| FDA Correspondence |
1. May 01, 2007 5:04 PM From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
Dr. Kirkpatrick, Thank you for helping me understand your position and question to FDA. I will follow up on your question about IRBs and the Guidance for Industry IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer. Virginia L. Behr |
2. May 01, 2007 5:46 PM From: Kirkpatrick, Anthony [mailto:akirkpat@health.usf.edu]
Thank you, Ms. Behr, for your prompt reply on the behalf of Joe Griffin. Also, thank for offering to follow up on my question on how to hold IRBs accountable to the “Guidance” published by the FDA, especially when IRBs enact policies contrary to FDA Guidance resulting in increase risk to research subjects. For example, is anyone at the FDA familiar with a malpractice case that ended up in a court where failure to follow FDA Guidance was an important factor in adjudicating the case.
Congratulations on your recent appointment to Acting Ombudsman.
Anthony F. Kirkpatrick, MD, PhD |
3. May 03, 2007 12:05 PM From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
Dr. Kirkpatrick,
I am working with Joe Griffen to give you an informed reply. Please be patient; we hope to get back to you early next week. If that isn't possible, we'll reply once I return from a short vacation (May 15th week).
Virginia |
4. May 03, 2007 12:23 PM
From: Kirkpatrick, Anthony
Thank you, Ms. Behr, for the update. The information that I am requesting from the FDA’s Medical Policy division of the Center for Drug Evaluation and Research is extremely important to the welfare of human research subjects.
I will be patient.
Anthony F. Kirkpatrick, M.D., Ph.D. |
5. May 11, 2007 12:15 PM
From: Griffin, Joseph P [mailto:joseph.griffin@fda.hhs.gov]
Dr. Kirkpatrick-
As a general rule, guidance that interprets and/or explains the regulations of a federal government agency is nonbinding and advisory only. Thus guidance does not have the force of law (i.e., FDA cannot compel compliance with a guidance). FDA can bring an enforcement action or otherwise compel compliance only if it determines that there has been a violation of the regulation or regulations that a guidance interprets.
The guidance you are concerned with (IND Exemptions for Studies of Lawfully Marketed Drugs or Biological Products for the Treatment of Cancer) is intended to assist sponsors, including sponsor-investigators of single site, investigator-initiated studies, in determining whether a planned study of a marketed cancer therapy is exempt from the IND requirements pursuant to section 312.2(b) of the IND regulations. It does shed some light on how FDA thinks about risk-benefit generally in situations where risk is high (therapies that are often highly toxic) and potential benefit is great (treating a disease that is fatal if untreated). However, it makes a specific case for greater latitude in the oncology setting in determining whether a planned study significantly increases the risk (or decreases acceptability of the risk) associated with the drug because of the exigencies of cancer treatment and the familiarity of oncologists generally in managing toxicity with higher than recommended doses, using different drug combinations than the approved combinations, and using drugs in alternative patient populations.
Note also that the guidance is directed at sponsors and sponsor-investigators and not IRBs. IRBs make an independent assessment of the acceptability of the risks and potential benefits of a planned clinical study to assure that human subjects are adequately protected. The issues that IRBs are required to consider are described in 21 CFR part 56 of the Code of Federal Regulations (see section 56.111--Criteria for IRB approval of research). IRBs are not specifically tasked with determining whether an IND is required for a given study. However, IRBs will often want to know whether a drug study is being done under an IND, and if not, whether there is a defensible rationale for doing the study without an IND. If an IRB is uncertain about the need for an IND, it will often direct the sponsor/investigator to ask FDA whether an IND would be needed.
In short, guidance is advisory only and the marketed cancer drugs guidance is not specifically applicable outside the oncology setting, is not directed at IRBs, and does not interpret a regulation that applies to IRBs. So there is no apparent mechanism for making an IRB apply this guidance, particularly in a non-oncology setting. If you are dissatisfied with an action taken by your IRB, I assume there is an appeal mechanism, including some kind of process for seeking redress from the IRB's parent institution. Hope this is responsive to your concerns.
Joe Griffin |
6. May 28, 2007 9:40 PM
From: Kirkpatrick, Anthony
Dear Mr. Griffin:
Our research foundation has some questions concerning your email of May 11. Would it be possible to set a telephone conference call for May 30 (Wednesday)?
Sincerely,
Anthony F. Kirkpatrick, MD, PhD |
7. May 29, 2007 12:14 PM
From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
Dr. Kirkpatrick,
What exactly do you want to discuss? We'd be happy to clarify any questions you have about our response.
Virginia |
8. May 29, 2007 3:36 PM
From: Kirkpatrick, Anthony
We would like to have clarified some of the items in Mr. Griffin’s email.
Thank you
My cell # 813 390-8690
Anthony F. Kirkpatrick, M.D., Ph.D. |
9. May 29, 2007 3:39 PM From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
That is fine. What questions do you have?
