Guilty ‘Til Proven Innocent: A Look at IRB Liability

1. Guilty ‘Til Proven Innocent:A Look at IRB Liability Dennis J. LaCroix, Esq. Senior Counsel - Compliance, Clinical Research & Healthcare Genzyme Corporation Linda G. Strause, PhD Executive Director, Oncology Clinical Operations Vical Incorporated Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. ACRP Annual Meeting 23 April 2007 Seattle, WA

2. Premise The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials. . .to ensure protection of the rights and welfare of human subjects of research. Source: FDA Guidance for IRBs and Investigators (1998 Update)

3. A Look at IRB Liability • Gelsinger context • Informed Consent focus • Thesis: IC process is broken! • Antithesis: IRB, defend thyself! • Synthesis: Best Practices. . .

4. IC Process Is Broken • Gelsinger Allegations • IRB Ineffectual • What IC process. . .??? • Subject Unprotected. . .!

5. Jesse Gelsinger On Sept. 17, 1999, Jesse Gelsinger, an 18 yr. old young man, died while participating in a gene transfer experiment at the Institute for Human Gene Therapy (“IHGT”) at UPenn. . . Jesse volunteered to participate in the experiment, knowing it would not benefit him in the least, because he was led to believe his participation had little risk and would directly benefit as yet unborn infants with OTC. . . Cf. Gelsinger Complaint, paragraphs 1 & 2

6. Confilct of Interest • Wilson, Genovo, UPenn, et al. • $20 million, 5% equity owner • Licenses to Genovo • Much benefit from RDAd vector • CISC knew of the conflicts. . . Cf. Complaint, para. 10-36; 51-54

7. IC Process. . .??? • Documents & Discussions • Deceptive & Misleading • Minimal Risk • Enormous Benefit Cf. Complaint, para. 59-62

8. IC Process. . .??? • Toxic effects understated • Monkeys not mentioned • No SAEs mentioned • Treatment efficacy noted • COIs not adequately disclosed Cf. Complaint, para. 61

9. Premise The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials. . .to ensure protection of the rights and welfare of human subjects of research. Source: FDA Guidance for IRBs and Investigators (1998 Update)

10. IRB Defend Thyself. . .! • Jesse’s wrongful death. . . (Cf. Complaint, para. 84-89, esp. 87) • Subject unprotected. . . • IRB Ineffective. . .

11. IRB Best Practices • IRB should adopt and follow written procedures • Initial and continuing reviews • Evaluation of degree of risk and changes • Review and documentation of Adverse and Serious Adverse Events • Document, document, document

12. BEST PRACTICES – Continuing Review Written progress reports from P.I. # of subjects in study Summary description of subject experiences (benefits, AEs) # of withdrawals & reasons Current risk/benefit ratios Get current I.C. document and compare to one cleared Frequency and nature of review is a factor of the study; but must be based on a written SOP

13. BEST PRACTICES – Continuing Review IND – what is duty to compare IND filings to info provided to the IRB? Not articulated in IRB guidesheets Might have caught some of the Gelsinger problems AE’s Must have a procedure to get these P.I.’s – have to be informed of your procedures for continuing review How do you do that? Handling of major changes to the research – convened meeting

14. Informed Consent Form • A process – not just paper

15. BEST PRACTICES – Informed Consent Preparing ICD’s Consider the reading level of the potential participants Use simple language – 8th grade If you need to use scientific terms, define them

16. Avoid using abbreviations or acronyms unless they are spelled out first Consider the age of the volunteer and the font size Version control & number pages BEST PRACTICESPreparing ICDs

17. Be concise Use the pronoun “you” consistently throughout to refer to the subject/participant Number the pages if the ICD is more than one page Spell everything correctly and use correct grammar. The most common error is the spelling of principal investigator: it is principal not principle BEST PRACTICESICD Development

18. BEST PRACTICESWhen to revise the ICD When risk/benefit ratio changes New information becomes available The Investigator decides, but needs ok from sponsor

19. Investigator’s involvement Signatures & initial lines & dates Witnesses Documentation Setting Enrollment goals Training on human subject protection BEST PRACTICESHow, What, When & Where of obtaining informed consent

20. Those obtaining informed consent from subjects must be trained in the areas of human subject protection [Note: Ultimately it is the regulatory responsibility of the Investigator to ensure IC has been obtained and all regulations, laws, SOP’s followed] BEST PRACTICESThe I.C. Process

21. Exchange of information between clinical investigators/study coordinators and subject Reading and signing the ICD Providing a copy to the subject Ongoing process of informed consent BEST PRACTICESThe I.C. Process

22. BEST PRACTICESThe I.C. Process During the IC discussion, the SC will measure the subject’s comprehension and understanding by asking study specific questions Have Investigator review with subject any questions they may have in regards to the study

23. If subject is willing to participate, ask subject to sign/date ICD; if requested on form, person obtaining IC should sign/date form Have witness sign/date ICD (if applicable) Provide subject copy of the consent form BEST PRACTICESThe I.C. Process

24. BEST PRACTICESThe I.C. Process Should there be a waiting period? [in Ireland, it’s six days] Retain original consent in separate study binder or regulatory binder Put copy of signed consent form in subject’s source documents

25. Note in source documentation that consent was administered PRIOR to initiation of study procedures Remember IC is an ongoing process Document at follow-up visits patients desire to remain on study BEST PRACTICESThe I.C. Process

26. BEST PRACTICESThe I.C. Process Investigator discusses with his/her potential participant the nature of the study If subject appears to meet eligibility requirements and shows interest in participating in the study, the patient can be referred to the study coordinator (SC) The SC reviews the ICD with the subject and addresses any questions within his/her scope of knowledge The SC provides the subject with the ICD and time to read the ICD

27. 45-60 minutes – Source: Christine K. Pierre, personal observation in clinical research setting How long does it take to obtain IC for a “routine clinical study”?

28. Raise the Bar • Guidelines and regulations are the base • Know the regulations: • 21 CFR 50 & 21 CFR 56 • 45 CFR 46 • FDA Information Sheets • Protect your committee: • Errors and Omissions Insurance • Directors and Officers Insurance

29. The University of Pennsylvania should evaluate the function of its IRBs. Specifically, the workload of each IRB may need to be decreased, in order to allow ample opportunity to carefully evaluate and monitor each clinical trial. There are approximately three to four thousand protocols per year with about 80 adverse events reported per one hundred protocols. Secondly, an IRB should have expertise, or, at a minimum, access to expertise, in evaluating the use of novel therapies such as gene therapy. It might help if individual IRBs were to deal with specialized areas of research, or be enlarged, so that they might be staffed with people knowledgeable about the issues before them. Furthermore, the IRBs should facilitate the sharing of information, especially the occurrence of adverse events, between different trials using similar therapies, such as the same viral vector. Source: April 25, 2000, Interim Report, U. of Penn. Internal Committee on Research Using Humans BEST PRACTICES – Are They Possible for the IRB?

30. “Research participation is a gift and contribution by the subject.” Jay Katz, 1994 As presented by Dale Hammerschmidt