DAIDS Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring

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DAIDS Safety Workshop Part IClinical Trial
Safety and Safety Monitoring

• Albert Yoyin, M.D. and Anuradha Jasti, M.D.
• DAIDS Regulatory Support Center (RSC) Safety
  Office
• Johannesburg, South Africa
• 29 Aug 2012

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Objectives

• Participants will be able to demonstrate an
  understanding of
• Human Subject Protections and Safety Monitoring
• Current context regarding safety in clinical
  trials
• Key roles and responsibilities related to safety
• Protocol requirements pertaining to safety
• Safety and adverse event terminology
• Expedited reporting of adverse events
• What makes a well-documented adverse event,
  including a comprehensive narrative

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History of Research Involving Humans
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History of Research Involving Humans
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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

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Regulations Non-Federally Supported Studies
Involving Human Subjects

• 21 CFR 50 Protection of Human Subjects
• Requirement for informed consent
• Elements of informed consent
• Documentation of informed consent
• 21 CFR 56 Institutional Review Boards
• Requirements for IRB review
• Membership, functions, review procedures, etc.
• Criteria for IRB approval
• Applies to all clinical investigators regulated
  by FDA

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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
• 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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Institutional Review Board (IRB)

• At least 5 members
• At least 1 in scientific area, 1 in
  non-scientific area
• At least 1 not affiliated with institution nor
  family member
• Individual knowledgeable/experienced in working
  with vulnerable populations of such research
• No member with conflict of interest (COI), except
  to provide information at IRB request
• May invite individuals to assist in review of
  special areas requiring expertise beyond that
  available on the IRB non-voting
• Be able to ascertain the acceptability of
  proposed research in terms of institutional
  commitments and regulations, applicable law, and
  standards or professional conduct and practice
• Authority to approve, require modifications, or
  disapprove all research activities
• Written notification to include a statement of
  the reasons for disapproval investigator has
  opportunity to respond in person or in writing

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IRB Review

• Initial and continuing review
• At convened meetings (at intervals appropriate to
  level of risk not less than 1/year)
• Majority of members must be present Approval by
  majority
• Approval of Informed Consent Form
• 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 Criteria

• Risks to subjects are minimized
• By using procedures consistent with sound
  research design which do not unnecessarily expose
  subjects to risk
• 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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Data Safety and Monitoring Board (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 (Exception
  from Informed Consent Requirements for Emergency
  Research)

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Data Safety and Monitoring Board (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, epidemiologist
• Advises the sponsor
• Continuing safety of trial subjects and those to
  be recruited
• Continuing validity and scientific merit of the
  trial
• Two important considerations Confidentiality and
  COI
• Knowledge of interim results could influence
  conduct of the trial

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Perspective

• Differing viewpoints on safety requirements
• Imposes 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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Perspective

• Subject participation in research is 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 subject well-being and safety at all
  times

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Current Safety Environment

• Increasing public demands for safety data
• Fast track approvals
• Post-market events leading to changes in labeling
  e.g., additional precautions, black box warnings
• Global reporting to EMA and other countries
  throughout the world
• Food and Drug Administration Amendments Act of
  2007 (FDAAA) Provides FDA with additional
  requirements, authorities, and resources with
  regard to both pre- and post-market drug safety
• Final Rule 21 CFR 312.32 (Sep 2010) focus on
  signal detection (only submit evidence-based
  Serious Suspected Unexpected AEs), encourage
  noise reduction (less submission)

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Clinical Trial Continuum From Drug Development
to Optimal Regimens to Treatment Strategies
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Safety Monitoring
To Ensure Subject Safety and Study Integrity
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Roles and Responsibilities Site Investigator
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Roles and ResponsibilitiesResearch Staff
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Roles and Responsibilities Study
Clinician/Physician
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Assurance of Safety and Well-BeingResearch vs.
Medical Roles

• 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

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Clinical Role vs. Research Role
Balancing Both Roles Balancing Both Roles
Clinical 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 Subjects 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
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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 management
• Decide if subject can continue in study

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Roles and Responsibilities Study
Clinician/Physician
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Roles and ResponsibilitiesStudy Team

• 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

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Roles and ResponsibilitiesStudy 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 (DMCs)
• Expedited reporting to sponsor/RSC
• SAE sent to RSC
• RSC processes event and sends queries to site to
  obtain additional information
• All follow-up information should be provided 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

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Mental Break
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Drug Development ModelSafety Data Flow in DAIDS
Clinical Trials
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Adverse Event Flowchart
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Adverse Event

• Protocol specifications for AE
• When to collect, e.g., study visit
• Method of collection, e.g., in person, telephone
  call
• Duration of collection, e.g., from enrollment to
  completion
• 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 timeframes
• Reporting form, e.g., SAE

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Documentation Differences Between AE CRF and SAE
Form

• Record on SAE Form (includes narrative)

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Documentation 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)
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
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Stretch Break
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Adverse 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 2010)
• Any untoward medical occurrence associated with
  the use of a drug in humans, whether or not
  considered drug related.

