February 19, 2007
Anthony Kirkpatrick, M.D.
Department of Anesthesiology
MDC 59
RE: IRB: #104237
Title: A Pilot Study of a 5-Day Infusion of Ketamine for Intractable Complex Regional Pain Syndrome
Dr. Kirkpatrick:
I am writing to you regarding the aforementioned IRB application which was originally reviewed by the Institutional Review Board (IRB) on December 21, 2005. At the time of initial review, the IRB requested a number of issues be addressed and/or changes be made. To date, the IRB has not received any correspondence from you that reflect that request. I am writing to encourage you to respond to the IRB's letter, which I have attached for your convenience.
I also wanted to address an issue that has recently come to my attention. I have been told that you believe that the IRB does not have the authority to require you to obtain an Investigational New Drug (IND) exemption for the use of ketamine in this research. I would like to address this in writing, so there is no confusion regarding the IRB's authority granted under federal regulations governing the use of drugs in clinical investigations.
The IRB, in reviewing your protocol, took into consideration whether an IND exemption should be sought for this study, based on the requirements outlined in 21 CFR 312. In your IRB Application you did not provide (1) any published animal data to support the use of this drug in the manner proposed; (2) any published or abstract information on other trials using this drug in a clinical investigation, for this indication; (3) any proposed dose escalation or justification for the high dose proposed in the clinical investigation; and (4) you did indicate that the risks associated with this clinical investigation are serious and may even include death. These four factors were paramount in the IRB's decision to require application for an IND and are based on 21 CFR 312.2(b)(i-v).
The IRB recognizes that ketamine is lawfully marketed in the United States. It also recognizes that, at this time, the clinical investigation is not intended to support a new indication for the use of ketamine or to support the change in the labeling for the drug. However, the IRB did determine, based on the information you provided in your application, that the investigation involves a vulnerable population and the proposed use significantly increases the risks associated with the marketed use of the drug (21 CFR 312(iii).
The clinical investigation you propose uses ketamine for an unapproved use. Therefore, it is considered, for all intents and purposes, a "new" drug. Also, because you are both initiating and conducting the clinical investigation ("i.e., under whom immediate direction the test article is administered or dispensed to, or used involving, a subject" [21 CFR 56.1 02(k)]), you become the "sponsor-investigator". Federal regulation 21 CFR 312.20 states "(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to Sec 312.2(a); and (b) A sponsor shall not begin a clinical investigation subject to Sec. 312.2(a) until the investigation is subject to an IND which is in effect in accordance with Sec 312.40."
Clearly, the IRB has not only the authority to require that you submit for an IND for this clinical investigation, but it would be derelict in its duty if it did not do so. However, since you disagree with the IRB's determination that an IND is required, you do have the authority, under 21 CFR 312.2( e), to instead submit, to the FDA, a description of the planned clinical investigation. The FDA will then address whether applying for an IND is warranted. The IRB will need both a copy of your initial correspondence to the FDA and the FDA's reply, which it is required to provide within 30 days, if you decide to pursue this avenue.
On a less regulatory note, it is the IRB's intention that the clinical investigation you propose be conducted with the strongest legitimacy possible so that the procedure, if successful, can be duplicated by others and become available to a population who appear to have few alternatives. In reviewing the protocol, I might suggest a way in which to strengthen the proposed research. You might want to consider establishing a Data and Safety Monitoring Committee. Members of that committee could include Dr. Thomas Freeman, who has knowledge of the proposed research, and the outside consultants who provided the IRB with a scientific review of the study. If these individuals would agree to serve on such a committee, they could assess the data after each patient and report their findings to the IRB. This, of course, is just a suggestion and is based on procedures I have encountered with other high-risk human research.
Response to the IRB's concerns will facilitate moving this study forward. IRB requests with which you disagree and for which you can provide justification for not addressing, will be considered by the IRB. There were 24 items which the IRB requested you to address, only one of which was application for an IND. To date, none of the information requested or changes required have been submitted to the IRB for consideration.
I encourage you to submit a written response to the IRB addressing all of the issues outlined in letter attached. The IRB application for this study is scheduled to be administratively closed if the IRB has not received a written response no later than March 16, 2007. As a reminder to one of our previous discussions, as a USF employee you cannot be involved in this or any clinical investigation at another facility or institution without USF knowledge and without IRB approval. This approval is typically granted through the USF IRB.
Sincerely,
Norma Epley, Assistant Director
Human Research Protection Program
Division of Research Integrity & Compliance
University of South Florida
Enclosure:
xc: Dr. Sally Houston, Associate Dean for Clinical Research, USF Health
Dr. Abdul Rao, Associate Vice President for Medical Affairs, USF Health
Ms. Camille McWhirter, J.D., Director, Research Compliance, USF Health
Dr. Barry Bercu, Chairperson, Medical Institutional Review Board
Ms. Patti Simmons, Director, Office of Clinical Research, TGH
