6. FDA to Foundation
October 16, 2006, 2:39 PM
From: Jani, Parinda [mailto:parinda.jani@fda.hhs.gov]
Sent: Monday, October 16, 2006 2:39 PM
To: Kirkpatrick, Anthony
Cc: bob.rappaport@fda.hhs.gove; timothy_r_lubenow@rush.edu; Jerry H. Trachtman, ESQ; Kirkpatrick, Anthony; Rumble, Warren F; Stradley, Sara; Rappaport, Bob A; Ripper, Leah W
Subject: RE: IND Exemption
Dear Dr. Kirkpatrick:
please see my response below to # 3.
The copy I have received has the highlights. In order for us to exempt an IND, we ask the sponsors to submit an IND, and if we determine that it is exemptable, we respond in writing. I apologize if any of our conversation mislead you to believe that the research protocol you have sent via email contains sufficient detail to render a written opinion on the IND exemption issue.]
7. Foundation to FDA
October 16, 2006, 2:13 PM
From: Kirkpatrick, Anthony [mailto:akirkpat@health.usf.edu]
Sent: Monday, October 16, 2006 2:13 PM
To: Ripper, Leah W
Cc: Jani, Parinda; bob.rappaport@fda.hhs.gove; timothy_r_lubenow@rush.edu; Jerry H. Trachtman, ESQ; akirkpat@hsc.usf.edu; Rumble, Warren F
Subject: FW: IND Exemption
Dear Ms. Ripper:
Thank you for taking the time to discuss the concerns expressed by our research foundation with a web site at www.rsdfoundation.org about the way your division handles INDs. Please let me know immediately if the following does NOT accurately reflect our discussion:
- You feel that the attached FDA criteria (which you have not read) with regard to determining IND exemptions do NOT apply to your division. For example, if a potential research subject has failed all reasonable treatment options that failure is NOT, in your opinion, a relevant factor in determining an IND exemption. Specifically, are the IND exemption criteria in the attached FDA document similar to or exactly same as those criteria that you use in determining an IND exemption in your division? If attached FDA criteria for an IND exemption do not apply to your division, you agreed to explain why that is the case. You point out that the FDA has limited staff and resources to write IND exemption guidelines / criteria. Therefore, if the criteria do apply to your division, it makes no sense to reinvent the wheel. You will adopt the attached FDA criteria or modify the criteria for your division. There should be no doubt in anyone’s mind that such a roadmap to determining an IND exemption will benefit clinical investigators and IRBs. In addition, the roadmap will permit your division to process IND exemptions in a more fair and efficient manner.
- You mentioned that it is contrary to FDA regulations for IRBs to require all researchers, without exception, to submit an IND application to the FDA for their clinical studies.
- You will determine why your PC failed to display the yellow highlights in the research protocol that I sent to you, which was forwarded by you to Ms. Parinda Jani (Chief of Projects and Management). Ms. Jani, in turned, forwarded the research protocol to Dr. Bob Rappaport (Division Chief of Anesthetics, Analgesics and Rheumatology Products). I spoke with Ms. Jani who assured me that the research protocol contains sufficient detail to render a written opinion on the IND exemption issue. In addition, you assured me that we would receive a written opinion on the IND exemption in response to a “written summary of the proposed protocol” in your email of October 10, 2006.
The copy I have received has the highlights. In order for us to exempt an IND, we ask the sponsors to submit an IND, and if we determine that it is exemptable, we respond in writing. I apologize if any of our conversation mislead you to believe that the research protocol you have sent via email contains sufficient detail to render a written opinion on the IND exemption issue.
- You said that I can expect a response to this email within one week.
Mr. Warren Rumble, FDA Ombudsman, assured me over a month ago that you would be able to address our concerns.
Sincerely,
8. Foundation to FDA
October 13, 2006
From: Kirkpatrick, Anthony
Sent: Friday, October 13, 2006 2:28 PM
To: Leah W Ripper (leah.ripper@fda.hhs.gov)
Cc: Tim Lubenow MD (timothy_r_lubenow@rush.edu); Jerry H. Trachtman, ESQ; Warren F. Rumble (warren.rumble@fda.hhs.gov)
Subject: IND Exemption
Dear Ms.Ripper:
Thank you for clarifying your email dated October 10, 2006. Also, thank you for offering to facilitate a review for an IND exemption by one of your medical officers.
