What Good Clinical Practice GCP Entails

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What Good ClinicalPractice (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

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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

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Consensus documents, ethics,and clinical research

• Primum Non Nocere First do no harm (Hippocrates
  Epidemics)
• 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

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Declaration of Helsinki Basic Principles I

• Concern for the interests of the subjects must
  always prevail over the interests of science and
  society
• 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)

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Declaration of HelsinkiBasic 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
  Helsinki

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Declaration of HelsinkiUse 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.

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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

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Elements of GCPs

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

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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

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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

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GCPs for Study Investigators(continued)

• PIs must provide adequate medical care for study
  subjects
• 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
  appropriate

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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)

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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

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FDA Form 1572Statement 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

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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,
  Coordinator)
• Contract that investigator signs/dates
• WARNING A willfully false statement is a
  criminal offense
• Form at http//forms.psc.gov/fdaforms.html

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Essential DocumentsInvestigators 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.

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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
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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
  body)
• 2 years following marketing of drug, or
• 2 years after Investigational New Drug (IND)
  application withdrawn if drug not marketed

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Essential DocumentsStandard Operating Procedures
(SOPs)

• 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
  productivity
• Janet F. Zimmerman

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Essential DocumentsSOPs

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

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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
  product
• Examples
• Signs or symptoms of an illness (postoperative
  pain, dizziness, nausea)
• Abnormal lab or ECG finding
• Concurrent illness or accident

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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

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SAEsHospitalization

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

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Recording and Reporting Serious Adverse Events

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

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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

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Recruiting StrategiesRecruitment always takes
longerthan 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
• IRB MUST APPROVE ALL ADVERTISEMENTS

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Special Populations NIH
Mandates

• 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
  minorities
• Justify (scientifically) exclusion of specified
  groups from a study

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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

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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

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Reasons for Recruitment Failure

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

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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
  treatment

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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)

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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)

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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
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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

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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

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Trial Audits by Sponsors or the FDA

• Sponsor audits
• FDA audits
• Types
• Study-oriented
• Investigator-oriented
• Bioequivalence
• Sanctions prosecution

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Purpose of a Site Audit by Sponsor

• Assess the integrity of case report form (CRF)
  data
• Was the protocol followed?
• Were GCP and study SOPs followed?
• Were both IRB approval and informed consent
  obtained?
• Good practice for FDA audit

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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)

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Study-Oriented FDA InspectionConduct 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
  maintained?
• How did monitor communicate with PI?
• How did monitor evaluate study progress?

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Study-oriented FDA Inspection Data Actually
Collected

• Data submitted to Agency/Sponsor compared with
  all available records possibly supporting the
  data
• 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

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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

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Whats Different About Investigator Oriented
Inspections?

• Audit is similar to study-oriented inspection,
  except
• 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

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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)

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Regulatory AdministrativeSanctions

• 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