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FDA’s Oversight of Clinical Trials Overview of GCP Bioresearch Monitoring Program

FDA’s Oversight of Clinical Trials Overview of GCP Bioresearch Monitoring Program. Carolyn Hommel Good Clinical Practice Program FDA February 25, 2004. “BIMO”. FDA calls its program of on-site inspections for GCP and GLP its “Bioresearch Monitoring Program” or “BIMO”

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FDA’s Oversight of Clinical Trials Overview of GCP Bioresearch Monitoring Program

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  1. FDA’s Oversight of Clinical TrialsOverview of GCP Bioresearch Monitoring Program Carolyn Hommel Good Clinical Practice Program FDA February 25, 2004

  2. “BIMO” • FDA calls its program of on-site inspections for GCP and GLP its “Bioresearch Monitoring Program” or “BIMO” • The program includes inspections of: • Clinical Investigators • Sponsors, monitors, CROs • Institutional Review Boards • Bioequivalence Laboratories and Facilities • GLP Facilities (nonclinical studies)

  3. GCP “BIMO” Inspections (Clinical Trials) • Each year, FDA conducts approximately 1100 GCP BIMO inspections most inspections are of clinical investigators • Clinical Investigators (700/year) • IRB’s (250/year) • Sponsors/CRO’s (100/year) • Bioequivalence Facilities (50/year) • Inspections may be conducted anywhere in the world for studies submitted to FDA

  4. Focus of FDA Inspections • Data auditing is a major component of GCP BIMO inspections conducted at clinical investigator and sponsor sites • IRB inspections are more oriented toward the process of IRB review and the maintenance of required records

  5. BIMO Inspections CompletedBy Program TypeAll Centers - FY’03 6% 11% 28% 55% n= 1,138

  6. BIMO Inspections Completed FDA FY 2003 11% 31% 0.2% 57% n= 1,138 2/19/04

  7. Program Objectives • To verify the quality and integrity of bioresearch data • To protect the rights and welfare of human research subjects

  8. Bioresearch Monitoring (BIMO) Compliance Programs • FDA has compliance programs which serve as written procedures for conducting BIMO inspections • Good Laboratory Practice CP 7348.808 • Clinical Investigator CP 7348.811 • Institutional Review Board CP 7348.809 • Sponsor, CRO Monitors CP 7348.810 • In Vivo Bioequivalence CP 7348.001 http://www.fda.gov/oc/gcp/compliance.html

  9. Clinical Investigator Program • Provides for study specific inspections and audits of physicians, veterinarians, and other investigators conducting clinical trials of human and veterinary drugs, medical devices, biologicals, etc.

  10. Clinical Investigator Regulations • In order to receive investigational articles, each clinical investigator must sign an agreement to follow regulations governing use of investigational products • Regulations • 21 CFR 312 (Human Drugs) • 21 CFR 812 (Medical Devices) • 21 CFR 511 (Veterinary Drugs)

  11. Primary Regulatory Obligations Include Commitment to • Follow the approved protocol or research plan • Obtain informed consent and adhere to FDA regulations regarding protection of human research subjects • Maintain adequate and accurate records of study observations • Administer test article only to subjects under control of the investigator

  12. Nature of Program • Study specific data audits announced in advance • Inspection includes interview with clinical investigator and in-depth data audit to validate study findings and verify investigator compliance with regulations

  13. GCP “BIMO” Inspections • Performed for every NDA • May be performed during the IND at any phase of product development • May be assigned based on complaints received by FDA (from subjects, IRBs, industry)

  14. Complaints Received: 1992-2003(CDER) 139 119 110 110 106* 15 13 11 11 9 8 9 92 93 94 95 96 97 98 99 00 01 02 03

  15. CI “For Cause” Inspection Assignments(CDER, FY 1992 - 2003) 109 69 64 61 29 16 5 12 11 6 9 8 FY 92 93 94 95 96 97 98 99 00 01 02 03

  16. GCP Inspections:Routine Vs. Directed • Routine • Inspections assigned for NDA/PMA’s • Directed • Problems identified at IND/IDE stage • Complaints to FDA • FDA, other Agencies • Sponsors/monitors • Institutions/IRB’s • Subjects/Public

  17. Compliance Classifications • NAI- No Action Indicated • No objectionable conditions or practices were found during the inspection (or the objectionable conditions found do not justify further regulatory action) • VAI-Voluntary Action Indicated • Objectionable conditions or practices were found, but FDA is not prepared to take or recommend any administrative or regulatory action.

