The History of GCP

GCP WORKSHOP, Dec 13, 2001

THE HISTORY AND

OVERVIEW OF GCP


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






Clinical Trial Process


What is GCP?

Good Clinical Practice

Refers to

Good Clinical (Research) Practice


Participants in a Clinical Trial

Sponsor•Monitor

Institute•Investigator•Ethics Committee•Administrator

Regulators

GCP


Framework for Clinical Trial Conduct

Declaration of Helsinki

ICH-GCP

Local regulations

Protocol, SOPs


International Scientific & Ethical quality Standard

DESIGN

REPO

RT

REC

OR

D

COLLECT

Patient Safety

Credibility of Data

The Concept of Good Clinical Practice


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


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


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


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“too clean” data & intact dogs in the dumpster• Outcome for fellow: License withdrawn; expelled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):


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


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


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


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


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


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


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


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


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


ICH Constitution - I• ICH parties

– EU– EFPIA– MHW Japan– JPMA– FDA– PhRMA


ICH Constitution - II

• Observers– WHO– EFTA– Canada

• IFPMA


ICH Steering Committee

• 2 seats for each of the 6 co-sponsors

• Non-voting member IFPMA offers Secretariat - Geneva

• 3 Observers


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


ICH Topics

• Q=Quality• S=Safety• E=Efficacy• M=Multidisciplinary


Quality Topics

• Q1: Stability• Q2: Analytical Validation• Q3: Impurities• Q4: Pharmacopoeias• Q5: Biotechnological quality• Q6: Specifications• Q7: GMP


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


Safety Topics

• S1: Carcinogenicity• S2: Genotoxicity• S3: Kinetics• S4: Toxicity• S5: Reprotox• S6: Biotech Safety • S7: Pharmacology• S8: Multidisciplinary


ICH-GCP: E6

• Ethics Committees

• Investigators

• Sponsors

• Essential Documents


Ethics Committee

• Underlying principle: Oversight of ethical aspects of a clinical trial

• Constitution

• Operations


Investigator

• Underlying principle: Patient safety

• Informed consent• Adverse events• Medical care• Documentation• Communication• Clinical trial supplies


Sponsor

• Underlying principle : data quality, compliance with guidelines

• Site, Investigator selection• Training• Monitoring• Drug supplies• Regulatory• Communication


Common GCP issues during study


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


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


Monitoring

Source data problems

CRF completion quality

Study team training issues

Incomplete essential documentation

Monitoring frequency issues


Clinical Trial Supplies

Randomization errors

Accountability problems

Improper storage conditions

Compliance issues

Blind breaking issues


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

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