Virginia |
10. May 29, 2007 6:52 PM
From: Kirkpatrick, Anthony [mailto:akirkpat@health.usf.edu]
We have received information in the past from the FDA that contradicts the information provided by Mr. Griffin.
The question we have is can we ignore that information and trust the information that we received from Mr. Griffin?
Sincerely,
Anthony F. Kirkpatrick, MD, PhD |
11. May 30, 2007 4:24 PM
From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
Dr. Kirkpatrick,
I received your two voicemail messages and it sounds to me like you have a few specific questions for us. It would probably be best if we answer you in writing so that we can be sure to have a clear answer and also so you have something to reference. Would that be alright?
Please let me know what questions you and Jerry have about Mr. Griffin's email. You mentioned the definition of independence, and two sections of the CFR. We'll answer them the best that we can. We look forward to hearing from you and/or Jerry. Virginia L. Behr |
12. May 31, 2007 11:04 PM
From: Kirkpatrick, Anthony
Ms. Behr:
Thank you for your timely response to my request.
Mr. Griffin has concisely answered my questions in his emails to me dated May 11, 2007 and October 11, 2006. I would appreciate Mr. Griffin confirming to me that my understanding of his emails is accurate. In particular, it is my understanding that (for studies involving lawfully marketed drugs in the United States):
In a letter to me dated December 21, 2006, Mr. Warren Rumble stated:
“I would like to clarify that it is the decision of an individual investigator and his/her Institutional Review Board (IRB) whether they believe an IND is required for conducting clinical studies with a drug product lawfully marketed in the USA.”
Mr. Rumble’s statement seems to suggest that an IRB has regulatory authority to require an IND, while Mr. Griffin’s correspondence clearly states this is not so. Hence, my request for clarification.
I look forward to receiving Mr. Griffin’s reply.
Anthony F. Kirkpatrick, MD, PhD |
13. June 04, 2007 4:41 PM
From: Griffin, Joseph P [mailto:joseph.griffin@fda.hhs.gov]
Dr. Kirkpatrick-
I have reviewed your statements describing your understanding of the IRB regulations and the relationship between FDA and IRBs. I have placed comments/edits after each of your statements. As described in more detail below, it seems you may misperceive to some extent the effect of the IRB regulations on the policies and procedures an IRB or it's parent institution may implement to ensure that research conducted within the institution complies with applicable regulations.
The IRB regulations are more prescriptive than proscriptive. For example, they describe the criteria an IRB must consider in determining whether to approve clinical research that involves a drug product, require that an IRB have written procedures that govern its review process, and require that IRB decisions be adequately documented. The IRB regulations do not, however, specify what factors an IRB cannot consider in its review of planned clinical research or what review processes/policies an IRB or its parent institution can or cannot implement concerning oversight of clinical research occurring in that institution.
Where there is some question about the need for an IND, it may not be entirely unreasonable policy for an IRB to consider the need for an IND as relevant to whether risks to subjects are minimized (i.e., within its purview for ensuring protection of human subjects). That policy may be based on a conclusion that FDA has a longer history and, hence, greater familiarity with the range of potential uses, doses, and safety issues with a given marketed drug and, therefore, it would be prudent to ensure that FDA has an opportunity to review planned research, or at least make a preliminary assessment as to whether such research requires an IND.
Also, institutions in which clinical research is conducted have, for many reasons, a vested interest in ensuring that such research complies with all applicable regulations. For example, an institution might reasonably conclude that the best way to ensure it's continued ability to conduct clinical research, to have access to federal and other grant money to fund such research, and to limit it's liability exposure arising from potential harm to subjects participating in such research is to have relatively stringent policies/procedures to ensure that any clinical research done in the institution is in compliance with all applicable regulations (including compliance with the IND requirements where applicable). The internal policies and procedures implemented to ensure compliance are determined by the institution.
So, the absence of any express regulatory requirement doesn't mean the IRB or the parent institution can't of its own initiative implement a policy/procedure that requires some confirmation about the need for an IND where the IRB has a question, either for human subject protection or general compliance purposes. I cannot agree with your statement 6 because the policies/procedures by which an institution, or an IRB acting on behalf of the institution, chooses to ensure that research conducted within that institution complies with applicable federal regulations are an internal matter for that institution. There is no regulation that would expressly prevent an institution from adopting such a policy, notwithstanding the prudence of the policy. However, this does not mean that all studies for which IND submissions are made pursuant to such a policy will be done under an IND. FDA ordinarily declines to accept IND applications for clinical research that is exempt from the IND requirements.
So, again, it seems that your issue is with the reasonableness of the policies/procedures/actions of your IRB and/or institution for evaluating clinical research and ensuring compliance with applicable regulations. And your mechanism to address your issue is within the institution. Hope this is helpful.
