Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring

Safety Workshop: Part I
Clinical Trial Safety and Safety Monitoring
Ling Chin, MD, MPH
NIAID/DAIDS/Office of Policy for Clinical Research Operations
Durban, South Africa
May 13, 2011
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
Objectives - 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
History of research involving humans
• 1747: Lind: first recorded clinical trial: British Navy surgeon,
evaluated 6 different interventions on 12 sailors for the treatment of
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: Selfexperimentation, Written agreements with other subjects, Payment
in gold, Restriction to adult subjects, Using the phrase “with his full
1939-45: Nazi medical war experiments
1938-72: Tuskegee Study of Untreated Syphilis in the Negro Male
History of research involving humans
Regulations: 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
Regulations: 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
NIH 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
• 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
IRB 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 Review: Approval Criteria
• Risks to subjects are minimized:
i. By using procedures consistent with sound research
design which do not unnecessarily expose subjects to risk
ii. 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
• Other criteria 45 CFR 46.111 or 21 CFR 56.111
Safety 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)
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
Data Safety and Monitoring Boards (DSMBs) /
Data Monitoring Committees (DMCs)
• 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,
• 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
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
• Participants in research are voluntary
• Placed their faith in the investigators
• Participation is a gift in the service of the public
• Investigators must not betray the public trust
• Must conduct trials with ethical and scientific integrity
• Must implement high standards for human subject
• Must assure participant well-being and safety at all
Current Safety Environment
• 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
• 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
Safety Monitoring
Roles and Responsibilities – Site Investigator
Roles and Responsibilities – Research Staff
Roles and Responsibilities –
Study Clinician/Physician
Assurance of Safety and Well-Being:
Research vs. Medical Roles
 Emergency intervention vs. Non-emergency care
• Acute on-site management, as necessary, and per site
• 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 Role
Balancing Both Roles
Clinical Role: Subject OK
• Is subject in imminent jeopardy?
• Provide appropriate management
commensurate with clinical
situation, e.g. toxicity
• Provide appropriate referral:
emergent care or back to regular
• Follow up with subject status
Not Subject’s Primary Clinician
Research Role: Study/Data OK
• 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
Adhere to reporting requirements
Adhere to toxicity management as
Adhere to stopping rules as specified
Therapeutic Misconception
• 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
Decide if subject can continue in study
Roles and Responsibilities –
Study Clinician/Physician
Action taken with Study product
after AE
Study product:
Dose held, changed,
or discontinued?
Study participation:
Study product:
Per site, per study?
Study status:
Safety pause, clinical hold,
early termination?
Continue, withdraw?
Roles and Responsibilities –
Study Team
Safety: Ensure safety and well being of subjects at all
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/RSC
• 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
• All follow-up information should be provided to RSC
Joshua Tree National Park in Southern California
Safety Monitoring Environment
IND Trials: Pre-market
OHRP 45 CFR 46
OHRP 45 CFR 46
21 CFR Part 312 – IND
21 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
ICH: 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
Drug Development Model:
Safety Data Flow in Clinical Trials
Adverse Event Flowchart
To other
Subject Enrolled
AE Reported
To Sponsor
Record AE*
Follow until
or Stability
Update SAE
Adverse Event
* 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 Form
Record in source
Attach additional
Record on AE
case report form
Record on SAE Form
(includes narrative)
Does AE
meet SAE
Documentation Differences Between AE CRF
and SAE Form: Data Elements
Data Elements
Start Date
Stop Date / Continuing
Is it SAE?
Action taken with Study Agent
Outcome (study participation)
SAE Form
Data Elements
Participant Identifiers
Study Agent details
Past medical history
Relevant labs, tests, procedures
Concomitant meds
Outcome of SAE
Other supporting information
Safety Data from Clinical Trials
Obligations to report safety data (IND or Non-IND
• 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
Adverse Event
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, 2011
Any untoward medical occurrence associated with the
use of a drug in humans, whether or not considered
drug related.
Adverse 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
AE Term - Examples
• 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
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
• A persistent or significant incapacity or substantial disruption of the
ability to conduct normal life functions, or a congenital anomaly/birth
• Is a congenital anomaly/birth defect
• Important medical events that may not result in death, be lifethreatening, 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
(ICH E2A, New Final Rule)
Suspected Adverse Reaction
Adverse 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
Suspected adverse reaction implies a lesser degree of
certainty about causality than adverse reaction
The Universe of Adverse Events
Suspected Adverse
Adverse Event vs. Event Outcome
• 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.
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
• 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)
• 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
Seriousness is NOT the same as Severity
Action 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
• Outcome of reaction/event at the time of last observation
Not recovered/not resolved
Recovered/resolved with sequelae
> ICH E2B (R3)
• Outcome of subject in study
Remains in Study
Lost to follow-up
Unexpected 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
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
• 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
Examples of Reasonable Possibility
Individual occurrence
 a single occurrence of an event that is uncommon and
known to be strongly associated with drug exposure
Hepatic Injury
Blood Dyscrasias
Stevens-Johnson Syndrome
Examples of Reasonable Possibility
One or more occurrences
 a single occurrence, or a small number of occurrences, of an
(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)
Tendon Rupture
Heart Valve Lesions in young adults
Intussusception in healthy infants
Examples 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.
known consequences of underlying disease
events common in study pop independent of drug therapy
i. non-acute death in a cancer trial
ii. acute MI in a long-duration trial with an
elderly population with cancer
Determination 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]
• 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,
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
Narrative 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].
Narrative Template
• Provide details of [Treatment] and [Treatment Rationale] on
basis of [Findings/Test Result(s)]. Describe [Treatment
• If hospitalization, provide [Dates Hospitalization], describe
relevant [Hospital Course], [Diagnostic Work-up],
[Procedures/Tests and Results], [Treatment], [Treatment
• 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].
Review and Assessment of SAE
• Assemble all information available and use medical
• 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
• Is it [Expected]?
• Is it [Related]?
Clinical Case Evaluation
• 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
Site vs. Sponsor Assessment
Site Assessment
Sponsor Assessment
• Site advantage: access
to subject; may elicit
further info, perform
PE, obtain tests, labs,
• Information from selfreport (may lack
• Know subject
• Judgment stands
• Open to dialog with
• Information limited to that provided by site
• Information on product will be more
extensive than site
May initiate queries to site: incur time and
Constraint: must comply to regulatory
reporting timelines
MO level: Serious? Unexpected?
SPT level: consultative role for MOs
Open to dialog with site
1947: 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
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
1948: Universal Declaration of Human Rights
The UN General Assembly proclaims THIS
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
1964: Declaration of Helsinki:
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:
• 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:
• 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
1964: Declaration of Helsinki:
• 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:
• 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
1966: 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
1979: 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
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
1979: The Belmont Report
• Respect for Persons
• Individuals should be treated as autonomous agents (capable of self
• 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
1982: 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)
1995: 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
• 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
1995: Guidelines for Good Clinical Practice
(GCP) for Trials on Pharmaceutical Products
• Compliance with this standard provides public assurance
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

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