the history of gcp
TRANSCRIPT
GCP WORKSHOP, Dec 13, 2001
THE HISTORY AND
OVERVIEW OF GCP
GCP WORKSHOP, Dec 13, 2001
1. Drug Discovery 2. Early Development (Pre-clinical, IND, Phase I and Early Phase II)
3. Advanced Clinical Trials (Phase III)
4. Drug Registration and Approval
5. Post-Marketing Strategies (Phase III-b and IV)
Drug Development Process
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GCP WORKSHOP, Dec 13, 2001
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Clinical Trial Process
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What is GCP?
Good Clinical Practice
Refers to
Good Clinical (Research) Practice
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Participants in a Clinical Trial
Sponsor•Monitor
Institute•Investigator•Ethics Committee•Administrator
Regulators
GCP
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Framework for Clinical Trial Conduct
Declaration of Helsinki
ICH-GCP
Local regulations
Protocol, SOPs
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International Scientific & Ethical quality Standard
DESIGN
REPO
RT
REC
OR
D
COLLECT
Patient Safety
Credibility of Data
The Concept of Good Clinical Practice
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Why GCP?
• Tuskegee trials - 1930s• German prisoners trials - 1940s• Harvard fraud - 1980s• California investigator - 1999• DHHS suspends IRB at University of
Illinois, Chicago - Sept 1999
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Why GCP? Case #1• Tuskeegee Trial (Alabama, U.S.A., 1932-1972)• > 600 men with syphilis
• 50% randomized to treatment• 50% randomized to NO TREATMENT
– Result: Untreated patients fared poorly A significant number of patients died
• No information given to patients; no permission was sought to withhold treatment; no clear endpoints.
• Outcome: Litigation, financial settlements• 16 May ‘97: Public apology from U.S. President
Clinton; support for lasting bioethics reforms• “…..the definitive example of an unethical study”
» Maggie Fox, Health and Science Correspondent, Reuters, 1999
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Why GCP? Case #2• German prisoner research trials (1940’s)• Objectives of various trials:
– Effect of cold, heat, chemicals on men, women and children
– “Time to death” testing in response to stressors in healthy “volunteers”
– Organ transplant experiments on healthy “volunteers”• Any information given (some?) is irrelevant because
prisoners were forced to participate• Outcome:
– 25 German scientists taken to court, 7 acquitted, 9 imprisoned, 9 given death sentence
– Nuremberg Code of 1947
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Why GCP? Case #3• CV Training Fellow tutored by Dr. Eugene
Braunwald, prominent U.S. cardiologist• Fellow fabricated study data; discovered because of
“too clean” data & intact dogs in the dumpster• Outcome for fellow: License withdrawn; expelled
from Harvard; “blackballed” from research• Outcome for Braunwald/Harvard: Written public
apology; retracted papers, great embarrassment resulting from questioned credibility of past and future work
The Harvard Fraud (U.S., 1980’s):
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Why GCP? Case #4• The New Jersey Investigator (U.S., 1990)
– Fabrication of data from non-existent patients supposedly enrolled in a clinical drug trial
– Drug got approved by FDA based on his data, among others
– Court Assessment: Investigator put patients’ lives at risk, due to drug approval based on his fabricated data
– Outcome: M.D. sentenced to imprisonment
• The California Investigator (U.S., 1999)– 8 years, 42 companies, 170 protocols; contaminated 91
clinical development plans with fraudulent data – Serving 15 years imprisonment
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Cases of Scientific Misconduct
• U.S. Halts Research On Humans at Duke. University Can’t Ensure Safety, Probers Find.– The Washington Post, May 12, 1999
• Drug Trials Hide Conflicts for Doctors– New York Times, May 16, 1999
• A Doctor’s Drug Trials Turn Into Fraud– New York Times, May 17, 1999
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Cases of Scientific Misconduct (2)• Doctor admits research fraud.
