October 26

Drug safety Hearings-Sept-Congress/ FDA – Lilly Plans to Disclose Data

Drug safety Hearings-Sept-Congress/ FDA – Lilly Plans to Disclose Data

Tue, 3 Aug 2004

A hearing about the possible connection between suicide and antidepressant drugs will be held on Aug 4, by the California Senate by Sen. Tom Torkalson, chairman of the Senate Task Force on Youth and Workplace Wellness and Sen. Deborah Ortiz, Chair of the Senate Health and Human Services Committee. A noon press conference will precede the hearing which is scheduled for 1:30 p.m. in Room 112, State Capitol. Federal hearings are scheduled for September.

FDA’s response to public criticism and Congressional investigations of the agency’s failure to take action to protect children’s lives is to convene advisory committee meetings. The meetings were announced even before committee members have been appointed to a newly formed Pediatric Advisory Committee and Pediatric Ethics Sub-Committee.

Sept. 10: FDA Pediatric Ethics Committee (inaugural meeting) will consider whether the scientific merit of a proposed NIH study outweighs the risk of administering dextroamphetamine to healthy children. Dexamphetamine is an addictive drug of abuse: it is linked to cardiovascular and central nervous system adverse effects. See:

This proposed trial is the latest example of medical abuse. It is a barometer of the prevailing culture in psychiatry and at the National Institute of Mental Health. It is immoral to entertain conducting an experiment that exposes healthy, but helpless children to the hazards of amphetamines. Those who propose it, have no regard for children’s rights and welfare. Such experiments are proliferating since the enactment of federal laws that encourage the testing of drugs in children. The FDA Modernization Act (1997) and Best Pharmaceuticals for Children Act (2002) provide lucrative 6 month patent extension rights to companies that test their drugs in children-whether the drugs are beneficial or harmful for children.

Sept. 13-14: a follow-up to the Feb 2 meeting will review FDA Analysis Of Antidepressant Pediatric Suicidality Data. Of concern is the process by which the FDA is selecting a new panel of experts to replace the Feb 2 panel-a panel that had urged the FDA to issue immediate stronger warnings to the public.

Eli Lilly is the latest drug company to announce plans to disclose trial data on the website. As the Wall Street Journal correctly observes, recent drug company “pledges” for “broader disclosure” of clinical trial data are meant “to quell the furor” about concealed evidence of drug-related harm. But public furor is unlikely to recede in the absence of enforced, mandatory, full and explicit disclosure.

As long as the drug industry controls the trial data and voluntarily reports–or conceals–the post-marketing adverse event data, the reports are not trustworthy. If public officials, who have been entrusted with oversight authority over the drug industry, betray their public trust and serve that industry’s interests, public furor is unlikely to be quelled. FDA’s failure to disclose severe adverse drug effects to physicians and patients, its delaying tactics and continued suppression of the agency’s own expert medical officer’s report and recommendations are a demonstration of bad faith. The suppressed report is posted on the AHRP website as a public service at: https://ahrp.org/risks/SSRImosholder/index.php

FDA’s record leads to suspicions that FDA officials cannot be trusted to select objective experts for the new Pediatric Advisory Committee. What safeguards are there to prevent the FDA from appointing panelists with financial ties to drug manufacturers?

Congressional committees have also fallen prey to drug industry influence. A July 20 hearing of the House Oversight and Investigations subcommittee–“Publication and Disclosure Issues in Anti-Depressant Pediatric Clinical Trials”–was scuttled when Cong. James Greenwood, the committee chairman, accepted a job offer by a pharmaceutical /biotech trade association.

The hearing has been re-scheduled for Sept. 9, at 11:00 AM.

The original (July 20) hearing had all the makings of breaking the silence about undisclosed hazardous side-effects linked to antidepressant drugs. Seven representatives of the major pharmaceutical companies, and a representative of the drug trade organization, PhRMA, were scheduled to testify under oath about their concealment of safety and efficacy data. Also scheduled to testify on July 20, was Dr. Robert Temple, Associate Director for Medical Policy, Food and Drug Administration.

* The FDA Hearing will be held at the Holiday Inn in Bethesda, Maryland. For those wishing to speak, call Anuja Patel to register: 301-827-6790. To submit a written report, call 800-741-8138 ex. 301-451-2544 or go to www.fda.gov, scroll down the page about half way and click References, then go to Dockets.

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

FDA Analysis Of Antidepressant Pediatric Suicidality Data To Be Reviewed
Sept. 13-14

FDA’s analysis of independently reviewed pediatric suicidality data for antidepressants will be discussed Sept. 13 & 14 during a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the newly formed Pediatric Advisory Committee.

The meeting is being held as a follow-up to a Feb. 2 meeting where advisory committee members expressed concern about the high degree of variability and lack of categorization of events believed to be suicide related.

FDA’s preliminary review of over 4,000 pediatric patients from clinical trials of several antidepressants identified 109 cases as “possibly suicide related.”

Since the Feb. 2 meeting, “experts in pediatric suicidality, assembled by Columbia University, have independently classified these reported events, and FDA has conducted an analysis of these data,” a Federal Register notice slated for publication Aug. 4 states.

The Columbia group employed a standardized methodology to categorize events into “suicidal,” “non-suicidal,” and “indeterminate.” The suicidal category has three subdivisions: “suicide attempt,” “suicidal ideation,” and “suicidal behavior without injury.”

“The committees will consider the results of FDA’s analysis of these independently classified events and will consider what further regulatory action may be needed with regard to the clinical use of these products in pediatric patients,” the Federal Register notice reports.

