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What Good Clinical Practice GCP Entails


'In any medical study, every patient--including those of a control group, if any ... Elective medical/surgical procedures. Scheduled treatments. Routine checkups ... – PowerPoint PPT presentation

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Title: What Good Clinical Practice GCP Entails

What Good Clinical Practice (GCP) Entails
  • John Butterworth, MD
  • Professor Head
  • Section on Cardiothoracic Anesthesiology
  • Director, Office of Clinical Trials Research
  • Wake Forest University School of Medicine
  • Winston-Salem, NC 27157 USA

Good Clinical Practices
  • Derived from the International Conference on
    Harmonisation (ICH)
  • U.S./European Union/Japanese collaboration to
    standardize practice/conduct of clinical research
    (other countries are joining)
  • Results of studies accepted in one country should
    be accepted in other countries
  • Based on the Declaration of Helsinki

Consensus documents, ethics,and clinical research
  • Primum Non Nocere First do no harm (Hippocrates
  • Nuremberg Code
  • Declaration of Helsinki (International Conference
    on Harmonisation)
  • Belmont Report
  • See
  • http//www.fda.gov/oc/gcp/regulations.html
  • http//ohrp.osophs.dhhs.gov/educmat.htm
  • http//ohsr.od.nih.gov

Declaration of Helsinki Basic Principles I
  • Concern for the interests of the subjects must
    always prevail over the interests of science and
  • Research must conform to accepted scientific
    principles design appropriate and clear in
    experimental protocol
  • Research must be conducted by qualified persons
  • Research must have importance proportionate to
    inherent risk (risks acceptable given the
    benefits to individuals)

Declaration of Helsinki Basic Principles II
  • Safeguard subjects integrity privacy
  • Abstain unless hazards are predictable
  • Present results accurately in publications
  • Inform subjects of their right to withdraw
  • Obtain true informed consent from the subject or
    legal guardian
  • Statement that in compliance with Declaration of

Declaration of Helsinki Use of placebos
  • In any medical study, every patient--including
    those of a control group, if any--should be
    assured of the best proven diagnostic and
    therapeutic method. This does not exclude the use
    of inert placebo in studies where no proven
    diagnostic or therapeutic method exists.

Compliance with GCPs
  • Assures protection of human subjects
  • Rights
  • Safety and well-being
  • Confidentiality
  • Assures consistent, high standards for designing,
    conducting, recording, and reporting trials
  • Ethical and credible studies

Elements of GCPs
  • IRB
  • Investigator
  • Sponsor
  • Clinical trial protocol and protocol amendment(s)
  • Investigators brochure
  • Essential documents

Elements of Good Clinical Practice for PIs
  • PIs will be held accountable for the ethical
    conduct and integrity of the study
  • Qualified PI and staff (training experience)
  • Appropriate delegation of responsibilities
  • Adequate time, staffing, resources facilities
  • Study drug accountability (especially for
    investigational not yet FDA approved drugs)
  • Appropriate communication with IRB

GCPs for Study Investigators (continued)
  • Comply with protocol complete the study
  • Enroll appropriate subjects
  • Try to meet recruitment goals
  • Follow randomization and blinding procedures
  • Treatment administration per protocol
  • Measurement of study outcomes
  • Maintain audit trail (paper/electronic)
  • Complete/process/file all study reports
  • Appropriate post-study follow-up for participants
  • Participate in dissemination of results

GCPs for Study Investigators (continued)
  • PIs must provide adequate medical care for study
  • Monitor, treat, report adverse events (AEs)
  • Inform participant primary care MD when care is
    needed for intercurrent illness(es)
  • PIs may refer subject to primary caregiver when

GCPs for Study Investigators
  • Things to do…
  • Call sponsor when unsure of a situation
  • Return study drug per protocol
  • Dispose of study drug per guidelines
  • Things not to do…
  • Do not dispense drug outside of protocol or
    without informed consent
  • Do not transfer drug to another site without
    sponsor approval and documentation
  • Do not use white-out on study documents
  • Do not discuss medications dispensed (especially
    for a blinded study)

Essential Documents
  • Study protocol with all amendments
  • Signed consent form for all subjects
  • IRB submission forms/approval memo(s)
  • All versions of consent form
  • Samples of all recruitment advertisements
  • For all investigational drug studies
  • Completed/signed FDA Form 1572
  • Investigators brochure

FDA Form 1572 Statement of Investigator
  • PI name/address
  • Name/address site(s) of study conduct
  • Name/address of clinical labs (local/central)
  • Name/address of IRB
  • Names of key personnel with patient contact
  • Signed, dated CVs of listed personnel
  • Agree to comply with protocol, personally conduct
    or supervise the study, inform subjects about
    investigational drug(s), comply with IRB
    requirements, report AEs, familiar with
    investigators brochure

FDA Form 1572 (continued)
  • Ensure that study personnel know obligations in
    meeting study commitments
  • Maintain adequate/accurate records, to be made
    available for inspection (FDA, etc.)
  • Update when add key personnel to study who will
    have participant contact (Co-investigator,
  • Contract that investigator signs/dates
  • WARNING A willfully false statement is a
    criminal offense
  • Form at http//forms.psc.gov/fdaforms.html

Essential Documents Investigators Brochure
  • Provided by manufacturer for drug trials of
    agents that are not yet FDA-approved
  • Summary of all physical, chemical,
    pharmaceutical, pharmacological, toxicological,
    pharmacokinetic, metabolic information relevant
    to the investigational product
  • All relevant animal clinical studies, adverse
    events, etc.

