Clinical Trials Controversy Spotlights Flawed System – Psychiatric News

Mon, 19 Jul 2004

Recent independent analyses of the published and unpublished SSRI antidepressant pediatric data submitted by manufacturers to the FDA reveal not only that a disparity exists between published and unpublished data, but it becomes increasingly clear that the data submitted-whether published or unpublished–is unreliable and not to be trusted. Given that the companies alone maintain control of the data and the testing process, the companies are in a position to manipulate the data to fit their needs.

A review of the SSRI pediatric trial data submitted by manufacturers to the FDA, appears in Psychiatric News, a publication of the American Psychiatric Association. This sobering review confirms that the system used to test drugs and report the findings is rigged from beginning to end: “The ongoing controversy surrounding SSRIs in children is now threatening the very foundations of clinical drug research on the efficacy and safety of all of the drugs physicians prescribe.”

In every single instance, an independent reviewer cannot but conclude that the system fails utterly: it fails to produce useful information for clinicians and the public. It fails to identify severe adverse drug effects and it fails to inform physicians about negative findings–i.e., lack of drug efficacy. When clinical trial results are negative, the data is concealed because such information is detrimental to the companies’ marketing goals. Indeed, this was acknowledged by GlaxoSmithKline in 1998. See: https://ahrp.org/risks/SSRI0204/GSKpaxil/pg1.html

Meta-analyses by the UK Medicines authority, published analyses in the British Medical Journal and the Lancet–and an embargoed FDA expert report by Dr. Andrew Mosholder–all reached similar conclusions: antidepressant drugs have failed to demonstrate a benefit for children/ adolescents while they have significantly increased (twofold) the risk of suicidal behavior. Therefore, antidepressant labels should warn physicians that children / adolescents should not be exposed to the drugs.

Dr. Arif Khan, who had conducted a meta-analysis of adult data from antidepressant trials, summed it up the pediatric trials this way: “What you see is that this suicidal behavior in the placebo group runs anywhere from 0.6 percent to just under 5 percent. In the drug groups it runs from a low of just under 3 percent to a high of 8 percent. There’s a lot of variability, but in general the pattern holds true. There is a fairly clear trend in increased risk in the drug groups versus the placebo groups, regardless of which drug you are looking at.”

Yet, we learn from a graph in Psychiatric News that the unpublished paroxetine (Paxil) data submitted by GlaxoSmithKline to the FDA presents the exact opposite finding: Glaxo submitted data showing that the overwhelming number of suicide attempts and suicidal ideation in adolescents occurred in the UNPUBLISHED PLACEBO group. If so, is it not unprecedented that such a singular, “favorable” finding has not been widely publicized??

Did the FDA challenge Glaxo to produce the original hand written evaluations / reports by the physicians who observed the children during the trials?

Unless there are mandatory legal requirements to submit the raw clinical trial data for independent review and analysis, companies are likely to manipulate the data that they present to the FDA and in publications.

Clinicians who have relied on published trial reports and FDA approved guidelines for their treatment recommendations have been badly served with manipulated data and deceptive claims.

If clinical trials fail to separate medicines that have been proven scientifically to be safe and beneficial from those that have not, then the trials are worthless for physicians who must make treatment recommendations.

FDA officials are hard pressed to explain the overwhelming negative findings from one after another pediatric antidepressant trial. Dr. Thomas Laughren, FDA team leader of psychiatric drugs, referred to the “regulatory context for doing these studies,” stating:

“In every other case, when a company does a study, the only gain they are going to get out of that study, is if it turns out positive. In this case, these studies were done primarily for pediatric exclusivity. .there was no requirement that they get positive studies to get exclusivity. Either way, if they did the trial according to the terms of the written requests, they would get exclusivity.”

“I am not suggesting in any way that companies set out to do inadequate studies, but having that somewhat unusual mind-set could operate against a trial in subtle ways, in terms of, for example, recruitment of patients. So, it is just another thing to keep in mind in terms of interpreting these largely negative data.” See: FDA advisory committee transcript. Feb. 2, 2004, p.290

The “regulatory context” to which Dr. Laughren refers: the FDA Modernization Act (FDAMA, 1997) and the Pediatric Research Equity Act (PREA, 2003). These laws provided drug manufacturers with a 6 month extension of patent exclusivity as an incentive for them to test patented drugs in children.

