Presentation at ACRP Annual Meeting, focusing on how an IRB can face liability in particular scenarios in the clinical trial arena, including a discussion of best practices for IRBs.

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 – 8th 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