Risperdal Had Only One Approval Study For Pediatric Bipolar Disorder, Study Remains Unpublished

Recently, I was poking through the package insert for Risperdal, an atypical antipsychotic made by Johnson & Johnson/Janssen, when I noticed that in its discussion of clinical studies for the drug's use in treating pediatric bipolar disorder, only one study was mentioned, consisting of 169 participants. I've been writing about pharmaceutical products for years and have been told by the FDA and sources in the medical world that the FDA requires two positive trials (meaning efficacy over placebo is demonstrated) for a drug to be approved for any indication. It struck me as odd that the FDA would approve such a tricky drug--it has black box warnings and plenty of lawsuits on its tail--with only one approval study for a disorder that is the source of much controversy within psychiatry itself and which the FDA only announced this summer was a "valid diagnosis" in its estimation.

Risperdal has been in the news lately over claims that a Harvard child psychiatrist, Joseph Biederman, pressured the company to give him hundreds of thousands of dollars to fund a center to study the use of psych meds in kids (that news came out of a Risperdal lawsuit), over evidence that the drug is causing breast development in some teenaged males, and over concerns voiced by an FDA panel of outside experts that the drug is being prescribed for conditions such as ADHD for which it has no approval.

Even worse, documents for a lawsuit against J&J recently revealed that the company termed clinical trials for the drug's use is kids as "growth opportunities."

With all of that in my head, I queried the FDA about why the drug had been approved with only one clinical trial for pediatric bipolar disorder. From Sandy Walsh, who's the press officer for the agency's psychiatry products division, comes this explantion:

"Yes, we do generally require 2 studies for a new indication, as we did with Risperdal for irritability of autism (as there were no prior approvals of any other age group for this claim). But it's a different story for pediatric claims that come after adult approvals for the same claim. Here we generally accept a single study to extrapolate from the adult data, i.e., Risperdal already had adult claims for schizophrenia and bipolar as discussed in the Pediatric Written Requests we issued. There was no special consideration here. This is a common situation, not just with psychiatric drugs.

"However, if one looks at the Pediatric Written Requests that have been issued for many of the SSRI's you will note that they require 2 studies for depression because of the noted many failures, but only 1 pediatric study for other conditions such as OCD or SAD. This is because the adult indication is the same and we have evidence of its effectiveness in adults and do not wish to enroll children unnecessarily (of course a big ethical issue as children cannot offer consent) in just repeating a trial when we already have other data in adults and will get the dosing and safety information from the pediatric efficacy study.

"The burden is to be as effective as possible with the data we have in designing pediatric trials. The FDA always looks to see what we can learn from adults. In some situations we can extrapolate efficacy data, not safety or dosing, from adult trials IF we can meet 2 basic assumptions concerning the similarity of the disease and the response to therapy between adults and children. Sometimes we are not certain if we can extrapolate and we take a middle road of exposure-response studies to test the hypothesis that we can extrapolate. In that case you may not even have a single efficacy trial as was used for the atypicals. I have enclosed the algorithm that is used by FDA in deciding what type of trial to conduct- it is slide 32 in the enclosed set of slides which are public. It also goes through the many questions the FDA asks in deciding if how to do trials in the pediatric population."

So there you have the FDA's explanation.

What's puzzling to me is that the trial described on page 11 of the insert (.pdf here) refers to a study involving 169 kids and teens taking the drug for "mania" (or who were getting a placebo), but I cannot locate a published study involving Risperdal's use to treat mania in a pediatric age group. Only 111 kids or teens took the drug in the study, some at what I consider ridiculously high dosages of from 3 mgs. to 6 mgs. a day. That's a pretty small group of patients upon which to rest a drug's approval in my opinion.

Feel free to do your own PubMed search here. What's more, I can find no news release around Risperdal's FDA approval for pediatric bipolar disorder--or mania, if you prefer--nor can I find a reference to a published study on Janssen's website. Janssen is the J&J subsidiary that handles Risperdal. It's common for companies to trumpet clinical studies to the heavens once a drug is approved for an indication or when it is published somewhere. They even like to put out press releases for poster sessions at conferences. But total silence when it comes to Risperdal for kiddie mania. The only mention I can find on J&J's main website is an investor's note from June 2007 when the company received an approvable letter for childhood schizophrenia and pediatric mania and even there there's no mention of clinical results for pediatric mania. The drug was approved (.pdf here) for use in kids with those conditions in August 2007.

But the FDA has not posted online, as required by law, the approval package for Risperdal for pediatric mania. That package is supposed to be put online 30 days after a drug is approved for a new indication. As you'll see right here, there's no approval package for those two indications.

Absent a published study of the drug for pediatric mania or its approval package being made available to the public, there's no way to assess what efficacy the drug demonstrated in its single clinical trial.

So, something weird is going on here.