– Dyer C: BMJ 316(7132):647, 1998
• The Stephen E. Breuning case: The impact of fraudulent research on the scientific literature.– Currie C: BMJ 315(7110):747-8, 1997
• Cardiologist admits research misconduct.– Dyer C: BMJ 314(7093):1501, 1997
• German oncology research shaken by fraud case.– Abbott A: Ann Oncol 9(1)1-2, 1998
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Cases of Scientific Misconduct (3)
• Authorship. Author saw fraud, misconduct and unfairness to more junior staff.– Garfield E, Welljams-Dorof A: JAMA
263(10):1424-6, 1998
• I accuse the University of Arizona at Tucson, Cusanovich, Cetas, Likins and consorts of perjury, denial of justice, infringements of ethics and human rights ……..– Wegmann RJ: Cell Mol Biol 44(8):1171-202, 1998
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DHHS Suspends IRB at University of Illinois, Chicago - 16 Sept 1999
• Some studies were never reviewed by IRBSome studies were never reviewed by IRB• No consent obtained in some trialsNo consent obtained in some trials• Lack of IRB support staffLack of IRB support staff• Decisions made by IRB without key documents Decisions made by IRB without key documents
being reviewed as related to subject recruitment, being reviewed as related to subject recruitment, enrollment, selection process for subjects, enrollment, selection process for subjects, pediatric informationpediatric information
• Safety of subjects was not properly assessedSafety of subjects was not properly assessed• More oversight of research required by the More oversight of research required by the
committeecommittee
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DHHS Suspends IRB at University of Illinois, Chicago - 16 Sept 1999
• IRB staff lacking education on Health and Human IRB staff lacking education on Health and Human Services proceduresServices procedures
• No documentation of rules being waived by IRB No documentation of rules being waived by IRB regarding consentregarding consent
• Insufficient membership during reviews by IRBInsufficient membership during reviews by IRB• No follow up review of changes in programs to No follow up review of changes in programs to
insure implementationinsure implementation• Failure of research groups to obtain renewals from Failure of research groups to obtain renewals from
IRBIRB
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DHHS Action for Suspended IRB• Stop reviewing all new studiesStop reviewing all new studies
• Stop enrollment in all federally funded Stop enrollment in all federally funded studiesstudies
• ReorganizeReorganize
• Come up with a plan to address the Come up with a plan to address the deficienciesdeficiencies
• Hire additional support staffHire additional support staff
• Develop an educational program for Develop an educational program for membersmembers
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Scientific Misconduct: India
• Untested AIDS Vaccine in Human Trials. – Good Clinical Practice Journal 6(3):5-6, 1999
• Case background:– Dr. Ishwar Gilada, Indian Health Organization– Administered untested vaccine to 10 HIV-
positive patients (Manisyl, a bovine immunodeficiency virus vaccine)
– No permission sought from DCGI– Patient took case to court
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International Conference on Harmonisation (ICH)
• ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussion of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines
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ICH Constitution - I• ICH parties
– EU– EFPIA– MHW Japan– JPMA– FDA– PhRMA
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ICH Constitution - II
• Observers– WHO– EFTA– Canada
• IFPMA
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ICH Steering Committee
• 2 seats for each of the 6 co-sponsors
• Non-voting member IFPMA offers Secretariat - Geneva
• 3 Observers
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ICH Process
• Step 1: Consensus building• Step 2: Start of Regulatory action• Step 3: Regulatory Consultation• Step 4: Adoption of a Tripartite
Harmonized Text• Step 5: Implementation
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ICH Topics
• Q=Quality• S=Safety• E=Efficacy• M=Multidisciplinary
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Quality Topics
• Q1: Stability• Q2: Analytical Validation• Q3: Impurities• Q4: Pharmacopoeias• Q5: Biotechnological quality• Q6: Specifications• Q7: GMP
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Efficacy Topics
• E1: Exposure• E2: Clinical Safety• E3: Study Reports• E4: Dose Response• E5: Ethnic Factors• E6: GCP• E7: Special Populations• E8: Clinical Trial Design• E9: Pediatrics• E10: Therapeutic Categories
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Safety Topics
• S1: Carcinogenicity• S2: Genotoxicity• S3: Kinetics• S4: Toxicity• S5: Reprotox• S6: Biotech Safety • S7: Pharmacology• S8: Multidisciplinary
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ICH-GCP: E6
• Ethics Committees
• Investigators
• Sponsors
• Essential Documents
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Ethics Committee
• Underlying principle: Oversight of ethical aspects of a clinical trial
• Constitution
• Operations
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Investigator
• Underlying principle: Patient safety
• Informed consent• Adverse events• Medical care• Documentation• Communication• Clinical trial supplies
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Sponsor
• Underlying principle : data quality, compliance with guidelines
• Site, Investigator selection• Training• Monitoring• Drug supplies• Regulatory• Communication
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Common GCP issues during study
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Informed Consent
Correct version Length of consent form Copy to patients Documentation - of contacts, in source files
etc Translations Ethics committee approval and information to ongoing patients Witness
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Recruitment and Study procedures
Screening procedures before consent Incomplete laboratory workup per
protocol Inclusion/Exclusion exceptions not
discussed with medical monitor Patient visits outside the protocol
allowed window Advertisements not approved by
sponsor/ethics committees Difficulties in enrollment - action from
investigator and sponsor
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Monitoring
Source data problems
CRF completion quality
Study team training issues
Incomplete essential documentation
Monitoring frequency issues
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Clinical Trial Supplies
Randomization errors
Accountability problems
Improper storage conditions
Compliance issues
Blind breaking issues
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Safety Reporting
Unreported SAEs Delayed reporting of SAEs Documentation in source files of AEs
and SAEs SAE reporting to institutional ethics
committee Additional safety information to
ongoing/new patients - consent addenda/amendments
Updates to investigators’ brochure