Clinical Trials Conference July 17, 2007

1. Clinical Trials ConferenceJuly 17, 2007 Managing and Complying with Clinical Quality Obligations Bradley Merrill Thompson Epstein Becker & Green, PC

2. Topics Importance of quality assurance Overview of risk management approach Good Clinical Practices GCP experience Quality and risk management techniques

3. Importance of Quality Assurance • More studies; more sites; greater volume • Expansion and fluidity of clinical investigator pool • New players in new roles (CROs, SMOs) • New technologies (electronic recordkeeping) • More participation by vulnerable subjects • Global expansion (areas new to GCP)

4. Quality Requirements (ISO 9000) • A quality requirement is a characteristic that a product or service must have to satisfy needs and expectations of the customer requirements

5. The end product of clinical research poolingof datain thedatabase trialreport collectionof data trial protocol analysis • A product is an output from a process • The output from the clinical research process is information

6. Quality in clinical research may be defined as . . . An answer A question Collection & analysis of data • Reliability and credibility of information providing an answer to a scientific question • Compliance of the trial process with defined requirements

7. Customers of clinical research • Society / consumers • Research subjects • Sponsors • Regulatory authorities worldwide • Hospitals / institutions • Ethics committees

8. Clinical research customers’ requirements Law & Regulations:EU DirectivesUS CFRlocal legislation Ethical Standards:Declaration of Helsinki Good Practice Standards:GXPs:ICH GCP, ICH GMP, OECD GLP

9. Topics A quality assurance approach Overview of risk management approach Good Clinical Practices GCP experience Quality and risk management techniques

10. Risk Management • Product Risk • FDA does, and you should, consider the intrinsic risk of the product you are investigating, when deciding the level of sophistication and elegance of your quality system. • Product risk is a function of: • Technology • Disease or condition • Setting • User • Remember that the clinical trials quality system is a design input under device QSR, in addition to being subject to Good Clinical practices • Systems require very similar approach and philosophy

11. Risk Management • Commercial Risk • FDA does, and you should, consider the commercial complexity of the structure of the clinical trial you are organizing when deciding the level of sophistication and elegance of your quality system and the extent of training needed • Use of CROs, sub-investigators, and so forth • The more complexity, the greater the burden to manage it well

12. Risk Management • Drive it with data • Study your products • Study the commercial arrangements to identify risks and weaknesses • Study FDA experience inspecting clinical trials • Study litigation brought against sponsors • Study reports investigating clinical trial quality

13. Why? If you don’t, you might … • Harm patients • Liability to patients • Data from expensive studies disqualified from use in FDA submissions • Or expensive fixes required • Civil and criminal liability to federal and state regulators • Such as OIG, FDA, and state agencies

14. Rejection of data Deficiency letter IDE, 510(k), or PMA withdrawal Untitled letters Warning letters Consent Agreement Disqualification CI, IRB, GLP IRB restrictions No new studies or subjects Application Integrity Policy Civil Money Penalties Seizure / Detention Injunction Criminal Prosecution FDA Regulatory Actions

15. Topics Importance of quality assurance Overview of risk management approach Good Clinical Practices What are they? Where do you find them? GCP experience Quality and risk management techniques

16. What are Good Clinical Practices? • GCPs are the rules—and self-determined standards—governing clinical research • GCPs promote scientific and ethical quality in the conduct of clinical trials • For clinical trials, GCPs set standards for the: Design Conduct Performance Monitoring Auditing Recording Analysis Reporting

17. What are they? • Ethics: Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). • Risk/Benefit: Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

18. What are they? • Protection: The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. • Well-Supported: The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. • Scientifically sound: Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

19. What are they? • IRB Review: A trial should be conducted in compliance with the protocol that has received prior intuitional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion. • Doctor Managed: The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician, or, when appropriate, of a qualified dentist.

20. What are they? • Well-staffed: Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). • Informed Consent: Freely given informed consent should be obtained from every subject prior to clinical trial participation. • Record keeping: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

21. What are they? • Confidentiality: The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). • Products: Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

22. What are they? • SOP Driven: Systems with procedures that assure the quality of every aspect of the trial should be implemented. • Others: Country specific requirements also must be factored in, such as financial conflict of interest and investigator payment rules

23. Basic US sponsor obligations • Select qualified investigators • Provide sufficient information to investigators to conduct the trial • Oversee the trial and enforce compliance • Monitor trial progress • Conduct safety analyses, provide notification, and submit reports (when appropriate) • Keep appropriate records • Review and evaluate safety and effectiveness

24. Basic US investigator obligations • Ensure IRB review • Protect the rights and welfare of trial subjects • Obtain informed consent • Follow the protocol • Personally supervise the study and clinical staff • Report adverse events • Submit appropriate financial disclosures • Keep appropriate records

25. Where do you find them in US? A Tale of Two Systems • In the US, the standards actually vary depending on the purpose of the clinical trial. • FDA rules for trials that will be conducted on articles subject to regulation by FDA and for possible submission to FDA • HHS (common rule) for research conducted or supported by HHS and those who voluntarily agree to be bound (federal-wide assurance) • Both sets of standards can apply

