Good Clinical Practice: Are We There Yet ? And What Comes Next ?

1. Good Clinical Practice: Are We There Yet ? And What Comes Next ? David A. Lepay, MD PhD Senior Advisor for Clinical Science Office of the Commissioner, US FDA July 25, 2007

2. What This Talk Will Cover • Introduction to FDA • FDA Expectations and Oversight in Clinical Research • New Challenges in Clinical Research • FDA GCP Strategies and Initiatives

3. FDA: Key Facts • Oldest consumer protection agency in the U.S. • Workforce of nearly 10,000 with an annual budget of approximately $1.9 billion • Regulates nearly 25% of the U.S. economy • Pharmaceuticals • Biologics (including blood products, vaccines) • Medical devices (diagnostic and therapeutic) • Veterinary medicines • Foods

4. FDA: Logistics • Based in Rockville, MD (15 miles from DC) • 20 District Offices across the U.S. • Dallas District Office • Resident Post in Houston • General inquiries: 1-888-INFO-FDA • Website: www.fda.gov • Note link to “Clinical Trials” pages for “Consumers” and for “Professionals”

5. FDA’s Authority over Clinical Research • FDA’s authority derives from the movement of investigational drugs/biologics/devices across U.S. national/state borders • An IND (research permit) must be in effect to lawfully ship an investigational drug within the U.S. for purposes of a clinical investigation • FDA regulations establish direct authority over all investigators, sponsors, monitors, contract research organizations, and IRBs/institutions conducting research under a U.S. IND

6. Levels of Authority • FDA must operate in accordance with the law (principally the Food Drug and Cosmetic Act) • Executes provisions of the law • Can’t exceed authorities granted under the law • FDA can promulgate regulations to implement the law; these carry the force of law • FDA can develop guidance ( FDA’s “best thinking”); guidance is not legally binding

7. Application Review at FDA • Review of research applications (IND/IDE) • Review of marketing applications (NDA/ BLA/PMA) • Postmarketing review

8. Review of Research Applications (IND/IDE) • Conducted by review teams in FDA’s Centers • Organized by therapeutic area • Focus is on subject safety and on the ability of proposed studies/protocols to meet their stated objectives • Applicants/sponsors are responsible for the protocols (including the design of protocols) submitted to FDA applications • Application/protocol may proceed unless FDA imposes a “hold”

9. Dispelling Some Myths • FDA does not “approve” protocols • FDA does not “approve” informed consent documents • FDA does not certify clinical investigators, clinical sites, sponsors, or IRBs • FDA does not directly regulate clinical laboratories (GLP = preclinical (animal) testing) • FDA does not regulate the practice of medicine

10. FDA Inspection of Clinical Research • FDA has authority to inspect any party involved in clinical investigations of FDA-regulated products • Investigators, sponsors, monitors, CROs, institutions, IRBs • Most often to validate data submitted to FDA in support of marketing applications • But also “systems” inspections and “for cause” inspections” at any phase of testing

11. FDA’s Regulations for Clinical Research • Small subset of the over 1300 parts to Title 21 of the Code of Federal Regulations • 21 CFR 312/812: IND/IDE Regulations • 21 CFR 314/814: NDA/PMA Regulations • 21 CFR Part 50: Informed Consent • 21 CFR Part 56: IRB Regulations • 21 CFR Part 54: Financial Disclosure by Clinical Investigators • [21 CFR Part 11: Electronic Records; Electronic Signatures]

12. Good Clinical Practice (GCP) • Ethical and scientific quality standard for designing, conducting, recording, and reporting clinical investigations/research • Embraces FDA regulations [at a minimum] • Elaborated upon in FDA guidance documents • Including internationally harmonized guidance (e.g., ICH E6: GCP Consolidated Guideline) • System of shared responsibilities: sponsor, investigator(s), IRB(s)/institution(s), regulators

13. What FDA Expects: Sponsors -1- • Includes sponsor-investigators of investigator-initiated studies): • Understand when an application to FDA (IND/IDE) is required

14. When is an IND/IDE Required ? • In general: An IND/IDE is required when an unapproved drug (biologic or significant risk device) is used in a clinical investigation

15. When is an IND/IDE Required ? • An IND may be required when an approved product is used in a clinical investigation based on use of the study information (e.g., to support a new indication, change in labeling, or change in advertising) or based on increased risk • Even when exempt from an IND, IRB review and Informed Consent are required

16. What FDA Expects:Sponsors -2- • Select qualified sites/investigators • Provide investigators with the information they need to conduct the investigation properly • Monitor conduct of the investigation • Prompt correction or termination/reporting • Safety monitoring and reporting (to FDA and to investigators)

17. What FDA Expects:Investigators • Understand what you are agreeing to: the FDA Form 1572

18. The Investigator’s Signed Attestation (1572) -1- • Personally conduct or supervise the investigation • Read and understand the Investigator’s Brochure • Ensure that an IRB compliant with FDA requirements will be responsible for the initial and continuing review and approval of the study

