guilty ‘til proven innocent: a look at irb liability dennis j. lacroix, esq. senior counsel -...

Guilty ‘Til Proven Innocent:Guilty ‘Til Proven Innocent:A Look at IRB LiabilityA Look at IRB Liability

Dennis J. LaCroix, Esq.Senior Counsel - Compliance, Clinical Research & Healthcare

Genzyme Corporation

Linda G. Strause, PhDExecutive 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

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

Gelsinger context

Informed Consent focus

Thesis: IC process is broken!

Antithesis: IRB, defend thyself!

Synthesis: Best Practices. . .

A Look at IRB Liability

Gelsinger Allegations

IRB Ineffectual

What IC process. . .???

Subject Unprotected. . .!

IC Process Is Broken

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

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

Documents & Discussions

Deceptive & Misleading

Minimal Risk

Enormous Benefit Cf. Complaint, para. 59-62

IC Process. . .???

Toxic effects understated

Monkeys not mentioned

No SAEs mentioned

Treatment efficacy noted

COIs not adequately disclosed Cf. Complaint, para. 61

IC Process. . .???

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

Jesse’s wrongful death. . . (Cf. Complaint, para. 84-89, esp. 87)

Subject unprotected. . .

IRB Ineffective. . .

IRB Defend Thyself. . .!

IRB should adopt and follow writtenprocedures

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

• 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

• 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

A process – not just paper

Informed Consent Form

BEST PRACTICES – Informed ConsentPreparing ICD’s

Consider the reading level of the potential participants

Use simple language – 8th grade If you need to use scientific terms, define

them

BEST PRACTICESPreparing 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

BEST PRACTICESICD 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

BEST PRACTICESWhen to revise the ICD

When risk/benefit ratio changes New information becomes available The Investigator decides, but needs ok

from sponsor

BEST PRACTICESHow, What, When & Where

of obtaining informed consent Investigator’s involvement Signatures & initial lines & dates Witnesses Documentation Setting Enrollment goals Training on human subject protection

BEST PRACTICESThe 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]


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


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


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


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


Note in source documentation that consentwas administered PRIOR to initiation ofstudy procedures

Remember IC is an ongoing processDocument at follow-up visits patients desire

to remain on study


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

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

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

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

“Research participation is a gift and contribution by the subject.”

Jay Katz, 1994 As presented by Dale Hammerschmidt