The acknowledgement by a senior FDA official–who has examined the trial data from these trials–is compelling evidence, I believe, that should prompt Congress to revisit these laws because Congress failed to include safety provisions to ensure that children would not be put at risks of harm or exploitation as drug testing subjects in poorly designed trials. The data from such flawed trials is worthless and it undermines the integrity of the medicine and science.

Below is an excerpt from Psychiatric News–the article is 9 pages includes graphs.

Contact: Vera Hassner Sharav
Tel: 212-595-8974

http://pn.psychiatryonline.org/cgi/content/full/39/14/1
Psychiatric News
July 16, 2004
Volume 39 Number 14 , p. 1

Clinical Trials Controversy Spotlights Flawed System

Jim Rosack

The ongoing controversy surrounding SSRIs in children is now threatening the very foundations of clinical drug research on the efficacy and safety of all of the drugs physicians prescribe.

Under the frequent-and often hyperbolic-headlines in major newspapers throughout the United States, the debate on whether SSRIs really cause children and adolescents to become suicidal has boiled down to a critical realization: Physicians now face a crisis of confidence in the American-bred system that conducts clinical research and, it would seem, publishes only the most marketable results.,

Physicians in the trenches are beginning to wonder what exactly they really know- or perhaps don’t know-about the drugs they are prescribing and how that knowledge base affects what is written on the prescriptions that bear their signatures.

Many of the concerns raised recently have been heard before. In this last year, however, they have risen to a level that seriously challenges physicians’ comfort level with prescription drugs. Particularly disconcerting are new allegations that question the integrity of not only the scientific evidence base, but also the system that produces the data and the researchers who analyze it.

In April the British Medical Journal published a paper by Jon Jureidini, M.D., head of the department of psychological medicine at Women’s and Children’s Hospital in North Adelaide, Australia, and colleagues. The article reviewed the evidence base for efficacy and safety of antidepressants in children and adolescents. The authors included in their review published clinical trials, as well as some unpublished data made public by the U.K. Committee on Safety of Medicines. At best, Jureidini’s conclusions were direct and to the point, but by some people’s estimation the conclusions seemed inflammatory, with abundant references to the individuals who led the research or wrote the articles, rather than to the research methods, data analysis, or conclusions.

“In discussing their own data, the authors of all of the four larger studies have exaggerated the benefits, downplayed the harms, or both,” Jureidini and his coauthors wrote.

“Improvement in control groups is strong; additional benefit from drugs is of doubtful clinical significance,” they said, adding, “adverse effects have been down-played.” They concluded that “antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression.”

Jureidini and his coauthors pointed out that “accurate trial reports are a foundation of good medical care. It is vital that authors, reviewers, and editors ensure that published interpretations of data are more reasonable and balanced than is the case in the industry-dominated literature on childhood antidepressants.”

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When the researchers analyzed the published and unpublished data together, the SSRI no longer held a reasonable benefit for pediatric depression to justify the apparent risks.

There was not a “massive difference” between “the published stuff versus the unpublished,” Kendall said, “but [the profile] certainly switches from a favorable riskbenefit profile to an unfavorable one.” And with each of the SSRIs the researchers examined, they found the same trend: the published data were significantly more favorable than the data that had not been peer reviewed.

Defining Context

Neither Keller nor Wagner responded to multiple requests for interviews for this article; however, Emslie agreed to an extended phone interview.

“Apart from the first Prozac trial and one of the Paxil trials, all the rest of the data [in question] arise from an act of Congress, not from the industry wanting to do these studies,” Emslie told Psychiatric News.

Indeed, the data on SSRI use in children largely resulted from Food and Drug Administration (FDA) requests to drug manufacturers issued through the old “Pediatric Rule”-a regulation born from the Food and Drug Administration Modernization Act of 1997 (FDAMA). However, FDAMA did not require that studies be carried out and provided little if any penalty for a company not agreeing to the FDA’s request. In essence, the Pediatric Rule gave companies’ an additional six months of patent protection for conducting minimal research to collect data on safety of a medication in pediatric populations. Under the Rule, the FDA requested pediatric data from manufacturers of the 100 top-selling medications in the U.S.