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Adverse Event Term

• The AE term should best describe what the subject
  says (i.e., verbatim description)
• Can use medical records, assessment, autopsy, and
  medical diagnosis to select primary AE term
• Can use other events section (clinically
  significant events) to submit associated events
• Accurate AE term is required to establish
  accurate safety database. At Safety Office all AE
  terms will be coded using a standard dictionary,
  MedDRA

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MedDRA Coding of Primary AE Terms

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Importance of AE Term in Pharmacovigilance

• All AE terms submitted by sites are
• part of the safety database
• coded using ICH recognized global terminology
  tool called MedDRA
• reported to Regulatory agencies Individual Case
  Safety Report(ICSR)/Annual Reports
• These terms become part of the regulatory/safety
  databases like AERS, VAERS, and WHO VIGIBASE
• Inaccurate AE term submission by sites puts
  subject and sponsor at risk

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MedDRA Definition

• Medical Dictionary for Regulatory Activities
• MedDRA is a medical terminology used to classify
  adverse event information associated with the use
  of biopharmaceuticals and other medical products
  (e.g., medical devices and vaccines)
• MedDRA was developed by ICH Expert working group
• Maintained by MSSO (Maintenance Support Service
  Organization) and is updated twice a year
• Each MedDRA term is assigned an 8-digit numeric
  code (using universal 8 digit code, for example
  headache is coded to LLT headache with LLT code
  of 10019211)

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Current MedDRA Hierarchical Structure

• Lowest Level Term (LLT) (70,177)
• Preferred Term (PT) (19,550)
• High Level Term (HLT) (1,713)
• High Level Group Term
  (HLGT) (335)
• System Organ
  Class (SOC) (26)

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Current MedDRA Hierarchical Structure Example
for Jaundice

• LLT Jaundice
• PT Jaundice
• HLT Cholestasis and jaundice
• HLGT Hepatic
  hepatobiliary disorders
• SOC
  Hepatobiliary disorders

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Why Do We Code?

• ICH approved global regulatory language
• Ease of the data exchange and reconciliation
  between the parties
• Enables data mining and signal detection (FDA
  AERS, WHO VIGIBASE)
• Most of the regulatory authorities require
  electronic submissions using MedDRA
• Less paper submissions, environmental care (go
  green)

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DAIDS MedDRA Policies

• MSSO MedDRA Term Selection Points to Consider
• http//www.meddramsso.com/subscriber_library_ptc.a
  sp
• DAIDS MedDRA Implementation Working Group (MIWG)
• Comprised of DAIDS, DMCs and RSC representatives.
  Include staff that performs MedDRA coding
  co-chaired by DAIDS and RSC
• Reviews ongoing MedDRA coding issues
• Maintains the DAIDS MedDRA Term Selection
  Guidelines
• Collect non-codable new AE terms
• Submits change requests to MSSO

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Applications of MedDRA

• Clinical trial databases (adverse events, medical
  social history, investigations, etc.)
• Investigators Brochures, Core Safety
  Information, Safety summaries
• Clinical Study Reports
• Individual Case Safety Reports
• Periodic Safety Update Reports
• Product Labeling

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AE Term SelectionPoints for Consideration

• Though coding is NOT the sites responsibility,
  accurate AE term submission is required for
  coding and regulatory submissions (FDA)
• No additions or omissions to AE term are
  recommended which would lead to inaccurate coding
  and data analysis
• Provide applicable identifiers and available
  diagnosis
• Multiple medical concepts
• select only one as Primary AE
• report only one medical concept per report

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AE Term SelectionPoints for Consideration

• Avoid using acronyms spell out the AE term
• Herpes zoster virus rather than HZV
• Provide details site/location
• Right leg pain rather than Pain
• Ocular pain rather than Pain
• Do not add or remove medical concepts
• Candida vulvovaginitis rather than
  Vulvovaginitis
• Gastrointestinal infection rather than
  Gastrointestinal illness (which need not be of
  infectious etiology)

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AE Term SelectionPoints for Consideration

• Provide applicable identifiers for abnormal test
  results. Only test name is not accurate
• Decreased hemoglobin rather than Hemoglobin
• Elevated glucose rather than Glucose
• Provide diagnosis, if available, rather than just
  signs/symptoms
• Myocardial infarction rather than Chest pain,
  Shortness of breath, Diaphoresis
• Anaphylactic reaction rather than Rash,
  Dyspnea, Hypotension, Laryngospasm

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AE Term SelectionPoints for Consideration

