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12:00 AM
May 01, 2006
 |  BioCentury  |  Product Development

Does size matter?

FDA last week launched what it hopes will be a lively public discussion on whether extremely sensitive outcomes measures or very large trials can produce efficacy results that are statistically significant but are too clinically trivial to support approval.

At bottom is the question of whether FDA should make approvals contingent on achieving minimum levels of efficacy. Senior staff say they want the issue aired publicly, but they lean against such a requirement.

Traditionally, FDA has said that in the absence of countervailing safety risks, any significant benefit on a clinical endpoint can serve as the basis for approval. Shifting from that position would have profound implications for drug development.

Robert Temple, director of FDA's Office of Medical Policy, gave a presentation entitled "Effect Size - Can the Effect Be Too Small?" during last week's meeting of the Cardiovascular and Renal Drugs Advisory Committee to review Cellegesic nitroglycerin ointment to treat anal fissure pain, from Cellegy Pharmaceuticals Inc. (CLGY, South San Francisco, Calif.) (see "Cellegesic Splits Its Panel," A9).

Norman Stockbridge, the primary reviewer of the NDA, determined that although no safety risks were identified, the product did too little good to merit approval. "If there is an effect of Cellegesic on anal pain, it is too small to be of clinical interest and comes with too high a cost - intolerable headache pain," Stockbridge wrote in a Dec. 20, 2004, memo summarizing the views of the Division of Cardio-Renal Drug Products review team(see Online Links, A6).

"The genesis of the presentation, and of some other discussion we've had internally, was the perception of the division that there was some doubt about whether the effect size shown for Cellegesic was of clinical consequence," Temple told BioCentury. "As a general matter it is an issue that has not had a lot of discussion here. If I had to say what the general policy has been, it is if you can show you are statistically better than placebo, that is good enough."

FDA's legal authority to require a minimum important difference (MID), as opposed to simply looking for...

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