Drug companies were slow to undertake pediatric research, and the FDA’s legal authority to mandate pediatric clinical trials was challenged. Finally, the Pediatric Rule was given the weight of law under The Pediatric Research Equity Act of 2003 (PREA) which left in place patent extension but further defined the FDA’s legal authority to mandate studies. In addition, PREA required pediatric studies as part of every application for approval of every drug-with few exceptions-retroactive to include all applications submitted since January 1, 1999.

However, between the Pediatric Rule and PREA, the FDA began receiving pediatric data that did not live up to the expectations of either Congress or the FDA.

“Many of the companies simply threw together the quickest, cheapest, easiest, clinical trial of their drug in kids they possibly could,” said one government official, a senior researcher who is familiar with the situation and agreed to comment if not named.

“The companies pretty much knew from the outset that they wouldn’t get a full pediatric indication, and the Pediatric Rule [initially] didn’t really have any stipulations that the data had to be good or the methods solid. The rule simply said if they submitted some data, they’d get their patent extended. And that, simply, translated into dollars,” the official explained.

Indeed, in many cases, the Pediatric Rule was directly responsible for hundreds of millions of dollars in additional sales of a branded product over the six-month extension.

The official continued, “Data collection in these studies was sloppy, recruitment was sloppy, the statistics and methods were manipulated, and, of course, only the positive studies were submitted. Why would a drug company put out data that are negative? That would amount to commercial suicide. But what can you expect, really? Garbage in, garbage out.”

Emslie agreed in part. “Getting all the positive as well as the negative data” is an issue, he said. But this is true for many different classes of medications,” not just antidepressants, he said (see box).

Wanted: All Relevant Data

The PREA was intended to ensure that the FDA was given all the appropriate pediatric data, both positive and negative, on a product so that an initial approval decision could be made on the whole data set, not just the most marketable data set.

The law includes language mandating that for any application to the FDA for a “new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration,” the application must include “data, gathered using appropriate formulations for each age group… to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations [and data to] support dosing and administration for each pediatric subpopulation for which the drug or biological product is safe and effective.”

If a drug maker fails to submit all of the data, the drug could be declared “misbranded solely because of that failure and subject to relevant enforcement action.”

Yet the FDA acknowledges that even today-a year and a half after the PREA went into effect-the agency isn’t sure whether it has all the data it’s supposed to have on the medications submitted under PREA’s requirements.

“I’m not aware of any standard mechanism in place for assuring that all pertinent data have been submitted,” Thomas Laughren, M.D., medical team leader of the FDA’s Neuropharmacological Drug Products division, told Psychiatric News. “It depends mostly on the review team being aware of what has been done.”

Nonetheless, Laughren was not aware of any instance in which a company was found to have purposefully withheld data from the agency.

In response to Laughren’s comments, the government official who asked not to be named said, “It is not only possible that the FDA does not have all the data, it is highly probable.”

Yet, Psychiatric News discovered that even if the FDA possesses all of the relevant data on a particular product, that data may not be easily accessible to the medical community, researchers, the media, or the public.

“Data become available only after an approval action,” Laughren said, “and then only data that clinical and statistical reviewers [at the FDA] decide to include in their reviews [become part of the drug approval package]. The original data sets are proprietary and never available unless a sponsor decides to release them.”

The FDA has attempted with some success to increase access to the information by posting a large amount of summary data on its Web site under an “Approvals” section.

If someone is looking for data not posted on the FDA’s Web site, the person must file a Freedom of Information Act (FOIA) request. Over the last year, in the course of this ongoing investigative report, Psychiatric News filed FOIA requests for “all approval package documents [and] their attachments and appendices” for each of the antidepressant medications being questioned. To date, a large amount of data has been received in response to those requests.

Over the last several months, several SSRI manufacturers have been accused in the media of attempting to “bury or hide” negative study data. The increasingly heated issue led the AMA, at the request of APA and the American Academy of Child and Adolescent Psychiatry, to advocate for a mandatory, federally administrated, clinical trials registry (see page 1). Separately, a large group of medical journal editors called for the same thing.

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C 2004 American Psychiatric Association

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