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No. 9: July 2-5, 2010

Is an IND necessary for pregabalin and paclitaxel studies?

Question: I am an oncologist in a group practice. I want to demonstrate that pregabalin, approved for management of pain associated with diabetic peripheral neuropathy, is effective in ameliorating the peripheral neuropathy associated with paclitaxel in the treatment of breast cancer. Both are approved drugs. Do I need to submit an IND?

Expert Comments: Your license as a physician to practice medicine allows you to use any drug for any purpose that you believe will benefit your patients. What moves this case out of clinical practice into clinical research is that you want to prove a hypothesis. The research protocol may conceivably be randomized, blinded, and placebo-controlled. By definition, “Clinical trials are not to evaluate a medicine under actual medical-practice conditions, but rather, under selected and often artificial conditions, to answer best the trial’s objectives.” (Bert Spilker, Guide to Clinical Trials, 1996, p.554).

This appears to be a Phase 2 study in which efficacy (decreased peripheral neuropathy) is the endpoint. At this point, the Food and Drug Administration (FDA) is interested primarily in patient safety — because this study is being conducted in a population in which pregabalin has not been approved.

FDA regulations, at 21 CFR 312.2(b)(1), list the criteria that must be met for IND exemption. Special attention must be paid to the third criterion, 21 CFR 312.2 (b)(1)(iii), that states: “The investigation does 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.”

There is published evidence that weekly treatment with paclitaxel resulted in statistically significant improvement in overall survival when compared with paclitaxel treatment every three weeks. However, peripheral neuropathy (Grades 2, 3, and 4) was highest in the group treated with paclitaxel once a week. (Sparano JA, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med. 2008 Apr 17;358(16);1663-1671)

A question that needs to be answered is what is the effect of pregabalin on the efficacy of paclitxel? The FDA would want to see evidence that pregabalin does not interact with paclitaxel in such a way to render it less effective. This evidence can be presented with published literature or animal data.

Looking back at 21 CFR 312.2(b)(1)(iii), the proposed investigation of pregabalin would not involve a different route of administration or a different dosage level than what is FDA-approved. The patient population, however, is different (i.e., patients with breast cancer). It is unknown if the use of pregabalin in this population being treated with paclitaxel would significantly increase the risk that the survival rate would be decreased.

Based on this possible increased risk of reduced survival, an IND should be submitted.

Because both drugs are lawfully marketed, the IND would be relatively simple. Basically, it would consist of a cover letter, forms FDA 1571 and 1572, and the clinical protocol. Once received by FDA, the 30-day safety review would begin. The options the FDA has are to accept the IND as submitted or request additional information and place the IND on clinical hold.

Keep in mind that even if an IND is not needed IRB approval and informed consent are necessary.

Comments by Harvey M. Arbit, PharmD, MBA, president of Arbit Consulting LLC. He specializes in FDA regulatory affairs related to investigator-initiated IND and IDE research.

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