Essential Documents
  • Research agreement (contract)
  • Budget
  • Completed case report forms (CRFs)
  • Participant screening logs
  • Source documents (lab slips, pathology reports,
    adverse event notes/reports, clinic chart notes)
  • Drug accountability logs
  • Letters, records of meetings telephone calls

not normally audited
Storage of Essential Documents
  • Keep records for the longest time period among
    these three requirements...
  • 1. Your institution (e.g. 5 years from date of
    final IRB report at Wake Forest University)
  • 2. Office for Human Research Protection, DHHS
    store IRB records for 3 years following study
    completion (based on date of submission of final
    fiscal report)
  • 3. FDA (or other national drug registration
  • 2 years following marketing of drug, or
  • 2 years after Investigational New Drug (IND)
    application withdrawn if drug not marketed

Essential Documents Standard Operating Procedures
  • The who, what, when, how, and why of clinical
    research operations
  • Ensure consistency, compliance, and
    accountability of personnel
  • Organizations without clinic-specific SOPs run a
    high risk of GCP non-compliance and poor
  • Janet F. Zimmerman

Essential Documents SOPs
  • Generic SOPs are available at WFUSM that could be
    adaptation for your study
  • Many sponsors will furnish you with SOP
    checklists for studies

Adverse Event (AE)
  • AEs are unfavorable or unintended medical
    occurrences that are...
  • temporally associated with the use of an
    investigational product
  • whether or not PI thinks AE is related to the
  • Examples
  • Signs or symptoms of an illness (postoperative
    pain, dizziness, nausea)
  • Abnormal lab or ECG finding
  • Concurrent illness or accident

Serious Adverse Event (SAE)
  • SAE AE that results in any of
  • death
  • life-threatening experience
  • in-patient hospitalization or prolongation of
    existing hospitalization
  • persistent or significant disability/incapacity
  • congenital anomaly/birth defect
  • important medical event (may jeopardize subject
    requires intervention to prevent serious adverse
    outcome) e.g. asthma attack

SAEs Hospitalization
  • At least 24-hour inpatient hospitalization or
    prolonged hospitalization means SAE rather than
  • In general, all other hospitalizations are
    considered to be AEs
  • lt 24 hours
  • Outpatient
  • Elective medical/surgical procedures
  • Scheduled treatments
  • Routine checkups

Recording and Reporting Serious Adverse Events
  • Record on SAE Form
  • Report to sponsor within 24 hours of
  • Report to IRB
  • Provide follow-up care of the patient and report
    on SAE until it has resolved or stabilized

Unexpected Adverse Event
  • An AE not previously observed (not listed in
    Investigators Brochure)
  • Could include AEs of a type already listed in IB,
    but of greater severity
  • duodenal ulcer vs. dyspepsia (indigestion)
  • severe dermatitis vs. mild skin rash

Recruiting Strategies Recruitment always takes
longer than initially anticipated
  • Physician/nurse referrals
  • Chart reviews
  • Direct patient contact (within practice)
  • Media (radio, TV, cable, newspapers)
  • Mass mailing
  • Mass screening (shopping mall, sporting events)
  • Internet

Special Populations NIH
  • Typically relate to women, minorities, children
  • Cost is not an acceptable reason for exclusion
  • Describe composition of study population with
    rationale for selecting these subjects
  • Describe recruitment plans for women and
  • Justify (scientifically) exclusion of specified
    groups from a study

Inclusion of Children
  • Diseases that affect children
  • Justify why not included
  • FDA Modernization Act (FDAMA) incentive six
    month extension of market exclusivity for
    performing drug studies in children
  • FDA may soon have statutory authority to mandate
    pediatric trials

Inclusion of Pregnant Women
  • Diseases that affect pregnant women
  • Justify why not included
  • Pregnancy is a nearly uniform exclusion criterion
    for studies of drugs NOT directly related to
    pregnancy or complications of pregnancy

Reasons for Recruitment Failure
  • Late start
  • Inadequate planning
  • Insufficient effort
  • Over-optimistic expectations
  • Unexpectedly common exclusion criteria
  • Unexpectedly scarce population

Unethical Study - HIV Transmission
  • Zidovudine reduces HIV transmission from mother
    to child by 2/3 (1994)
  • Complex costly treatment regimen
  • Simpler regimen suspected effective
  • 15 of 16 placebo-controlled trials in developing
    countries, 9 of these were U.S. funded (1997)
  • Heated debate re ethics of new trials using
    placebo since clearly not best alternative