26. Clinical research customers’ requirements • US FDA • FDA IRB • FDA informed consent • FDA Part 812 investigator and sponsor obligations • FDA Part 312 investigator and sponsor obligations • Investigator financial conflict • Drug and device quality system requirements • FDA Part 11 electronic records • FDA guidance • Both • Fraud and abuse, antikickback, false claims • HIPAA • Industry standards (e.g., PhRMA Principles) • State law privacy • Other state law • Common Rule • HHS IRB • HHS informed consent • HHS reporting obligations • HHS guidance

27. International Conference on Harmonization (ICH) Tripartite Guideline for GCP (1996) • Provides a unified standard for the conduct of clinical trials in Japan, US, and EU • Facilitates the mutual acceptance of clinical data by regulatory authorities in Japan, US, and EU • Assures the safety and protection of clinical trial subjects • Ensures the credibility of data collected in clinical trials

28. Topics Importance of quality assurance Overview of risk management approach Good Clinical Practices GCP experience FDA’s experience enforcing them Sponsor’s experience defending them Studies examining weaknesses Quality and risk management techniques

29. Clinical investigator inspections What does FDA look for during the inspection? The FDA Inspection (Audit) compares • Source Medical Record Data vs • Case Report Forms vs • Data Listing Submitted to NDA

30. Clinical investigator inspections • Clinical Investigator inspection determines • Source of subjects • Did subjects exist? • Did they have the disease/condition under study? • Did they meet inclusion/exclusion criteria? • Consent obtained? • IRB review and approval obtained?

31. Clinical investigator inspections • Clinical Investigator inspection determines • Did the subjects receive the assigned study drug in the dose, route and frequency specified by the protocol? • Are the case report forms complete and in agreement with source data? Compare with NDA data listing. • Are adverse experiences reported to sponsor and IRB? • Was the protocol followed? • Adequacy and completeness of records?

32. Investigator inspections: all centers - 2006 183 379 66

33. Clinical investigator deficienciesCDER inspections - FY 2006 Foreign n = 89 Domestic n = 290

34. Prevalence of OAI inspections (DSI Data) Total number of FDA inspections FY04 – FY06* = 1175 Total OAI cases = 31 Percent OAI = 3% *FY06 to date

35. Prevalence of OAI inspections (DSI Data) Routine FDA inspections FY04 – FY06* = 936 Total OAI cases = 2 Percent OAI = .6% Directed FDA inspections FY04 – FY06* - 239 Total OAI cases = 25 Percent OAI = 11% *FY06 to date

36. Complaints to the Division of Scientific Investigations (DSI) • The number of complaints about clinical investigators and clinical trials continues to increase • DSI encourages such reporting (new Electronic Complaint Form) • Follow-up on complaints is of vital strategic importance • Real-time follow-up • Public protection • Public confidence

37. Informed Consent Issues Falsification Failure to report adverse events Failure to follow the protocol Inadequate Records Qualifications of persons performing physicals Failure to get IRB approval, report changes in research Failure to follow FDA regulations Drug accountability Recruitment Practices Poor Supervision No active IND Violations of GLP regs Monitoring practices Blinding Charging for the test article Misleading advertisements What are they complaining about?

38. Complaints received: 1992-2006

39. CI “for cause” inspection assignments(CDER, FY 1992 – 2005*) *FY05 through 10/05

40. BIMO inspects more than just clinical investigators • Sponsors and monitors • IRBs • GLP • Bio-equivalence

41. BIMO inspections completed 800 700 600 S-M 500 CI 400 IRB 300 BIOEQ 200 GLP 100 0 FY97 FY98 FY99 FY00 FY01 FY02 FY03 FY04 FY05 *FY06 723 683 690 692 678 657 627 580 556 549 *FY06 to date

42. BIMO warning letters by year and type

43. All GCP warning letters by year (2004 – May 2007) 2004 2005 2006 *2007 *Thru May 2007

44. Warning letter observations for investigators, including sponsor-investigators (Total 2004 – May 2007)

45. Sponsor FDA warning letters • Sponsors are more likely to have problems with monitoring, which makes sense • Records and reports still a frequent observation (and an easy target for FDA) • Not surprisingly, FDA more likely to target investigators with human subject violations, such as IRB and IC violations, because these are investigator responsibilities

46. Warning letter observations for sponsors (Total 2004 – May 2007)

47. Total warning letters for drugs, devices, and biologics (Total 2004 – May 2007)

48. FDA warning letters as focused on drugs vs. devices. vs. biologics • Many, many more device letters • Wide difference in number of letters makes it difficult to make apple-to-apple comparisons. • However, relatively more observations in device warning letters relating to: • Sponsor deficiencies • Monitoring

49. Warning letter observations for drugs, devices, and biologics (Total 2004 – May 2007) Biologic Device Drug

50. Sponsor’s experience defending studies in litigation • University of Pennsylvania Study (1999) • Death of 18 year-old Jesse Gelsinger in a gene therapy trial for the treatment of an inherited liver disease resulted in an undisclosed settlement and U.S. Senate hearings • Study approval required termination of the trial if patients suffered serious side effects • Researchers failed to alert FDA to reports of earlier patients whose liver damage warranted termination • The level of ammonia in Gelsinger’s liver should have excluded him from participating in the trial