  18. Compliance Classifications • OAI- Official Action Indicated • Regulatory and/or Administrative actions will be recommended due to significant objectionable observations • Warning Letters and other correspondence • Accessible from the GCP Website http://www.fda.gov/oc/gcp (Enforcement Information)

  19. Clinical Inspections Center for Drug Evaluation and Research - FY’03(Domestic & International) 6% 5% 37% n = 369 52% 2/19/04

  20. Clinical Investigator Deficiency CategoriesFY’03 39% 29% 13% 7% 7% n=369* *Inspections conducted for CDER

  21. Regulatory/Administrative Follow-up • Rejection of study • Disqualification • Prosecution

  22. Institutional Review Board (IRB) • Means any board, committee or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. • The primary purpose of such review is to assure protection of the rights and welfare of the human subjects.

  23. Regulatory Basis of Program • All FDA regulated research involving human subjects must be covered by an IRB operating in accordance with 21 CFR 56 • Informed consent must be obtained from all human research subjects in accordance with 21 CFR 50

  24. Nature of Program • Program provides for regularly scheduled inspections of IRBs to verify compliance with regulations • IRBs associated with active INDs (Form FDA 1572) • Program objective is protection of human research subjects, rather than data validation

  25. Nature of Program • Inspections are announced and scheduled in advance • Consists of interviews with responsible IRB staff • In-depth review of SOPs, files and records • Active studies used to assess IRB operations and conformance to regulatory requirements

  26. IRB ClassificationsAll Centers - FY’03 11% 26% 7% 56% n = 313 2/19/04

  27. IRB Inspections - Deficiencies (FY’02: CDER assigned) 40% 36% 27% 22% 19% 9% 8% Written Procedures Continuing Review Consent Elements Exp. Review Members Minutes Quorum N= 161

  28. Regulatory/Administrative Follow-up • Restriction of IRB approval of new studies or entry of subjects • Disqualification

  29. Sponsor, Contract Research Organization, Monitor Program • Program provides for inspections of those parties responsible for initiating, overseeing, and submitting the results of research to FDA • Regulations • 21 CFR 312 • 21 CFR 812 • 21 CFR 50, 54, 56

  30. Regulatory Obligations of Sponsors • Label investigational products appropriately • Initiate, withhold, or discontinue clinical trials as required • Refrain from commercialization of investigational products • Control the distribution and return of investigational products • Select qualified investigators to conduct and monitor studies

  31. Sponsor Obligations (continued) • Disseminate appropriate information to investigators • Evaluate and report adverse experiences • Maintain adequate records of studies • Submit progress reports and the final results of studies

  32. Nature of Program • Study specific inspections routinely announced in advance consisting of records audit and interviews • Inspection assigned for each NME in CDER and each PMA in CDRH • Objective is to evaluate compliance with regulations and validate data

  33. Nature of program (continued) • Principal areas covered: • Organization and personnel • Selection of clinical investigators • Selection of monitors and monitoring procedures followed • Reporting of adverse experiences and reactions • Test article characterization and accountability

  34. Sponsor/Monitor/CRO InspectionsCommon Deficiencies - FYs 1998-2000 n= 39 23% 21% 18% 15% 13% 10%

  35. Sponsor/Monitor/CRO Inspections All Centers - FY 03 12% 17% 36% 35% n = 127 Updated 2/19/04

  36. Regulatory Requirements • Bioequivalence studies are conducted primarily • To support an abbreviated new drug application (ANDA) for generic copy • For new dosage form or formulation of marketed drug

  37. Bioequivalence Inspection Program • Bioequivalence studies supporting NDAs may be inspected when appropriate • Pivotal to decision-making • Concerns about data integrity

  38. Bioequivalence Regulations • 21 CFR 320, 314, 312 • 21 CFR 50, 56 (Consent, IRB)

  39. Bioequivalence Inspection Program • Inspection of clinical facilities and analytical labs associated with bioequivalence studies • Focus is on bioequivalence studies supporting ANDAs; in particular: • New facilities • Previously violative sites • Suspicious data • Non-conventional study

  40. Nature of Inspections • Includes physical inspection and technical evaluation of laboratory facilities and methods; multiple facilities may be involved • Includes audit of analytical and clinical data • Conducted by inspection team including laboratory chemist and field investigator

  41. Bioequivalence Inspections 92 87 83 82 75 74 70 61 FY 96 97 98 99 00 01 02 03

  42. Bioequivalence InspectionsClassificationsFY’03 28% 64% 4% 4% n =84 *Updated 2/19/04

  43. GCP Help and Information • FDA Web Site dedicated to GCP Information: • http://www.fda.gov/oc/gcp • Contact the OGCP Staff: • Email: gcpquestions@oc.fda.gov • Telephone: 301-827-3340 • Facsimile: 301-827-1169

  44. Where to Get Help • Write: Food and Drug Administration 5600 Fishers Lane, HF-34 Parklawn Building, Room 9C-24 Rockville, MD 20857

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