19. The Investigator’s Signed Attestation (1572) -2- • Obtain IRB approval prior to initiating the study • Inform subjects and obtain informed consent in accordance with Part 50 • Promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects and others

20. The Investigator’s Signed Attestation (1572) -3- • Follow the protocol • Report adverse events to the sponsor • Ensure that those assisting in the conduct of the studies are informed about their obligations • “comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements in this part”

21. What FDA Expects:IRBs -1- • Understand your importance, your authority, and your responsibility under the regulations • Understand your most fundamental roles • Protection of research subjects • Ethical review of protocols (and assurance of scientific review) • Informed consent • Ensuring through continuing review that the study remains ethical to continue and that informed consent is current

22. What FDA Expects:IRBs -2- • Understand the roles of others • Investigator as the contact point with subjects • Expectation that the investigator will (and therefore is able) to personally conduct or supervise the study • Sponsor bears primary responsibility for monitoring and analyzing safety reports/data from the study • FDA is available to answer questions (including whether an IND/IDE is needed)

23. What FDA Expects:For All Parties • Understand the Basic Elements of Data Quality: Remember “ALCOA” • Attributable • Legible • Complete/Contemporaneous • Original • Accurate

24. “The Times They Are A- Changin’ ” • FDA regulations remain a “floor” for the conduct of regulated research • FDA continues in its most basic expectations for sponsors, investigators, and IRBs BUT

25. Changing Clinical Trial Landscape: Studies • More and varied clinical studies/study designs • Novel therapeutic modalities: proof of concept • Broader range of subject populations • Greater use of information technology • Electronic record-keeping • Electronic patient-reported outcomes • Remote monitoring

26. Changing Clinical Trial Landscape: Investigators • Smaller base of experienced clinical investigators (CIs) • Reported decline in number of CIs • Increasing proportion of CIs who do only a single study • More delegation • More sponsor-investigators/investigator- initiated studies

27. Changing Clinical Trial Landscape: Study Sites • More clinical sites per study • More private clinics vs. academic centers • More sites are not meeting subject accrual targets/timeframes • Sponsors reporting a greater proportion of sites that contribute only one subject or don’t/can’t contribute even a single subject • Start-up costs average $30K per site

28. The “Fear” Factor • Greater financial investments bring greater implications of failure • Growing concerns about litigation • Growing public fear and distrust • More information; less informed

29. Public Confidence in Clinical Research • Harris Interactive Survey • Online • May 6-17, 2004; April 19-26, 2005 • Previous surveys in 2000, 2001, and 2003 • N= 5,822 (’04 survey); N= 2,261 (’05) • Adults 18+ (General Public) Slides courtesy of Jill Guary, MS, CCRC, Director, Clinical Research, Harris Interactive (www.harrisinteractive.com)

30. Subjects who participate in clinical trials are making a contribution to science

31. Subjects who participate in clinical trials are taking a gamble with their health

32. Subjects who participate in clinical trials are like guinea pigs

33. Compliance Has Improved Over Time (FDA CI Inspections) FY’06 FY’77 20% 48% 6% NAI 20% OAI NAI OAI VAI VAI 60% 46% n = 596 Classified n = 15

34. Complaints to FDA are Increasing, FY 1998-2006 354 266 214 202 155 132 127 93 10 98 99 00 01 02 03 04 05 06 3/2/07

35. Good Clinical Practice at FDA • Public Concerns = Strategic Objectives • Safety • Information to the Individual Subject • An Ethical, Understandable, Transparent System • Rapid Recognition and Resolution of Problems

36. Themes • Quality Systems • Risk Management • Critical Path • Less “Can” Be More

37. Some Specifics • Subject Safety • “Establishment and Operation of Clinical Trial Data Monitoring Committees” (final guidance issued March 2006) • “Adverse Event Reporting – Improving Human Subject Protection” (issued for public comment on April 9, 2007) • “Supervisory Responsibilities of Investigators” (issued for public comment on May 10, 2007)

38. Some Specifics • A Strong IRB System • IRB Registration (Proposed Rule) • “Using a Centralized IRB Review Process in Multicenter Clinical Trials” (Final guidance issued March 2006) • Coordination among government agencies • (Non-governmental, voluntary accreditation programs)

39. Some Specifics • Advancing Technology • “Computerized Systems Used in Clinical Trials” (final guidance issued May 10, 2007) • Opening a Dialogue on “Quality” • DIA-FDA Workshop, “Developing and Implementing Quality in Clinical Investigations: From Design to Completion”, May 10-11 in D.C. • Public docket established to receive additional comments to FDA

40. Next Step: Building Confidence in Clinical Research • FDA needs your help • Talking to subjects • Setting standards for all who engage in clinical research • Focusing on quality • Reporting when serious problems occur • Actively participating in dialogue to promote participant protection and build capacity for future research

41. Closing Perspective You Too Are On This Road GCP is Not So Far Away… But We Will Get There Only If We Look Out for Each Other and Head There Together