The research protocol at the following web link requires that the patient fail all reasonable treatment options for a medical condition that has potentially life-threatening consequences (i.e., suicide). Therefore, it might be reasonable that your medical officer give the protocol an expedited review with regard to an IND exemption:
http://www.Mexican_Research_Protocol.html
As discussed on the phone, the protocol permits subjects 15 years and older. The youngest subject in the German study was 14 years. We feel it reasonable to include the “pediatric” population as evidenced by the relatively high risk of life-threatening complications in this patient population (i.e., suicide). In addition, ketamine is commonly used in the pediatric population with a lower risk of hallucinations or “bad dreams”. A recent report by CNN published at the following web link points to the risk of suicide in the pediatric population due to CRPS:
http://www.rsdfoundation.org/en/CNN_RSD.htm
In writing this protocol pursuant to 21 CFR § 312.2(b)(1)(iii) of FDA regulations, I used the published FDA criteria that were attached to my email to you dated October 10. I am attaching these FDA criteria to this email as well.
I can be reached any time by cell # 813 ______ or university # 813 974-2870. I am currently in Chicago hosting the annual meeting of the International Research Foundation of RSD / CRPS.
Sincerely,
Anthony F. Kirkpatrick, MD, PhD
9. FDA to Foundation
October 11, 2006
From: Griffin, Joseph P [mailto:joseph.griffin@fda.hhs.gov]
Sent: Wednesday, October 11, 2006 8:52 AM
To: akirkpat@tampabay.rr.com; Ripper, Leah W
Cc: Rumble, Warren F; Tim Lubenow MD; Jerry H. Trachtman, ESQ; Norden, Janet M
Subject: RE: 1RE: IND Exemptions
It is true that we do not have generalized guidelines for determining when an IND is needed, including when an IND is or is not needed for a clinical investigation of a marketed drug. We are currently developing that guidance. Yes we do have guidance to assist manufacturers and investigators in determining whether an IND is needed for a study of a marketed cancer therapy. The analyses and examples in that guidance concerning whether risk is significantly increased provide some insight into how FDA thinks about this issue generally and thus may be relevant to studies of marketed drugs in other therapeutic areas. At present, this guidance is likely the most useful information available from FDA on this issue.
As Ms. Ripper has stated, the regulations provide investigators or sponsors the option of seeking FDA's advice on whether the IND regulations apply. Any questions concerning the investigational use of a specific marketed product or products that cannot be resolved independently should be directed to the review division with expertise in the therapeutic area. The amount and form of the information that FDA would need to respond to a question about application of the IND regulations will vary with the complexity of the question.
Also, keep in mind that FDA does not have a regulatory role in therapeutic decisions between a physician and his or her patient about off-label use of a marketed drug for treatment purposes (as opposed to use in a study). This is practice of medicine. FDA only regulates investigational use of a marketed drug used in an endeavor that meets the definition of a clinical investigation (including regulatory provisions for potentially exempting that use).
Hope this is helpful.
Joe Griffin
Office of Medical Policy
Center for Drug Evaluation and Research
FDA
10. FDA to Foundation
October 10, 2006
From: Ripper, Leah W [leah.ripper@fda.hhs.gov]
Sent: Tuesday, October 10, 2006 12:36 PM
To: akirkpat@tampabay.rr.com
Cc: Rumble, Warren F; Tim Lubenow MD; Jerry H. Trachtman, ESQ; Norden, Janet M; Griffin, Joseph P
Subject: 1RE: IND Exemptions
Dear Dr. Kirkpatrick,
At this time, we do not have any written guidance on standards or criteria for exempting an investigational study from the requirements for an IND other than what is found in our implementing regulations at 21 CFR 312.2(b). Questions from investigators about a particular study are referred to the review division with the clinical expertise pertinent to the indication to be studied. The reviewing medical officer reviews the study and applies the criteria in the regulation. Depending on the situation, the decision may be verbal based on a telephone conversation with the investigator or may be in writing in response to submission of a written summary of the proposed protocol or the protocol itself. Generally, IRBs accept these exempt letters in lieu of an IND.