• Multiple medical concepts select only one as
  primary AE and report only one medical concept
  per report
• Peptic ulcer disease and Cerebrovascular
  accident
• Report as two separate events
• Hyperemesis and Antepartum hemorrhage
• Report as two separate events

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AE Term SelectionPoints for Consideration

• Multiple medical concepts that are associated
  Review and select one Primary AE and report
  others as associated events
• Prematurity, Low birth weight, and
  Respiratory distress syndrome
• Rash, Jaundice, and Hepatitis B
• If multiple events occurred at the same time
  period and all were clearly associated with each
  other
• select one as Primary AE
• report the rest as associated events

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Mental Break
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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
• Is a persistent or significant incapacity or
  substantial disruption of the ability to conduct
  normal life functions, or
• 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

(ICH E2A, Final Rule)
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Suspected Adverse ReactionAdverse Reaction

• 21 CFR 312.32 (Sep 2010)
• 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 Events
Suspected Adverse Reactions
Adverse Events
Adverse Reactions
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Adverse Event vs. Event Outcome

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

• Hospitalization in the absence of a medical AE is
  not in itself an AE and does not need to be
  reported in an expedited timeframe, 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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Severity

• 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 Severity
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Action Taken with Drug

• Action Taken with Drug
• Withdrawn
• Dose reduced
• Dose increased
• Dose not changed
• Unknown
• Not applicable gt ICH E2B (R3)
• Refer to protocol
• Refer to DAERS

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Outcome

• Outcome of reaction/event at the time of last
  observation
• Recovered/Resolved
• Recovering/Resolving
• Not recovered/not resolved
• Recovered/resolved with sequelae
• Fatal
• Unknown gt ICH E2B (R3)
• Outcome of subject in study
• Remains in Study
• Withdrawn
• Lost to follow-up
• Death

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Unexpected Adverse Event

• 21 CFR 312.32 (Sep 2010)
• 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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Causality

• 21 CFR 312.32 (Sep 2010)
• 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
• Assessed by
• Reporting health professional
• Sponsor

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Examples of Reasonable Possibility

• Individual occurrence
• a single occurrence of an event that is uncommon
  and known to be strongly associated with drug
  exposure

Angiodema Anaphylaxis
Hepatic Injury Blood Dyscrasias
Stevens-Johnson Syndrome Rhabdomyolysis
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Examples of Reasonable Possibility

• One or more occurrences
• a single occurrence, or a small number of
  occurrences, of an event that is not commonly
  associated with drug exposure, but 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
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Examples of Reasonable Possibility

• Aggregate analysis or 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
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Determination of Causality

• Standard determinations include
• Is there Drug Exposure and Temporal
  Association?
• Is there Dechallenge/Rechallenge or Dose
  Adjustments?
• Any known association per Investigators
  Brochure or Package Insert?
• Is there Biological Plausibility?
• Any other possible Etiology?
• More on this during case discussion on causality

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Narrative

• 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
• Medical history
• Clinical course of the event and therapy details
• Diagnosis (workup, relevant tests/procedures, lab
  results)
• Other information that supports or refutes an AE
  

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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/nursing infant provide Gestational
  Age, (or mothers 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 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 SAE

• Assemble all information available and use
  medical judgment
• Standards 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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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 subjects case
• 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

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Site vs. Sponsor Assessment
Site Assessment
Site advantage has access to subject may elicit further info, perform PE, obtain tests, labs, records Information from self-report (may lack validation) Know subject best Judgment stands Open to dialog with sponsor
Sponsor Assessment
Information limited to what was submitted from site May initiate queries to site incur time and delay Constraint Must adhere to reporting timelines to FDA MO level Serious? Unexpected? Related? Open to dialog with Site PI, DAIDS MO
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• Questions?

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• Appendix

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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 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

74
1948 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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1964 Declaration of HelsinkiINTRODUCTION

• 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

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1964 Declaration of HelsinkiPRINCIPLES FOR ALL
MEDICAL RESEARCH

• 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

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1964 Declaration of HelsinkiPRINCIPLES FOR ALL
MEDICAL RESEARCH

• 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

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1964 Declaration of HelsinkiMEDICAL RESEARCH
and MEDICAL CARE

• 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

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1964 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

80
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

81
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
• 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

82
1979 The Belmont Report

• 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

83
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)

84
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 documented
• Guidelines developed by WHO in consultation with
  national drug regulatory authorities within WHOs
  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

85
1995 Guidelines for Good Clinical Practice (GCP)
for Trials on Pharmaceutical Products

• 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

86
Safety Monitoring Environment
IND Trials Pre-market Postmarket
OHRP 45 CFR 46 OHRP 45 CFR 46
FDA 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
IRBs/ECs IRBs/ECs
Sponsor Sponsor
87
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

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