Testimony of: Knudsen, James, accompanied by Robert Temple, Paul Seligman, Thomas Laughren, and Tarek Hammad, of the Food and Drug Administration and Dr. Mosholder.
FDA’S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA’S REVIEW OF SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN
HEARING BEFORE THE SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS OF THE COMMITTEE ON ENERGY AND COMMERCE HOUSE OF REPRESENTATIVES ONE HUNDRED EIGHTH CONGRESS SECOND SESSION
SEPTEMBER 23, 2004 Serial No. 108–125
Dr. Mosholder testified that Dr. Thomas Laughren’s presentation of the data analysis to the FDA advisory committee–failed to include not ony Dr. Mosholder’s conclusion about the suicide risk, but Dr. Laughren’s presentation failed to include the data that substantiated that conclusion:
Mr. WALDEN: "Was your data analysis fully and fairly presented at the February 2004 Advisory Committee meeting and, if not, what should
Mr. MOSHOLDER. As far as the clinical trial data, Dr. Laughren gave the presentation of that.
Mr. WALDEN. Was it full and fair?
Mr. MOSHOLDER. It did not include all of the results or data that I had in my draft presentation.
Mr. WALDEN. I guess the point is did it include the most important recommendations?
Mr. MOSHOLDER. Well, it didn’t include—well, apart from the recommendations, the data I think that I would have included—let
me put it that way—would——
Mr. WALDEN. If you had been there presenting it, what would you have included that wasn’t included?
Mr. MOSHOLDER. I would have included the analysis of the serious subgroup of suicidal events and the meta analysis where the data was combined across studies. I think that—if I were doing or
if I had a chance to do the presentation, that is what I would have included.
Mr. WALDEN. So the way you would have presented it would have painted a much more serious situation to that Advisory Committee than the way it was painted, when it comes to the risk of suicidality in adolescents and children? Is that accurate?
Mr. MOSHOLDER. I guess we will never know what the Advisory Committee might have made of——
Mr. WALDEN. No, no, no. The difference in the two presentations.
Mr. MOSHOLDER. I think, if I had been doing it, it would have perhaps been more obvious."
BMJ 2004;329:307 (7 August)
Secret US report surfaces on antidepressants in children
Internal memos and a secret government report about the negative effects of antidepressants in children—suppressed by the US Food and Drug Administration—have surfaced publicly.
The Alliance for Human Research Protection, a national network dedicated to ensuring ethical standards in medical research, published the documents on 26 July. http://www.ahrp.org/risks/SSRImosholder/index.php
The published documents confirm earlier news accounts that a government expert with the FDA’s Office of Drug Safety, Dr Andrew Mosholder, found that children taking antidepressants were twice as likely to become suicidal as children taking placebo. He reportedly urged the agency to follow the lead of British health authorities by warning doctors that the risks of the newer antidepressants, except fluoxetine, might outweigh the benefits when used in children.
The leaked documents show his data and conclusions. The FDA has subsequently acknowledged to the BMJ that Dr Mosholder was prevented from presenting his report at an advisory committee meeting on 2 February and was told that if he was asked any questions during the meeting he could respond to queries only by using a prepared script approved by his supervisors.
Dr Mosholder had evaluated data from 22 studies using nine drugs in 4250 children and found that 74 of the 2298 children taking antidepressants had a "suicide related event" compared with 34 of the 1952 children taking placebos.
When questioned about the decision to suppress Dr Mosholder’s report, Dr Robert Temple, associate director for medical policy in the FDA’s drug evaluation centre, defended the agency’s actions. "We thought the analysis was premature," he told the BMJ.
Both the raw data and Dr Mosholder’s interpretation were "imperfect" said Dr Temple, adding that some of the behaviours labelled "suicidal" were highly suspect and could have been accidents, such as a child "who hit her head with her hand." FDA officials acknowledged, however, that some cases classified as "accidental injury" could be suicide related. Because of this, the FDA has contracted with Columbia University to further study and classify events that might be considered to be suicide related.
Some of these events, he added, such as superficial cutting, "might be due to anxiety" and not represent true suicidal intent.
Dr Thomas Laughren, the FDA’s team leader for psychiatric drug products, told the BMJ that he had reported the relative risk ratios of all the drugs evaluated at the advisory meeting and that it was Dr Mosholder’s conclusions, and not the data, that were withheld.
Responding to critics who say studies of antidepressants other than fluoxetine show little or no efficacy in children, Dr Temple said absence of proof should not be interpreted to mean the drugs are ineffective.
Dr Jerome Hoffman, an epidemiologist and professor of medicine at the University of California at Los Angeles, told the BMJ that the flip side of Dr Temple’s claim that antidepressants in children could be life-saving is that they could be life threatening—as suggested by Dr Mosholder’s report.
"Most Americans undoubtedly believe that the FDA demands reasonable evidence that a drug is safe before it is allowed to be used," said Professor Hoffman. "But this episode suggests that they reject this
precautionary principle' in favour of the idea that no drug is dangerous unless it isproven’ to be so."
"The FDA… attempted to silence Dr Mosholder [but] repeatedly claimed to `support his concern’ for the safety of children," added Professor Hoffman, "but this apparently didn’t extend to supporting his desire to express that concern publicly. That may be the most dangerous aspect of this entire affair."
The FDA has launched a criminal investigation to find out which employees leaked Dr Mosholder’s report. Meanwhile the suppression of the report has triggered Congressional investigations by Senator Charles Grassley, who has interviewed employees in the agency’s Office of Drug Safety, where Dr Mosholder worked.