Joe Griffin
From: Kirkpatrick, Anthony [mailto:akirkpat@health.usf.edu]
Ms. Behr:
Thank you for your timely response to my request.
Mr. Griffin has concisely answered my questions in his emails to me dated May 11, 2007 and October 11, 2006. I would appreciate Mr. Griffin confirming to me that my understanding of his emails is accurate. In particular, it is my understanding that (for studies involving lawfully marketed drugs in the United States):
1. IRB’s independently assess acceptability of risks and potential benefits when evaluating a given study in accordance with 21 CFR 56.111, Criteria For IRB Approval of Research. 21 CFR 56.111 is not a regulation which gives an IRB authority to require an investigator to file an IND with the FDA. Agree. 2. There is no FDA regulation which gives an IRB authority to require an investigator to file an IND with the FDA. Would restate as follows: "There is no FDA regulation that expressly instructs an IRB to require an investigator to file an IND with the FDA." 3. Mr. Griffin states in his May 11, 2007 email, “If an IRB is uncertain about the need for an IND, it will often direct the sponsor/investigator to ask FDA whether an IND would be needed.” There is no FDA regulation which authorizes an IRB to require an investigator to file an IND with the FDA if an IRB is uncertain about the need for an IND, nor is there a regulation which requires an investigator to ask the FDA if an IND is needed. Would restate as follows: "There is no FDA regulation that expressly instructs an IRB to require an investigator to file an IND with the FDA, nor is there a regulation which requires an investigator to ask the FDA if an IND is needed." 4. The determination of whether an IND is required for a given study is made by the investigator/sponsor, in accordance with FDA regulations. Agree. 5. There is no FDA regulation which authorizes an IRB to determine if an IND is required for a given study. Would restate as follows: "There is no FDA regulation that expressly instructs an IRB to determine if an IND is required for a given study. 6. An IRB is not in compliance with FDA regulations if it adopts a policy which requires every investigator who comes before it to file an IND with the FDA. Disagree. See explanation above.
In a letter to me dated December 21, 2006, Mr. Warren Rumble stated:
“I would like to clarify that it is the decision of an individual investigator and his/her Institutional Review Board (IRB) whether they believe an IND is required for conducting clinical studies with a drug product lawfully marketed in the USA.”
Mr. Rumble’s statement seems to suggest that an IRB has regulatory authority to require an IND, while Mr. Griffin’s correspondence clearly states this is not so. Hence, my request for clarification.
I look forward to receiving Mr. Griffin’s reply.
Anthony F. Kirkpatrick, MD, PhD |
14. June 28, 2007 9:23 PM
From: Anthony Kirkpatrick MD, PhD [mailto:akirkpat@tampabay.rr.com]
Dear Mr. Griffin:
Based on our recent communications regarding IRB responsibilities, the International Research Foundation for RSD / CRPS will publish its findings. As a courtesy to the FDA, please find a summary of our findings prior to publication at the following site: http://www.rsdfoundation.org/en/FDA_Regulation.html
If our findings in Part III do not accurately reflect the position of the FDA's Office of Medical Policy, please let us know no later than July 5, 2007.
Sincerely,
Anthony Kirkpatrick, MD, PhD
CC:
Robert Temple, MD Director, Office of Medical Policy Steven Galson, MD Director, Center of Drug Evaluation and Research
Andrew von Eschenbach, MD Commissioner of FDA (Acting) Virginia Berh Ombudsman (Acting) |
16. July 02, 2007 11:34 AM From: Behr, Virginia L [mailto:virginia.behr@fda.hhs.gov]
Dr. Kirkpatrick,
I conferred with the Office of Medical Policy and we do not agree that the information provided you by FDA supports all the conclusions in your "findings." To the extent you purport to rely on information received from FDA to arrive at those findings, presumably you would have no problem publishing your inquiries and FDA's responses (in their entirety) to those inquiries along with your findings. Virginia L. Behr FDA/Center for Drug Evaluation and Research Email: Virginia.Behr@fda.hhs.gov or CDERombudsman@fda.hhs.gov |
17. July 02, 2007 3:48 PM
From: Kirkpatrick, Anthony
Ms. Behr:
As we have advised FDA, our goal is to provide accurate information for the use of investigators and IRBs. We have no interest in publishing erroneous information. Please identify the conclusions which FDA does not agree are supported by the information provided by FDA, so that we may revise or delete them as appropriate in order to assure accuracy.
Anthony F. Kirkpatrick, MD, PhD |
18. July 02, 2007 4:37 PM Sent: Monday, July 02, 2007 4:37 PM
Dr. Kirkpatrick,
We have put alot of thought into our responses to you and feel that our explanations were pretty clear. We think that if you publish our responses in their entirety, the information will be kept in context.
Thank you, Virginia L. Behr Email: |
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