June 30

NYS AG Expands Pharmaceutical probe – Forest Labs

NYS AG Expands Pharmaceutical probe – Forest Labs

Wed, 30 Jun 2004

The New York Times reports (below) that New York State Attorney General, Eliot Spitzer, is broadening his legal investigation. “Mr. Spitzer said in a speech on Monday to health care lawyers that he would continue to investigate how drug companies disclose trial data.”

Forest Laboratories is the second company to receive “a wide-ranging request” for drug testing and drug marketing information. Forest was asked for information “about how the company tested and promoted drugs like its antidepressant Celexa for so-called off-label, or as yet-unapproved, uses.”

The Times indicates that Spitzer’s probe follows on the heels of the Times’ revelation that Forest had concealed a failed, unpublished trial of its antidepressant drug, Celexa.

The Wall Street Journal reports (below) that PhRMA, the principal trade group of drug manufacturers, is “seeking to calm the storm” over public disclosure of drug companies’ failure to disclose negative clinical trial results–in order to increase sales. The Journal reports that PhRMA has just issued revised disclosure guidelines to its members “urging drug companies to publish trial results in journals, present them at scientific meetings, or post them on the Internet.”

However, the WSJ notes that PhRMA guidelines allow for “exceptions and restrictions that could limit the scope and usefulness of the guidelines.” In fact, the guidelines would allow companies to withhold the most problematic evidence of a drug’s hazards from the public. For example, studies large and small whose results were found to be invalid; or studies that are halted early “before a valid conclusion could be reached, after new animal test data became available.” Furthermore, the WSJ reports, the majority of “exploratory studies” would be excluded from public dissemination.

It is unlikely that Mr. Spitzer and his legal will be impressed with these gestures of partial data disclosure.

AHRP is concerned about the nature of those unregulated “exploratory studies” referred to in the PhRMA guidelines. Do these “exploratory studies” involve human subjects? Do they adhere to ethical research requirements?

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

Drug Firms Address Furor on Tests
[print edition: Drug Makers Urged to Publish Data]
New Guidance on Results Aims to Calm Concerns Over Negative Trial Data
June 30, 2004; Page D7

The pharmaceutical industry is seeking to calm the storm over alleged suppression of negative clinical-trial results with new standards concerning the public release of data from human tests.

The new guidance to members of the Pharmaceutical Research and Manufacturers of America, the industry’s principal trade group, could become effective as soon as this week, when the organization is expected to post the guidance on its Web site. The group initially issued general principles in October 2002 urging drug companies to make timely public communications of meaningful study results, but didn’t offer specifics. The new guidelines attempt to make the principles more practical to implement.

Under the new plan, the group is urging drug companies to publish trial results, regardless of whether they are positive or negative, in journals, present them at scientific meetings, or post them on the Internet.

While the new standards have been in the works since late last year, they come on the heels of questions raised about unpublished studies that show negative results about antidepressant use in children and adolescents. Some doctors and journals are urging more public disclosure, including requiring drug companies to list their clinical trials in a public registry.

The guts of the current proposal, comprising eight pages of questions and answers, reiterates that companies should publish results on marketed drugs or those destined for market. The benchmark for disclosure is whether a clinical study tested a specific medical hypothesis, such as whether a drug is superior to a placebo, or dummy pill. All late-stage, or so-called Phase III, studies would fall in this category, the PhRMA guidance said. Results from these types of statistically sound studies “allow firm conclusions to be drawn to support product claims,” the guidance says. Some preliminary studies might also meet this criterion, the guidelines said, as could trials of drugs already on the market, such as comparative tests. The principles apply only to trials begun after October 1, 2002.

“We want patients and physicians to understand exactly what we’re doing in clinical trials,” said Peter Corr, who worked on the PhRMA guidance and is a senior vice president for science and technology at Pfizer Inc.

The PhRMA member companies approved them in a recent vote. “I can’t imagine a company would sign on to these policies and not do it,” Dr. Corr says. “We’re not going to sit on something because it’s a negative trial.”

The standards represent the most specific response by the drug industry to charges that it has played down unfavorable results from human tests of drugs.

“This guidance is much more specific and affirmative on the publication of clinically meaningful study results than anything the trade association has set forth before,” said Mark Barnes, a lawyer specializing in clinical-research issues for law firm Ropes & Gray in New York.

In drawing a line between “hypothesis testing” studies and exploratory ones, the industry introduces a new concept that could lead to a public policy debate on who decides how to classify studies, Mr. Barnes said.

There are exceptions and restrictions that could limit the scope and usefulness of the guidelines. Some studies, both small and large, might be unsuitable for release because their results were found to be invalid, the guidance says. Laboratory malfunctions or unreliable samples could undermine a trial. A study might also be halted early, before a valid conclusion could be reached, after new animal test data became available, for instance.

