The History Of Gcp

THE HISTORY AND OVERVIEW OF GCP

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Drug Development Process

1. Drug Discovery

2. Early Development (Pre-clinical, IND, Phase I and Early Phase II) 3. Advanced Clinical Trials (Phase III)

5. Post-Marketing Strategies (Phase III-b and IV)

4. Drug Registration and Approval 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 Regulators

GCP Institute

•Investigator •Ethics Committee •Administrator

Sponsor •Monitor

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Framework for Clinical Trial Conduct

Protocol, SOPs Local regulations ICH-GCP Declaration of Helsinki

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The Concept of Good Clinical Practice

D

International Scientific & Ethical quality Standard

RECO R

REPORT

DESIGN

COLLECT

Patient Safety

Credibility of Data GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

Why GCP? Case #3 The Harvard Fraud (U.S., 1980’s):

• 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 GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

DHHS Suspends IRB at University of Illinois, Chicago - 16 Sept 1999 • • • •

Some studies were never reviewed by IRB No consent obtained in some trials Lack of IRB support staff Decisions made by IRB without key documents being reviewed as related to subject recruitment, enrollment, selection process for subjects, pediatric information • Safety of subjects was not properly assessed • More oversight of research required by the committee GCP WORKSHOP, Dec 13, 2001

DHHS Suspends IRB at University of Illinois, Chicago - 16 Sept 1999 • IRB staff lacking education on Health and Human Services procedures • No documentation of rules being waived by IRB regarding consent • Insufficient membership during reviews by IRB • No follow up review of changes in programs to insure implementation • Failure of research groups to obtain renewals from IRB GCP WORKSHOP, Dec 13, 2001

DHHS Action for Suspended IRB • Stop reviewing all new studies • Stop enrollment in all federally funded studies • Reorganize • Come up with a plan to address the deficiencies • Hire additional support staff • Develop an educational program for members GCP WORKSHOP, Dec 13, 2001

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 HIVpositive 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 cosponsors • Non-voting member IFPMA offers Secretariat - Geneva • 3 Observers GCP WORKSHOP, Dec 13, 2001

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: Q2: Q3: Q4: Q5: Q6: Q7:

Stability Analytical Validation Impurities Pharmacopoeias Biotechnological quality Specifications 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 GCP WORKSHOP, Dec 13, 2001

Safety Topics • • • • • • • •

S1: S2: S3: S4: S5: S6: S7: S8:

Carcinogenicity Genotoxicity Kinetics Toxicity Reprotox Biotech Safety Pharmacology Multidisciplinary GCP WORKSHOP, Dec 13, 2001

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 GCP WORKSHOP, Dec 13, 2001

Clinical Trial Supplies Randomization errors Accountability problems Improper storage conditions Compliance issues Blind breaking issues GCP WORKSHOP, Dec 13, 2001

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

GCP WORKSHOP, Dec 13, 2001