Unanticipated Risk in Clinical Research

1. Unanticipated Risk in Clinical Research Principles and Practice of Clinical Research November 18, 2003 Stephen E. Straus, M.D.

2. Clinical research involves risks and benefits both for the participant and the investigator Unanticipated injuries to research subjects lead to progressive changes in research regulation, oversight and conduct

3. Benefits of Conducting Clinical Research • Acquiring special expertise • Improving patient outcome • Humanitarian gesture • Grant support • Professional advancement

4. Risks of Conducting Clinical Research • Time consuming • Studies may fail • Lower income • Intense regulatory and public scrutiny • Personal and professional liability

5. Benefits of Participating in Clinical Research • Diagnosed by experts • Personalized attention and education • Access to novel therapies • Committed follow-up • Improved prognosis • Humanitarian gesture • Free care and other financial incentives

6. Risks of Participating in Clinical Research • More frequent and more invasive interventions • Assignment to placebo or ineffective treatments • Greater time investments • Less privacy • Known and unanticipated side effects

7. An Unexpected Death in aGene Therapy Trial: Background • Investigators at U of P and their partners in industry invent an adenovirus vector that expresses ornithine transcarbamylase • Approval granted by IRB, IBC, RAC, FDA to conduct clinical trials in OTC-deficient patients • Research patient Jessie Gelsinger dies

8. An Unexpected Death in a Gene Therapy Trial: Reactions • NIH, FDA, DHHS, Congressional investigations and hearings • Prolific media coverage • New mandates for DSMB, AER, clinical research training and conflict of interest reporting • Creation of OHRP; IRB closures • Law suits

9. Questions Asked on ‘The Morning After’ • Protocol: Scientifically and ethically appropriate? • Patient consent: Fully informative? • Investigator training: Adequate? • Financial conflicts: None? • Approvals: All obtained and updated? • Subject selection: Appropriate?

10. Questions Asked on‘The Morning After’ • Protocol adherence: Consistent? • SAEs: Identified? Reported promptly? • Documentation: Complete? • Study monitoring: Independent? • Data entry: Accurate? • Statistical analysis: Valid? • Reports: Objective?

11. Chronology of FIAU Studies 1970’s Synthesis of fluoropyrimidine analogues FIAC and FIAU Both inhibit herpesvirus replication

13. Chronology of FIAU Studies 1983-6 Phase I-II studies of IV and oral FIAC 30-1000 mg/m2 for 5-10 daysin cancer and AIDS patients with HSV, VZV, or CMV infections; suggest antiviral activity, but with nausea, ALT rises, and bone marrow suppression

14. Chronology of FIAU Studies 1984 FIAC and FIAU inhibit HBV DNA polymerase activity

15. Chronology of FIAU Studies 1990 ACTG 122A: Oral FIAC 0.6-5.0 mg/kg/d x 14d in CMV-infected AIDS pts. Nausea, fatigue, and CPK elevations limit the dose to 1.0 mg/kg/d, without anti-CMV effects. FIAC studies cease. FIAU is safe for 28d in animals.

16. Chronology of FIAU Studies 1990-1 ACTG 122B: Oral FIAU in 10 HIV- infected pts at 1 mg/kg x 14d. Nausea and fatigue at 1.7 mg/kg/d are dose-limiting. 6 HBV/HIV- infected pts treated at NIH. Marked suppression of HBV levels, with ‘acceptable’ side effects.

18. Chronology of FIAU Studies 1991-2 Dose de-escalation studies in 43 pts with HBV/HIV confirm short-term tolerance and antiviral activity down to 0.1 mg/kg/d.

19. Chronology of FIAU Studies 1991 Protocol modified to allow retreatment of earlier study subjects. 3/4 NIH pts die 2-5 months after ending retreatment: pancreatitis on ddI; 2 with liver failure. Autopsies - no microvesicular fat.

20. Chronology of FIAU Studies 1992 NIH trial in 24 HIV-negative HBV pts: FIAU 0.05-0.5 mg/kg/d x 28d. Dose- related inhibition of HBV DNA. ALT ‘flares.’ Complications: peripheral neuropathy and cholecystitis 4 mo after FIAU; neuropathy and hepatic failure 3 mo after treatment - dies 2 mo later. Autopsy - microvesicular fat!

22. Chronology of FIAU Studies 1992 Eli Lilly assumes FIAU development. More animal studies. March, Lilly multi-center trial of 0.1 vs 0.25 1993 mg/kg/d x 90d. NIH 180d trial: 15 pts enrolled; all get baseline nerve conduction studies.

23. Chronology of FIAU Studies May- Dose reduced or stopped for GI June upset in 3 pts and tingling in one. 1993 One pt admitted for fatigue and nausea. June 26, Pt presents with lactic acidosis. 1993 Trial is stopped. NIH, FDA, HHS, and Lilly are notified. All pts are admitted.

