2004N-0181 - Critical Path Initiative; Establishment of Docket
FDA Comment Number : EC16
Submitter : Dr. Barry Gidal Date & Time: 08/02/2004 06:08:38
Organization : University of Wisconsin School of Pharmacy
Category :
Issue Areas/Comments
Comment Issues
1. Hurdle Identification. Please describe the product development issue, the nature of the evaluation tool that is out-of-date or absent, how this problem hinders product development, and how a solution would improve the product development process.
A significant hurdle exists regarding the evaluation and approval of new anti-epileptic drugs in the US. Despite the approval of many new drugs for epilepsy over the last decade, only 1 is approved for use as initial monotherapy. Because of the complex logistical and ethical issues surrounding monotherapy trials in this country (as opposed to Europe), very few have been conducted for the newer generation agents. Because of this, FDA approval is lacking. The result is, few patients are given the opportunity to start treatment with an agent that may be far better tolerated. In short, regulatory constraints may in effect be hindering patients access to optimal, timely epilepsy treatment.

Currently, the FDA will only accept data showing superiority of a new drug vs. a control group for a monotherapy indication. This has led to studies that intentionally under treat the control population in order to demonstrate a difference between groups. The control group typically would be a placebo; but, in epilepsy, a patient could get a very low dose of an anti-epileptic drug (pseudo-placebo). Recruitment and retention in these types of monotherapy trials is difficult, if not impossible. Many of us have concerns that the randomization of a patient with active, uncontrolled seizures to a pseudo-placebo is both unwise and unethical. These types of studies expose patients to an unacceptable risk of worsening of seizures.

One potential solution to this problem is to use alternative trial designs such as non-inferiority, equivalence trials. These trials are accepted for approval of drugs for monotherapy in Europe but not in the U.S. In this instance, the patients in the control group would receive a therapeutic dose of a comparator drug. The new drug entity would have to demonstrate similar efficacy and better tolerability. Alternatively, a trial could be conducted using historical controls, as has been proposed by Dr. French (U Penn).

I would strongly encourage FDA to consider alternative trial designs and allow this data to be considered.

The ?Critical Path? initiative by the FDA is an excellent step in identifying hurdles and improving the process for getting new and better treatments to patients. I sincerely hope that FDA will act to include Epilepsy in the ?Critical Path Opportunity List? .

3. For each problem identified, please indicate the type of drug, biologic, or device to which the hurdle applies.
Antiepileptic drugs
5. Nature of the Solution. For each problem identified, please describe the evaluation tool that would solve the problem and the work necessary to create and implement the tool/solution. For example, would a solution come from scientific research to
Consider adopting the use of historical controls in AED monotherapy trial designs. The rationale for this has been extensively discussed in a paper
authored by Dr. Jackie French.
4. For each problem identified, if a solution would facilitate the development of drugs, biologics, and/or devices for a particular disease or categories of disease, please indicate which diseases would be affected?
Epilepsy in both children and adults
2. Please rank each hurdle identified in Question 1, above, in priority order according to which hurdles create the most severe product development problems.
The primary hurdle to be overcome is in the approach to AED monotherapy trial design.