When an IND application is submitted and found upon review to be for a study that is exempt under the regulations, an IND is not granted. Instead an exempt letter is issued and the file is closed.
Such submissions are considered to be confidential, commerical information and are therefore protected from public release under the Freedom of Information Act.
I hope this is helpful. Please call me at 301-796-1282 if you would like to discuss the matter further.
Lee
_____________________________________
Lee W. Ripper
Associate Director for Regulatory Affairs
Office of Drug Evaluation II
Office of New Drugs
10903 New Hampshire Ave.
Bldg. 22, Room 3218, Mail Stop 3105
Silver Spring, MD 20993
Phone: 301-796-1282 | Fax: 301-796-9717
Mailing Address: FDA, CDER, OND, ODE II IO
5901-B Ammendale Road
Beltsville, MD 20705-1266
NEW EMAIL ADDRESS: leah.ripper@fda.hhs.gov
_______________________________________
11. Foundation to FDA
October 10, 2006
From: Anthony Kirkpatrick MD, PhD [mailto:akirkpat@tampabay.rr.com]
Sent: Tuesday, October 10, 2006 10:17 AM
To: Ripper, Leah W
Cc: Rumble, Warren F; Tim Lubenow MD; Anthony Kirkpatrick MD PhD; Jerry H. Trachtman, ESQ
Subject: FW: IND Exemptions
Dear Ms. Ripper:
I have not heard a word from your Office of Medical Policy in over a month regarding the attached letter. When will we have a clarification of the issue regarding IND exemptions?
Patients’ lives are hanging in the balance. As an example, please view the CNN report at the following link:
http://www.rsdfoundation.org/en/CNN_RSD.htm
As you are aware and as noted in the CNN report, complex regional pain syndrome (CRPS) is a medical condition where some patients fail all reasonable treatment options, which can have potentially life-threatening consequences (i.e., suicide). A lack of clarity from the FDA on the IND issue is contributing to confusion among some IRBs. Patients can not wait and are traveling to Germany and Mexico to volunteer for research studies. Under these circumstances, please ask your colleagues in the Office of Medical Policy to expedite a reply to our letter.
I am traveling to Chicago to host the annual meeting of the International Research Foundation for RSD / CRPS and can be reach any time at cell # 813 _______ or akirkpat@tampabay.rr.com
.
Sincerely,
Anthony Kirkpatrick, MD, PhD
Please reply using:
akirkpat@tampabay.rr.com
12. Foundation to FDA
September 8, 2006, 12:40 AM
From: Kirkpatrick, Anthony [mailto:akirkpat@health.usf.edu]
Sent: Friday, September 08, 2006 12:40 AM
To: Ripper, Leah W
Cc: timothy_r_lubenow@rush.edu; Rumble, Warren F
Subject: IND Exemptions
Dear Ms. Ripper,
Please take a close look at the attached letter to the FDA.
Mr. Warren Rumble, FDA Ombudsman, assured us that you would be able to address our concerns.
Please feel free to contact me by cell (813 ______ ) or pager (813 _______ ) or operating room (813 974-2870).
Sincerely,
Anthony F. Kirkpatrick, MD, PhD
13. FDA to Foundation
September 8, 2006, 11:03 AM
From: Ripper, Leah W [mailto:leah.ripper@fda.hhs.gov]
Sent: Friday, September 08, 2006 11:03 AM
To: Kirkpatrick, Anthony
Cc: timothy_r_lubenow@rush.edu; Rumble, Warren F; Norden, Janet M; Griffin, Joseph P
Subject: FW: IND Exemptions
Dear Dr. Kirkpatrick,
By copy of this email, I am forwarding your inquiry to Joe Griffin and Janet Norden in our Office of Medical Policy. They are our subject matter experts on IND exemption policy and will respond to your questions.