24. Chronology of FIAU Studies July- Despite termination of FIAU, 5 pts August die of progressive liver failure, lactic 1993 acidosis, pancreatitis, myopathy and neuropathy.Two survive with emergency liver transplantation. Five suffer reversible effects. Three remained well. The investigations begin

25. FIAU in the Media • Newspapers, magazines, radio, and TV report patient deaths • Patient and family anger is highlighted • Trial design and consent forms criticized • Investigators accused of negligence for ignoring clues to FIAU’s dangers

26. FIAU in the Media • Investigator charged with retribution against an angry patient • Video broadcast on ABC’s ‘Prime Time Live’ • Speculation on the mechanism of FIAU toxicity and implications for antiviral drug development • Summary reports on the sequential investigations

27. Congressional Inquiries Sept, 1993 House Committee on Government Operations requests all documents, including patient records. Oct,1993 Committee raises “serious questions of possible misconduct.” Requests an ‘impartial’ DHHS review of the study.

28. Congressional Inquiries Nov, The Senate Committee on Labor 1993 and Human Relations inquires. June, The House Committee calls the NIH 1994 Director’s investigation a “whitewash.” Demands an independent review by the IOM. 1995 Congressional interest wanes.

29. FDA Investigations Aug, FDA investigators inspect all study 1993 sites and records Sept, FDA Antiviral Drugs Advisory 1993 Committee discusses mechanisms and implications of FIAU toxicity Nov, FDA issues inspection reports, citing 1993 lack of prompt notification of deaths

30. FDA Investigations Nov, Task Force reports that investigators 1993 misinterpreted the ‘ALT’ flares May, FDA ‘Warning Letters’: late death 1994 reports; inadequate consent forms, and poor clinical judgment Oct, FDA proposes new regulations for 1994 documenting and reporting SAEs

31. NIH Responses June 26, Study terminated: Pts, Clinical 1993 Directors, IRBs, FDA, and drug sponsors notified July Formal study summaries sent to Institute Directors and DHHS Sept NIH Office of Human Subjects Research reports to OPRR that the protocols complied fully with NIH’s Multiple Project Assurance

32. NIH Responses Nov NIH Clinical Center Quality Assurance Service reports that the patient charts are “exemplary” Dec NIH Director convenes an ad hoc 1993 Advisory Committee to review the studies. All investigators and patients interviewed, and all records examined.

33. NIH Responses June, NIH Director’s Advisory Committee 1994 concludes that the studies were appropriate, conducted according to “the best of current clinical practice,” and that the FIAU toxicity is “a novel type of reaction that was unexpected.”

34. Institute of Medicine Review June, Independent review commissioned by 1994 the Secretary, DHHS. All records reviewed again, and all investigators, patients, sponsors, and FDA Medical Officers are interviewed. March, The IOM concludes that the studies were 1995 justified, properly designed, and well conducted.There was “no evidence of negligence.” The proposed FDA reporting guidelines are considered to be excessive.

35. Legal Issues Aug, Private and NIH legal counsel sought by 1993 the investigators Nov , First lawsuit filed. Referred to the 1993 Department of Justice for defense under the Federal Tort Claims Act 1994 Additional suits filed Dec, All lawsuits are settled out of court 1995

36. The Scientific Community Responds • Meetings on treatment and mechanisms • Public interest groups decry ‘lack’ of clinical research safeguards • Industry points out inherent risks of clinical research • Ethicists debate informed consent and the competing loyalties of clinical investigators • Hepatitis drug development ceasesfor 2 years

37. Mechanisms of FIAU Toxicity • Utilized by gamma polymerase and incorporated into nuclear and mitochondrial DNA • Loss of oxidative enzymes • Depletion of glycogen stores • Microvesicular fat accumulation • Lactic acidosis • Cellular apoptosis • Liver failure, pancreatitis, myopathy, neuropathy

38. Recommendations • Preclinical studies: Analyses in relevant species, but may not predict all events in humans. • Training: For all PI’s and associate investigators • Review: Separate scientific and ethical reviews with relevant expertise. Support IRB’s and train their members.

39. Recommendations • Consent forms: Uniform consent text; Simplify and shorten; emphasize dialogue; update; document electronically • Follow up: Adequate for the nature and known risks of trial materials • Data entry: Create one set of electronic records for all study patients. Support data management

40. Recommendations • Reporting: ‘harmonize’ all reporting forms and requirements. • Monitoring: Formalize and support DSMB’s. Provide on-line access to study records. • Incentives: Reward clinical research conduct and participation. Cover study-related injuries.

41. Conclusion There is no way to avoid all risk while participating in, or conducting, clinical research.

42. National Institute of Allergy and Infectious Diseases National Institutes of Health U.S. Department of Health and Human Services