October 26

Spitzer Expands drug Probe: Johnson & Johnson / New FDA analysis Confirms SSRI Risks to Kids – WSJ

Spitzer Expands drug Probe: Johnson & Johnson / New FDA analysis Confirms SSRI Risks to Kids – WSJ

Thu, 5 Aug 2004

A front page article in The Wall Street Journal reports that a second FDA analysis of 25 clinical trials of SSRI antidepressants in children was conducted after a Columbia University team tinkered with the original adverse event classifications that were submitted to the FDA. The analysis by another FDA expert, Dr. Tarek A. Hammad, confirms that SSRIs pose suicidal risks for children, but notes unexplained variations between drugs. The differences may be attributed either to the drugs or the design of the trials-which like the classifications are open to manipulation.

“The finding is likely to reignite debate over the issue and the agency’s handling of it.”

Indeed, FDA’s failure to protect children from hazardous drugs by turning a blind eye to the concealment of vital information from prescribing physicians and the public has led to mounting public pressure.

“The issue has taken on more urgency as antidepressant prescriptions for young people have grown, even though few studies have been published for most of the drugs demonstrating that they work in that population.”

The New York Post reviewed a sampling of adverse event reports of children who became violent, self-mutilated, and attempted suicide during Paxil clinical trials from 1994 to 2001.

“One internal document lists 23 children and teens as making suicide attempts.” [Edelman]

The New York Times reported yesterday that New York State Attorney General, Eliot Spitzer, has broadened his probe of the drug industry’s fraudulent marketing practices.

“Johnson & Johnson is the third drug company to come under scrutiny from Mr. Spitzer in recent months over its handling of clinical trial data and drug marketing practices. Mr. Spitzer has previously said that he planned to use legal action or the threat of legal action to force greater industry disclosure of clinical trial findings, an issue that has drawn intense public interest.”

The public has awakened to the fact that senior FDA officials have shown little interest in using their authority to protect children from drugs whose hazardous effects they knew.

FDA officials have approved at least a dozen hazardous drugs that had to be recalled after killing adults and children. FDA officials have ignored the scientific evidence of hazardous drug effects, and approved drug labels that failed to warn physicians about those serious drug hazards. FDA officials failed to intervene when harmful drugs were fraudulently marketed for off-label use–thereby exposing millions of unsuspecting adults and children to concealed risks of harm.

Both SSRIs and the atypical antipsychotics have become blockbuster profit producers-primarily because they are inappropriately prescribed to millions of (mostly healthy) adults and children for a wide array of behavioral problems and newly invented “conditions.” [Koerner] The hazards of psychotropic drugs manifested during clinical trials were concealed: the scientific literature never mentioned that in clinical trials, “one in every 145 patients who entered the trials” for four atypical antipsychotics-[ ]-died.” [Whitaker, p. 269.]

Instead of protecting the public health, FDA officials have aggressively and improperly invoked FDA’s pre-emptive authority by intervening in court cases to shield drug manufacturers who were challenged about their failure to include warnings on drug labels. [Young]

Under FDA’s current, drug industry promoting policy, drug manufacturers are marketing harmful drugs that induce diabetes, stroke, violent and self-injurious behavior. They market such drugs with impunity, much as toxic snake oil remedies were hawked prior to the enactment of the Food, Drug, and Cosmetics Act, 1938.

The Post reports that according to new FDA data:
“At least 110 American kids have killed themselves while taking antidepressants during the past decade.”

That number does not begin to reflect the actual number of suicides by children prescribed an antidepressant–inasmuch as only 1% to 10% of adverse drug reactions are ever reported to the FDA.

A more realistic assessment can be made by applying a unique computer model– IMR (Investigative Medication Routine)-a unique program designed by Graham Aldred, a systems engineer in the UK, that calculates the number of SSRI drug-induced suicides (or other adverse drug reactions) from actual drug sales data. [Aldred]

FDA’s failure to track post-marketing adverse drug effects effectively conceals the actual number of people harmed by drugs. However, the facts are tumbling out. Adverse prescription drug reactions are the third largest cause of death in the US, topped only by tobacco and alcohol. According to an article in the Journal of the American Medical Association, over 100,000 hospitalized patients died as a result of an adverse drug reaction. The researchers found that over 75% of these ADRs were dose-dependent, which suggests they were due to the inherent toxicity of the drugs rather than to allergic reactions. [Lazarou]


See: Mr. Aldred’s suicide calculations from the combined adult and children US sales data for Prozac, Paxil, and Zoloft at:

David Armstrong and Anna Wilde Mathews, Pfizer Case Signals Tougher Action On Off-Label Drug Use THE WALL STREET JOURNAL May 14, 2004; Page B1


Brendan I. Koerner, Disorders Made to Order. Mother Jones. July/August 2002.

