Studies conducted under the Best Pharmaceuticals for Children Act will be included in labeling, FDA Office of Medical Policy Director Robert Temple, MD, told the House Energy & Commerce/Oversight Subcommittee Sept. 23.

"We have pretty much decided to do that," Temple said in response to questioning from Rep. Bart Stupak (D-Mich.).

FDA has not required negative studies to be included in labeling before because "failing to show something in a trial doesn't mean it doesn't work," Temple said. "We're in the process of changing our view on that."

"In reconsidering this, what we've come to think is really the whole point of the Best Pharmaceuticals for Children Act, mostly, is to find out if what you think you know about adults is applicable to children. It's more relevant than usual to say, 'Hmm, I didn't see anything in children.'"

FDA is in the early stages of formally developing a policy on the new position, the agency said.

The change in FDA's policy on pediatric study requirements is part of a wider fallout from increased congressional scrutiny into the agency's handling of a suicidality signal for children on antidepressants.

The Oversight Subcommittee convened two hearings on the effect of antidepressants in the pediatric population in September. The first hearing fell several days before a joint meeting of the Pediatric and Psychopharmacologic Drugs Advisory Committees Sept. 13-14.

At that hearing, Acting Deputy Commissioner of Operations Janet Woodcock, MD, testified that the FDA had not yet reached a conclusion on the effectiveness of antidepressants in children (¹ Also see "Pediatric Antidepressant Role Not Settled, FDA Says; Pfizer Defends Zoloft" - Pink Sheet, 20 September, 2004., p. 7).

At the second hearing, held several days after the advisory committee meeting, Temple said FDA was close to a decision on antidepressant labeling. He acknowledged that the agency likely would require a black box on the suicidality risk (² Also see "Antidepressant “Black Box” Decision Imminent, FDA Tells Congress" - Pink Sheet, 27 September, 2004., p. 3).

Subcommittee members during the Sept. 23 meeting suggested that FDA had suppressed findings of the Office of Drug Safety Medical Officer Andrew Mosholder, MD, by not allowing him to present data indicating a link between antidepressant use and suicidality in children at a February advisory committee meeting.

Committee Chair Joe Barton (R-Texas) expressed displeasure with FDA's initial level of cooperation on the matter. "I was upset at FDA's lack of full cooperation with the documentation process pursuant to the committee's request," he said.

"Since that hearing, I have met with the Acting FDA Commissioner Dr. Lester Crawford about the issue," Barton added.

FDA officials maintained that the agency followed the right course of action after learning of Mosholder's findings.

Rep. Diana DeGette (D-Colo.) asked, "Do you wish that the agency would have taken him more seriously and allowed him to present the findings?"

FDA felt the data were too premature to be the basis for immediate action, Temple responded. "Our concern, as I've said before, was that the action we take be based on the best possible data."

Standard measures of suicidality did not indicate an increased risk in children taking antidepressants, he added.

Mosholder provided an analysis of pediatric data submitted on GlaxoSmithKline's Paxil (paroxetine) that showed a signal for suicidality, Temple said, but methodology used to arrive at the signal was not airtight.

"What we got was something unexpected, mainly the adverse reaction reports - when interpreted, when translated - revealed an excess of these suicidal behaviors," he stated. "We had very little experience with...what those things mean."

While reclassifying adverse events, Mosholder became unblinded, suggesting some incidences of suicidality "might not be true bill," Temple said.

"If there was a bias toward interpreting certain things that the drugs do, like agitating people or making them hostile, as suicidality, that could give you the wrong trend. It could cause you to think there were suicidal events when in fact there were not. That's why we thought we needed an independent look at these cases," Temple said.

"There was nothing wrong with Dr. Mosholder's analysis....That's not at issue. What was at issue was what the cases were; whether they really showed suicidality."

FDA contracted Columbia University to evaluate the pediatric suicidal event data submitted by antidepressant manufacturers (³ Also see "Antidepressant Suicide Data To Be Evaluated For FDA By Columbia University" - Pink Sheet, 26 January, 2004., p. 7).

An agency analysis of Columbia's evaluation, completed in August, determined there was a risk ratio of 1.78 for definite suicidal behavior/ideation in pediatric antidepressant patients, a slight decrease from Mosholder's earlier conclusions (⁴ Also see "Antidepressant Suicidality Needs Interim Risk Management, FDAer Maintains" - Pink Sheet, 30 August, 2004., p. 4).

Mosholder's analysis was not suppressed at the February advisory committee meeting, Temple declared.

"It wasn't that we disagreed with him. What we thought was the data weren't ready....What we were worried about, for better or for worse, is that it would appear to be an FDA conclusion, and we thought that was premature and not the right thing to do."

The Senate Finance Committee, which launched an investigation into FDA's actions on the Mosholder analysis, was also troubled by the agency's reaction to its inquiry (⁵ Also see "FDA Handling Of Antidepressant Inquiry “Troubles” Senate Investigators" - Pink Sheet, 14 June, 2004., p. 34).

The House subcommittee questioned whether FDA tried to alter Mosholder's testimony to the Finance Committee, and if an investigation by the Office of Internal Affairs was aimed at silencing Office of Drug Safety employees.

"The Mosholder investigation is a substantive demonstration that drug safety remains a stepchild in the FDA/drug company partnership," Subcommittee Ranking Member Peter Deutsch (D-Fla.) said.

Chairman Barton praised Mosholder for standing by his analysis throughout the ordeal, and suggested he should be recognized as ABC's "man of the week" (see chart: " ⁶ Rep. Barton Supports FDA's Mosholder For ABC's 'Man Of The Week' ").

Antidepressant Fallout Includes Change In FDA Pediatric Study Procedure

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