The majority of “exploratory studies” would be excluded from public dissemination. These generally small studies, designed to gather preliminary information about a drug or disease, could constitute trade secrets because they illuminate the path a company might take in developing new product. But keeping these studies hidden might also deprive doctors of data supporting or refuting use of drugs for unapproved uses.

Dr. Corr says exploratory studies generally aren’t statistically powerful enough to form conclusions that would apply across the board. Occasionally, these pilot studies uncover information that is relevant and sound. “Sometimes you get a dramatic effect,” he acknowledges. “We would say that should be released if it would alter the treatment of patients.”

The guidelines don’t specify how clinical results should be disseminated. One reason, the guidance notes, is that some medical journals accept fewer than one in 10 manuscripts for publication. Internet posting of data is another possibility.

Even if trial results become public more often, patients may still have to hunt for them because no central repository for the information exists.

A registry of clinical trials might someday allow for outsiders to track which study results had gone unpublished or weren’t presented at medical meetings. In the meantime, the honor system would prevail, a prospect unlikely to appease critics of the industry for selective disclosure.

June 30, 2004
Forest Asked to Supply Information on Marketing of Some Drugs

Forest Laboratories said yesterday that it had received a wide-ranging request from the New York attorney general, Eliot Spitzer, asking for information about how the company tested and promoted drugs like its antidepressant Celexa for so-called off-label, or as yet-unapproved, uses. A representative of Mr. Spitzer’s office, who asked not to be identified, said that the request covered 10 products sold by Forest. But that person said that Mr. Spitzer is particularly interested in how Forest tested and promoted two of its antidepressants, Celexa and Lexapro, which are widely used off-label by doctors for the treatment of pediatric depression.

The type of informational request received by Forest is the first step in what could turn into a formal investigation by Mr. Spitzer’s office of the company’s test disclosure and promotional practices or result in a lawsuit against it.

GlaxoSmithKline, the manufacturer of Paxil, another antidepressant widely used to treat children, received a similar request from Mr. Spitzer before his office filed a lawsuit earlier this month accusing it of defrauding doctors by highlighting positive results from some clinical trials of that drug in youngsters while playing down negative ones. The company has denied any wrongdoing.

An executive of Forest, which is based in New York, said no one was available yesterday to comment.

Forest stated that the request from Mr. Spitzer indicated that he believed that the company might have violated New York State law. The company said in its statement that it believed that it had not done anything wrong, adding that it was cooperating with the request.

Because the federal Food and Drug Administration has not approved the use of Celexa or Lexapro for pediatric depression, Forest is legally barred from promoting them for such uses. But doctors are allowed to prescribe drugs off-label where they see fit, and Celexa is the fourth most prescribed medication for pediatric depression.

Mr. Spitzer’s action follows by a week an article in The New York Times which disclosed that Forest did not tell a medical journal about a failed, unpublicized trial of Celexa in children and adolescents when it published an article this month about a positive trial of the same drug in the same types of patients. Some of the article’s authors were Forest employees.

Last Thursday, Forest put out a statement seeking to defuse controversy over how it had handled the disclosure of the failed Celexa trial, which was conducted in Europe from 1996 to 2002. The European study was sponsored by H. Lundbeck, the Danish company that developed citalopram, which Forest markets in this country as Celexa.

At the time, Forest reiterated its position that it had not included any reference to the failed Celexa study in the recent article because there were no published references to it that the article’s authors could cite. The basic finding of that study – which reported that Celexa showed no effects greater than a placebo – was noted in a chart published in October 2003 in a medical textbook written in Danish.

Forest had publicized the successful trial of Celexa through company news releases as far back as 2001, starting months after the trial was completed and before its data was submitted to a medical journal for consideration.

It was also on Thursday that Forest announced that preliminary results from a clinical trial of Lexapro which showed that it worked no better than a placebo in treating pediatric depression.

That result also may raise questions about the positive Celexa test because Lexapro contains the drug escitalopram, which is the active ingredient found in citalopram, or Celexa.

Because Celexa’s patent is about to expire, Forest has been aggressively marketing Lexapro as a treatment for adult depression. The company said in its statement that it intended to discuss with federal regulators its plan to start additional pediatric tests of Lexapro in the hope of eventually winning approval for such uses.

In recent weeks, pharmaceutical companies have faced growing pressure on the issue of selective disclosure of drug test results. The American Medical Association has called on the federal government to create a database in which trials can be tracked from start to finish. And several medical journals are considering a proposal that would require trials to be registered at the outset as a prerequisite to the results’ eventual publication.

Also, Mr. Spitzer said in a speech on Monday to health care lawyers that he would continue to investigate how drug companies disclose trial data.

Copyright 2004 The New York Times Company

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