Lazarou et al, Incidence of Adverse Drug Reactions in Hospitalized Patients, Journal of the American Medical Association (JAMA), Vol. 279. April 15, 1998, pp. 1200-5.

Robert Whitaker, Mad in America, Perseus, 2001.

Gary Young. FDA legal strategy would pre-empt tort suits. The National Law Journal, March 5, 2004, Vol. 128; No. 44; Pg. 3

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


FDA Revisits Issue Of Antidepressants for Youths
New Analysis May Pressure Agency to Set Limit on Use Because of Suicide Risk
August 5, 2004; Page A1

A new Food and Drug Administration analysis of clinical-trial data shows evidence of a link between antidepressant drugs and suicidal tendencies among young people. The finding is likely to reignite debate over the issue and the agency’s handling of it.

The new analysis, which focused on 25 studies of nine drugs, found that children and teenagers who took the medicines were more likely to have behavior or thoughts that appeared suicidal, compared with those who got placebo pills. When the analysis used a far broader category of incidents that might possibly reflect suicidal intent — some of them classified as “not enough information” — the young people who took the drugs were twice as likely to engage in the behavior.

What makes the issue so controversial is how the FDA has dealt with an internal debate on the matter. Congressional investigators have been examining the agency’s decision to block a staffer from revealing this past February his finding of a tie between antidepressants and suicidal tendencies in young people, which drew on many of the same trials. FDA officials said his conclusion was premature, and based on ambiguous data. The new FDA analysis relies on an in-depth review of the data by outside researchers.

The new findings are likely to intensify pressure on the agency to consider stronger action to limit use of the drugs by young people. The FDA is scheduled to present a final version of the analysis to an advisory committee in September, asking for its recommendations on what safety steps it needs to take.

The FDA’s new analysis, which hasn’t been made public, was contained in a draft document reviewed by The Wall Street Journal. An FDA spokeswoman said the agency was still reviewing the data, and couldn’t comment before the committee meeting.

In March, the agency called on makers of major antidepressant drugs to beef up warnings on their labels urging doctors to watch all patients for indications of increasing depression or suicidal thinking. In Britain, regulators have gone further and specifically discouraged the use of a number of the drugs for depressed patients under the age of 18.

The new analysis by an FDA medical reviewer tabulates the results of an outside re-examination, requested by the agency, of the clinical-trial data. The document, dated July 19, focuses on an array of antidepressant drugs including Pfizer Inc.’s Zoloft, Forest Laboratories Inc.’s Celexa, Wyeth’s Effexor, GlaxoSmithKline PLC’s Wellbutrin and Paxil, and Prozac, made by Eli Lilly & Co. and available generically.

The results varied sharply from drug to drug, and even multiple trials of the same drugs sometimes found differing levels of possible risk. Also, some of the results weren’t strong enough to achieve statistical significance. No participants in any of the trials actually completed a suicide attempt.

Nevertheless, the document’s findings appear to be consistent with the controversial earlier analysis done by an FDA epidemiologist, Andrew Mosholder. He wasn’t allowed to publicly present his conclusions at an advisory-committee meeting in February. He shared his views with agency officials as early as last December.

The issue has taken on more urgency as antidepressant prescriptions for young people have grown, even though few studies have been published for most of the drugs demonstrating that they work in that population. According to an analysis by Washington State University researchers, the rate of antidepressant prescriptions for children and adolescents more than tripled in the U.S. from the early 1990s to 2001. In 2002, an estimated 10.8 million prescriptions for the most widely used antidepressants were dispensed for patients under 18 years old, according to an FDA analysis. Some psychiatrists credit the drugs for the sharp decline in the suicide rate among young people since 1994.

