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.