HUMAN RIGHTS as a common standard of achievement for all peoples and all nations

• All human beings are born free and equal in dignity and rights• Everyone has the right to life, liberty and security of person• No one shall be subjected to torture or to cruel, inhuman or

degrading treatment or punishment

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• Statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects

• Considerations related to the well-being of the human subject should take precedence over the interests of science and society

• Medical research subject to ethical standards that promote respect for all human beings and protect their health and rights• Vulnerable populations need special protection

• Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements

• Risks involved have been adequately assessed and can be satisfactorily managed

• Cease any investigation if risks found to outweigh potential benefits or if conclusive proof of positive and beneficial results

1964: Declaration of Helsinki:INTRODUCTION1964: Declaration of Helsinki:INTRODUCTION

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• Must conform to generally accepted scientific principles … thorough knowledge of the scientific literature, other relevant sources of information, adequate laboratory and … animal experimentation

• Design … experimental procedure should be clearly formulated in an experimental protocol. … submitted for consideration, approval to a specially appointed ethical review committee, … independent of the investigator, sponsor or any other kind of undue influence. The committee has the right to monitor ongoing trials

• Should be conducted only by scientifically qualified persons …. under supervision of a clinically competent medical person

• Participation by competent individuals as subjects must be voluntary

1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH 1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH

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• Every precaution to protect privacy … and confidentiality of personal information … and to minimize the impact of the study on their physical, mental and social integrity

• Right to abstain from participation or to withdraw consent … at any time without reprisal. … obtain the subject's freely-given informed consent … in writing

• Both authors and publishers have ethical obligations. … preserve the accuracy of the results. Reports of experimentation not in accordance with principles of DoH should not be accepted for publication

1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH 1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH

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• May combine medical research with medical care only to extent justified by its potential preventive, diagnostic or therapeutic value and … participation will not adversely affect the health of the patients who serve as research subjects.

• Benefits, risks, burdens and effectiveness of a new intervention must be tested against best current proven intervention, except in the following circumstances:

• Use of placebo, or no treatment, is acceptable where no current proven intervention exists; or

• For compelling and scientifically sound methodological reasons, placebo is necessary to determine efficacy or safety of an intervention– patients who receive placebo/no treatment will not be subject to any risk of

serious or irreversible harm– extreme care to avoid abuse of this option

1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE

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1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE

• At conclusion, patients are entitled to be informed about outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study

• Refusal of a patient to participate or to withdraw from the study must never interfere with the patient-physician relationship

1966: International Covenant on Civil and Political Rights1966: International Covenant on Civil and Political Rights

• Adopted by UN General Assembly

• Article 7:

No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his free consent to medical or scientific experimentation

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1979: The Belmont Report1979: The Belmont Report

• Issued by National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

• Boundaries between research and practice

• 3 ethical principles for research:• Respect for Persons• Beneficence• Justice• Interests other than those of the subject may on some

occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected

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• Respect for Persons• Individuals should be treated as autonomous agents (capable of self

determination)• Persons with diminished autonomy deserve protection• Application: Informed consent

• Beneficence• Two general complementary rules:

– Do not harm– Maximize possible benefits and minimize possible harms

• Application: Risk/Benefit assessment

• Justice• Fairness in the distribution of the benefits and burdens of research• Application: Fair procedures and outcomes in the selection of subjects

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1979: The Belmont Report1979: The Belmont Report

1982: International Ethical Guidelines For Biomedical Research Involving Human Subjects1982: International Ethical Guidelines For Biomedical Research Involving Human Subjects

• Prepared by the Council for International Organizations of Medical Sciences (CIOMS)

• Responsiveness to the health needs and priorities of the community• Biomedical research with human subjects is to be distinguished from the

practice of medicine, public health and other forms of health care, which is designed to contribute directly to the health of individuals or communities

• 2002 Revision:• Ethical justification & scientific validity (#1), Ethical review (#2-3)• Informed consent (#4-6), Inducement to Participate (#7)• Benefits and Risks (#8) Choice of control (#10)• Equitable distribution of burdens and benefits (#12)• Special pops: vulnerable, children, incapable of consent, women, pregnant

women (#13-17)• Right of injured subjects to treatment and compensation (#19)• Obligation of external sponsors to provide health care services (#21)

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1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products

• GCP Definition: • (globally applicable) standard for clinical studies• encompasses the design, conduct, monitoring, termination, audit,

analyses, reporting and documentation of the studies• ensures studies are scientifically and ethically sound• clinical properties of the pharmaceutical product (diagnostic,

therapeutic or prophylactic) under investigation are properly documented

• Guidelines developed by WHO in consultation with national drug regulatory authorities within WHO’s Member States

• Handbook for Good Clinical Research Practice (GCP) as an adjunct to Guidelines

• Adopted by International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use

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• Compliance with this standard provides public assurance that:• The rights, safety, and well-being of trial subjects are protected,

consistent with the principles that have their origin in the Declaration of Helsinki

• Clinical data are credible

• Facilitates mutual acceptance of clinical data internationally among regulatory authorities in participating regions

• Defines specific responsibilities: • Institutional Review Boards/Independent Ethics Committees• Investigators• Sponsors• Monitors

1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products

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