Drug-industry studies of antidepressants in young people have also become the crux of a broader debate over the disclosure of negative clinical trial results. In June, New York State Attorney General Eliot Spitzer sued GlaxoSmithKline, alleging that the company concealed findings in pediatric tests of Paxil.

The FDA has said it felt Dr. Mosholder’s findings were premature and based on ambiguous data. Last February, at the advisory-committee meeting, the agency did reveal the underlying data examined by Dr. Mosholder, but not the staffer’s conclusions. Two congressional committees are currently examining the agency’s handling of the epidemiologist’s report. Dr. Mosholder declined to comment.

To get a more definitive answer about possible ties between the drugs and suicidal behavior, the FDA commissioned a new examination of the pediatric-trial data by an outside team of reviewers led by Columbia University researchers. The point was to sort through the incidents in the trials and figure out which ones truly reflected suicidal tendencies. Dr. Mosholder wrote that this re-evaluation was unlikely to significantly change his conclusion, but a number of FDA scientists said that the ambiguous data he used could produce a misleading result. The new analysis was supposed to be more definitive.

Now, the reclassified data appears to show evidence of a link between the drugs and suicidal tendencies in the pediatric patients who participated in the trials. The July document was prepared by a medical reviewer named Tarek A. Hammad, who works in the division of the FDA’s drug center that reviews psychiatric drugs. xxx cut xxx

That variability is consistent with earlier examinations of the trial data by FDA officials, including Dr. Mosholder. Dr. Mosholder, in a report dated in February, urged that the agency take steps to discourage pediatric use of the drugs, except in the limited cases mentioned on the labels of some of them. Essentially, this would have meant the agency would recommend that doctors use only Prozac for depressed young patients. This was similar to the recommendation of British regulators.

August 4, 2004
Spitzer Asks Drug Maker for Off-Label Use Material

Johnson & Johnson said yesterday that the New York attorney general, Eliot Spitzer, had asked for information about six of its drugs, including marketing materials, the results of clinical trials and data on prescriptions for so-called off-label use.

Johnson & Johnson is the third drug company to come under scrutiny from Mr. Spitzer in recent months over its handling of clinical trial data and drug marketing practices. Mr. Spitzer has previously said that he planned to use legal action or the threat of legal action to force greater industry disclosure of clinical trial findings, an issue that has drawn intense public interest.

In June, Mr. Spitzer sued GlaxoSmithKline, saying it had misled doctors by highlighting positive test data for Paxil, its popular antidepressant, while playing down negative results. The company has denied any wrongdoing. Several weeks later, he asked Forest Laboratories to provide his office with test data and marketing materials about its products, including the antidepressants Celexa and Lexapro.

Johnson & Johnson made the disclosure about the request from Mr. Spitzer in a regular quarterly report filed with the Securities and Exchange Commission. It identified the drugs at issue as Topamax, an antiseizure medication; Risperdal, an antipsychotic drug; Procit, an anemia medication; Reminyl, an Alzheimer’s medication; Remicade, a treatment for rheumatoid arthritis; and Aciphex, a drug to relieve acid reflux.

The prescriptions on which Mr. Spitzer is seeking information are those for off-label uses – or treatments other than the federally approved uses of the medication. While doctors are free to prescribe an approved drug for any use, drug companies are allowed to actively market drugs only for the approved treatment.

The type of informational request received by Johnson & Johnson is not a subpoena. But depending on the findings, such a request can be the first step in a process that could eventually lead to a civil suit. Federal investigations are also under way into several of the drugs at issue in Mr. Spitzer’s inquiry, including Topamax, Remicade and Risperdal. Jeffrey J. Leebaw, a spokesman for Johnson & Johnson, based in New Brunswick, N.J., said that the company “is responding to the request.”

Mr. Spitzer is not alone in calling for the greater disclosure of clinical test data. The American Medical Association recently urged Congress to pass legislation requiring drug makers to list all drug trials and their results in a publicly available database. Several leading medical journals are also considering a proposal that would require a trial to be registered in such a database as a prerequisite to subsequent publication of the trial’s results – making it less likely that an unsuccessful trial could escape notice.

The drug industry, long criticized for not moving toward fuller disclosure, has scrambled to respond. .cut.

Copyright 2004 The New York Times Company


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