Unethical Treatment of Human Subject-Gene
Transfer Trial
  • 18 yr. old boy with mild form of rare liver
    disease (ornithine transcarbamylase deficiency)
  • Symptoms controlled with drugs and diet
  • Gene-therapy study to determine safety, not
    efficacy (no cure) consent incomplete
  • Parents inadequately advised re risks
  • Investigator had financial conflict of interest
  • 4 days after injection of virus vector that had
    killed animals, patient brain-dead (17 Sep 99)

Hexamethonium challenge study
  • Normal volunteer subjects
  • Use of inhaled hexamethonium as pulmonary
    vasodilator extensive literature on
    hexamethonium toxicity (in older publications not
    conveniently accessed using on-line search
    engines (PubMed))
  • Volunteer 1 developed prolonged flu not
    reported to IRB
  • Volunteer 3 died of respiratory failure
    following treatment (2 June 2001)

Investigator Fraud Fiddes Case
  • Dr. Fiddes, president of clinical research firm
  • Conducted gt200 studies for 47 sponsors
  • Fictitious study subjects, fabricated laboratory
    results, substituted urine samples, falsified
    medical records, used the same radiograph for
    multiple subjects
  • Pulled chart pages prior to audits
  • Intimidated suspicious support staff
  • Passed all audits, but caught by whistle
    blowing disgruntled former employee
  • Pleaded guilty to conspiracy charge
  • Sentenced to 15 months in prison

NY Times
Investigator Conflicts of Interest
  • Professional gain publications/promotion
  • Financial gain
  • Patient finders fee to collaborators
  • Recruitment bonuses
  • Affiliation with/funding from sponsor for future
    studies, consultant relationships
  • Other incentives (e.g., travel, presentations)
  • Per patient payment system presents conflicts of
    interest inherent in capitalist society

Potential Consequences of Investigator Conflicts
of Interest
  • Attempting to ? study enrollment
  • Coercing subjects to enroll and discouraging
    withdrawal, treatment alternatives
  • Enrolling fictitious or ineligible patients
  • Bias trial toward positive results
  • Failure to report AEs
  • Failure to comply with protocol regimens
  • Alteration of outcome data
  • Data fabrication

Trial Audits by Sponsors or the FDA
  • Sponsor audits
  • FDA audits
  • Types
  • Study-oriented
  • Investigator-oriented
  • Bioequivalence
  • Sanctions prosecution

Purpose of a Site Audit by Sponsor
  • Assess the integrity of case report form (CRF)
  • Was the protocol followed?
  • Were GCP and study SOPs followed?
  • Were both IRB approval and informed consent
  • Good practice for FDA audit

Inspections by the Food and Drug Administration
  • FDA Bioresearch Monitoring Program PIs,
    sponsors, CROs, IRBs, animal labs
  • 315 investigative site audits annually (lt1 of
    sites conducting ?1 clinical trial)
  • Recent increased concern about fraud
  • 3 types of clinical investigator inspections
    study-oriented (97), investigator-oriented (3),
    bioequivalence study (where only 1 study may be
    sufficient for NDA approval)

Study-Oriented FDA Inspection Conduct of the Study
  • Who did what how was authority delegated?
  • Where was the study performed?
  • How and where were data collected?
  • How was test article/drug accountability
  • How did monitor communicate with PI?
  • How did monitor evaluate study progress?

Study-oriented FDA Inspection Data Actually
  • Data submitted to Agency/Sponsor compared with
    all available records possibly supporting the
  • Completed CRFs for all patients
  • All Source Documents
  • All Informed Consent documentation
  • Post-study records to assess follow-up
  • Investigators Brochure Regulatory Binder
  • Study Protocol

What Triggers Investigator-Oriented Inspections?
  • Pivotal study of singular importance
  • Sponsor notifies FDA of problems with PI
  • Participant complains about protocol or subject
    rights violations
  • PI involved in a large number of studies or in
    studies outside area of expertise
  • Unexpectedly large number of subjects with
    specific disease or study eligibility
  • Lab or clinical results out of expected range

Whats Different About Investigator Oriented
  • Audit is similar to study-oriented inspection,
  • More extensive data audit
  • More CRFs will be reviewed
  • Other studies may be examined
  • FDA may exclude PI from this study, future
    studies, or refer PI for criminal prosecution

After the Audit Concludes
  • Field Investigator writes Establishment
    Inspection Report (EIR) for FDA use
  • Letter usually sent to investigator
  • No significant deviations observed (no response
    required from PI)
  • Informational letter identifying deviations from
    regulations or GCP (may require PI response)
  • Warning Letter identifying serious deviations
    requiring PIs prompt correction (letter may also
    be sent to sponsor IRB)

Regulatory Administrative Sanctions
  • PI disqualification process
  • FDA writes PI seeking response to critique
  • If inadequate explanation or no response, written
    notice of 21 CFR part 16 hearing
  • Written report submitted to FDA Commissioner
  • May remove PI from present and future studies
  • May notify all sponsors that PIs data may be
    eliminated (may jeopardize INDs or NDAs)
  • Knowing and willful falsification may lead to
    criminal prosecution
  • Loss of medical license
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