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. 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) Premise

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

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

5. 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 Jesse Gelsinger

6.  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 Confilct of Interest

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

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

9. 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) Premise

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

11.  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 IRB Best Practices

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.  A process – not just paper Informed Consent Form

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

16. BEST PRACTICES Preparing ICDs  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

17. BEST PRACTICES ICD Development  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

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

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

20. BEST PRACTICES The I.C. Process  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]

21. BEST PRACTICES The I.C. Process  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

22. BEST PRACTICES The 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. BEST PRACTICES The I.C. Process  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

24. BEST PRACTICES The 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. BEST PRACTICES The I.C. Process  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

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

28.  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 Raise the Bar

29. BEST PRACTICES – Are They Possible for the IRB? 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

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