FDA Tones Down Warning on Use Of Antidepressants In Children

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Thu, 3 Mar 2005 21:47:39 -0500

[sSRI-Research] FDA Tones Down Warning on Use of

Antidepressants in Children

 

 

 

 

http://pn.psychiatryonline.org/cgi/content/short/40/5/1-a

 

 

 

FDA Tones Down Warning on Use Of Antidepressants In Children

Jim Rosack

 

 

The U.S. Food and Drug Administration (FDA) posted the final language

for its new, required labeling of antidepressants last month,

including the black-box warning and patient medication guide that must

be dispensed with each prescription.

 

With no explanation, the FDA has significantly modified the wording

describing the association between antidepressants and suicidal

thoughts and behaviors.

 

In the final version of the warning, the first sentence in the black

box has changed. The October draft's sentence initially read:

" Antidepressants increase the risk of suicidal thinking and behavior

(suicidality) in children and adolescents with Major Depressive

Disorder (MDD) and other psychiatric disorders. " The revised sentence

limits the association between the two, more narrowly defining its

scope. The sentence now reads: " Antidepressants increased the risk of

suicidal thinking and behavior (suicidality) in short-term studies in

children and adolescents with Major Depressive Disorder (MDD) and

other psychiatric disorders. "

 

The change may be subtle, but it is significant. Even more significant

is the deletion of a sentence from the first paragraph of text in the

" WARNINGS-Clinical Worsening and Suicide Risk " section of the label.

The draft warnings posted by the agency last October read: " A causal

role for antidepressants in inducing suicidality has been established

in pediatric patients. " That sentence has been deleted from the final

version of the new label and replaced with " Antidepressants increased

the risk of suicidal thinking and behavior (suicidality) in short-term

studies in children and adolescents with Major Depressive Disorder

(MDD) and other psychiatric disorders. "

 

" This is clearly an important change, " said David Fassler, M.D., a

child and adolescent psychiatrist and clinical associate professor of

psychiatry at the University of Vermont School of Medicine. Fassler,

an APA trustee, chaired the combined APA/American Academy of Child and

Adolescent Psychiatry task force that developed the new resource

<www.parentsmedguide.org >, which reviews the clinical trials data on

the use of antidepressants in kids, and explains the FDA warnings (see

story at left).

 

" The change in wording, " Fassler continued, " brings the FDA warning

closer to the actual science. I'm glad they responded to the extensive

and detailed input from both practicing psychiatrists and the research

community. Hopefully, the FDA will consider further revisions in the

future, as more long-term and follow-up data become available. "

 

However, Darrel Regier, M.D., M.P.H., director of research at APA and

executive director of the American Psychiatric Institute for Research

and Education, emphasized, " We continue to be concerned about the use

of the term `suicidality,' which the public widely equates with risk

for completed suicides. "

 

It would have been more instructive, Regier said, had the FDA noted

that there was no systematic monitoring for suidicality in some of the

clinical trials it reviewed; thus, the only suicidal thoughts or

behaviors that were noted were those that were spontaneously reported.

In 17 of the 24 clinical trials reviewed, however, participants were

directly questioned about suicidal thoughts or behaviors.

 

" We believe that additional research is necessary to determine how to

evaluate both the systematic assessment and spontaneous adverse-event

reports in these studies, " Regier said. " Such research should continue

to inform recommendations coming from the FDA. "

 

The process that leads to the final approved language included in

drug-product labeling is often convoluted, complicated, and intricate.

Essentially the FDA and the drug company (which the FDA refers to as

the " sponsor " of the application for approval to market a drug)

negotiate the final wording. In many instances the sponsor submits its

own version of the wording for FDA approval. In the case of the

antidepressant warnings, however, it was the FDA that had informed

sponsors of the language it was proposing in October of last year.

 

While the FDA would not comment on what input shaped the final wording

of the labeling, it is likely that the agency's staff in the Office of

Drug Safety took primary responsibility for drafting the language.

They may have taken into account input from the advisory committees;

public comments; and written comments submitted by clinicians,

researchers, and professional associations, including APA and AACAP,

as well as others.

 

Revisions of draft language usually occur through a back-and-forth

negotiation that ends with the ball in the FDA's court.

 

" Although every attempt is made to negotiate labeling with the

sponsor, " noted FDA spokesperson Christine Parker, " the agency has the

final say on the wording. "

 

Indeed, Parker told Psychiatric News, " In our January 12, 2005, and

January 26, 2005, letters, we informed the sponsors that `Failure to

make these changes within the specified period of time could make your

product misbranded.' " Drugs that are labeled misbranded no longer

meet agency standards and thus lose marketing approval.

 

The new labeling was effective immediately upon issuance of the

January 26 letter, Parker said. Sponsors were required to submit their

individual revised product labeling to the FDA within 10 days, and all

sponsors complied. However, weeks or even months may pass before

patients see the new labeling.

 

" Stock on pharmacy shelves with the old labeling can be dispensed, and

stock in distributors' warehouses with the old labeling can still be

shipped to pharmacies, " noted Parker. The new labeling " will gradually

make its way into the pharmacies over the next couple of months. "

 

Parker emphasized that " all Internet listings of the labeling would be

expected to include the new labeling immediately. "

 

Medications with black-box warnings may continue to be advertised to

both health care professionals and consumers, Parker noted.

 

" The body of the ads do not have to contain the box warning verbatim,

but the body of the ad must include the information contained in the

boxed warning, along with other important risk information about the

product, " she explained. " Risk information, including the black-box

warning, must be presented with comparable prominence to benefit

information. "

 

The FDA's final versions of the warnings on antidepressants are posted

online at < www.fda.gov/cder/drug/antidepressants/default.htm>.