Lee
_____________________________________
Lee W. Ripper
Associate Director for Regulatory Affairs
Office of Drug Evaluation II
Office of New Drugs
10903 New Hampshire Ave.
Bldg. 22, Room 3218, Mail Stop 3105
Silver Spring, MD 20993
Phone: 301-796-1282 | Fax: 301-796-9717
Mailing Address: FDA, CDER, OND, ODE II IO
5901-B Ammendale Road
Beltsville, MD 20705-1266
NEW EMAIL ADDRESS: leah.ripper@fda.hhs.gov
_______________________________________
14. Foundation to FDA
September 6, 2006
September 6, 2006
Lee W. Ripper
Associate Director for Regulatory Affairs
Office of Drug Evaluation II
Office of New Drugs
10903 New Hampshire Ave.
Bldg. 22, Room 3218, Mail Stop 3105
Silver Spring, MD 20993
Dear Ms. Ripper:
Thank you for providing your contact information.
I am Chairman of the Scientific Advisory Committee and Timothy Lubenow, MD, is the Vice President for the International Research Foundation for RSD / CRPS. We are writing a report which will be published on the Foundation’s web site:
www.rsdfoundation.org
The intent of the report is to clarify the FDA policy that will help investigators and IRBs identify which studies are exempt from an IND application, thus saving the investigators from submitting unnecessary IND applications.
As you are aware, the protocol related criterion that the FDA considers in assessing IND exemption is: The investigation may not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product (21 CFR § 312.2(b)(1)(iii)). Thus, when determining if the risk is significantly increased (or acceptability of the risk is significantly decreased), FDA staff must examine the parts of the protocol that concern dose, schedule, route of administration, and patient population.
Please provide us with the citations of authority containing the standards that your office relies upon in determining if a study submitted to your office is exempt from an IND application. We would also appreciate your furnishing us several case examples where these standards were applied and an IND exemption was granted.
In the preamble to the IND regulations, which published in the Federal Register on March 19, 1987, the Agency explained that the exemption was not necessarily intended to tie the investigator to the doses and routes of administration and patient population described in the approved labeling, but to permit deviations from the approved labeling to the extent that such changes are supported by the scientific literature and generally known clinical experience. The Agency recognizes that a considerable amount of professional judgment is exercised in determining whether the planned investigation significantly increases the risk associated with the use of the drug. FDA maintains that “because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of medicine, the individual investigator should usually be able to determine the applicability of the exemption.” * (Emphasis added)
It is our understanding that the FDA seeks to avoid the submission of unnecessary IND applications. IRBs are required to review proposed studies in consultation with the investigator to determine if the criteria for IRB approval, as set forth in 21 CFR §56.111, are met. It is our further understanding that if the 21 CFR §56.111 criteria are met, and if the investigator believes that the IND exemption applies and the IRB does not consult with or challenge the investigator on that issue pursuant to 21 CFR §312.2(b)(1)(iii), the IRB has no discretion to require an IND application as a condition of IRB approval.
Some investigators have advised our Foundation that their IRBs require the investigator to submit an IND application, even when the FDA’s criteria for an IND exemption has not been challenged by their IRB, for the sole purpose of attempting to shift liability to the FDA. Is it possible for an IRB to be subject to sanctions by your agency if the submission of an IND application is based only upon the IRB’s attempted risk management, and it is not required by the FDA under 21 CFR §312.2(b)1?
Please confirm that our understandings are correct.
Sincerely,
Anthony F. Kirkpatrick, MD, PhD
Chairman, Scientific Advisory Committee
International Research Foundation for RSD / CRPS
Timothy Lubenow, MD
Vice President
International Research Foundation for RSD / CRPS
CC: Warren Rumble
Ombudsman
FDA, Center for Drug Evaluation and Research
* New Drug, Antibiotic, and Biologic Drug Product Regulations, Federal Register, March 19, 1987, Vol. 52, Nr. 53, p. 8802.
PART II: Foundation Appeals FDA Decision as Improper and Retaliatory