Also on the agenda for the two-day meeting is discussion of further research needed to address questions of pediatric suicidality with antidepressant use. FDA’s conduct with regard to the pediatric data remains under investigation by the Senate Finance Committee. The investigation was recently expanded with an inquiry regarding the relationship between CDER’s Office of New Drugs and Office of Drug Safety.

In the wake of the investigation, eight out of 10 of the selective serotonin reuptake inhibitors have added class warnings on suicidality to labeling. Pfizer is negotiating language for Zoloft; Solvay’s Luvox was withdrawn in 2002.

The Sept. 13-14 meeting will be the first meeting of the full Pediatric Advisory Committee. The Pediatric Ethics Subcommittee will meet Sept. 10 to discuss a study protocol for dextroamphetamine; a full committee review will follow Sept. 15.

Dextroamphetamine Study Including Healthy Children Will Be First Test For Pediatric Ethics Subcmte.

FDA’s Pediatric Ethics Subcommittee will consider whether the scientific merit of a proposed NIH study outweighs the risk of administration of dextroamphetamine to healthy children during its inaugural meeting on Sept. 10.

The “Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder; A Functional Magnetic Resonance Study” protocol covers the administration of a single 10 mg dose of dextroamphetamine to both children with ADHD and healthy volunteer children. The study would be conducted by the National Institute of Mental Health.

“The central question raised by this protocol is whether the administration of dextroamphetamine in healthy children is permissible under the federal regulations as a minimal risk procedure,” NIMH IRB Chair Donald Rosenstein, MD, explained in a March 5 letter to HHS.

NIH’s Institutional Review Board requested a special panel review by HHS after two split votes on the level of risk: on Oct. 28, 2003 four members voted there was minimal risk versus six votes for more than minimal risk; on Nov. 4, 2003 the committee was divided with five votes for minimal risk and seven votes for greater.

“Although the official vote of the NIMH IRB was divided,” Rosenstein stated, “the final decision of the Board was that this is a study which offers no direct medical benefit to participants but has scientific merit.” IRB members were concerned about “possible risks to a healthy child from exposure to a psychoactive controlled substance (albeit a single dose),” he noted. Some members suggested that patients “might subsequently conclude that experimentation with stimulants or related substances of abuse (e.g. cocaine) was not a hazardous activity.”

“In contrast, several Board members considered a single dose of dextroamphetamine to pose only minimal risks since the likely acute physiological and psychological effects of this medication were commensurate with risks ordinarily encountered in the daily lives of children,” Rosenstein added.

Another concern was that the proposed compensation of up to $570 “may constitute an undue inducement for potential study subjects and/or their parents.”

The newly-formed Pediatric Advisory Committee will consider the subcommittee’s recommendation during its Sept. 15 meeting, in addition to hearing adverse event reporting for Pulmicort/Rhinocort (budesonide), Clarinex (desloratadine), Flonase/Flovent/Cutivate (fluticasone), Ocuflox (ofloxacin), Fludara (fludarabine) and Fosamax (alendronate) as mandated in the Best Pharmaceuticals For Children Act.

On Sept. 13 and 14 the committee will meet in a joint session with the Psychopharmacologic Drugs Advisory Committee to review the issue of pediatric suicidality associated with antidepressants.

Lilly Plans Broad Access To Results of Drug Trials
August 3, 2004; Page B1

Seeking to defuse criticism that pharmaceutical companies hush up negative results in clinical trials, U.S. drug maker Eli Lilly & Co. plans to disclose extensive data on almost all clinical trials, past and present, for the drugs it sells.

Under the new policy, once a drug is on the market, Indianapolis-based Lilly will publish data from all early to late-stage clinical trials, including safety information and outcomes. Test results that did not support the hypothesis or that were contrary to the expected outcome also will be disclosed, the company says. Results of trials on unapproved uses of medicines — known as off-label use — also will be available.

Lilly’s plan, expected to be in place by the end of the year, goes beyond the more limited and less detailed policies announced by other drug companies. Lilly plans to offer access to data from all phases of its clinical trials while other drug companies haven’t decided if they’ll publish the same amount of information or just the later-phase trials. Lilly’s policy could spur other drug makers to follow suit.

Drug companies have long been criticized for selectively releasing data from clinical trials. Companies typically trumpeted studies that were favorable for a given drug and quietly shelved those that showed side effects, safety problems or raised questions about the drug’s effectiveness.

Alan Breier, Lilly’s chief medical officer, says the company decided to publish such trial details because the “the public is demanding greater openness.” Dr. Breier also says that Lilly wanted to be certain that its medicines were being used properly. “Patient care is served best by open disclosure,” he says.


Outcomes from some clinical trials for antidepressant use in children have not been published to date.

Prozac/Eli Lilly 6 2
Paxil/GlaxoSmithKline 7 2
Zoloft/Pfizer 5 1
Celexa/Forest 3 3
Effexor/Wyeth 2 2
Source: The Lancet, April 2004

Lilly’s trials will be published on a company Web site open to the public.

In June, the American Medical Association called for all drug companies’ trials to be registered with the federal government (they aren’t currently). While the AMA didn’t offer a specific outline, it said a government-run system that tracks data from all clinical trials would help make the research more open to the public.

The AMA also wants trials of experimental drugs to be disclosed — something the drug industry opposes because of concerns that competitors would learn their research and development secrets. Lilly won’t publish results of trials on drugs that aren’t yet approved, but it will list on its Web site when late-stage trials are to begin.

Questions about the safety of antidepressants in children have brought the issue of medical disclosure to a head. Doctors and regulators were stymied by incomplete public data as they weighed whether children taking antidepressants were initially at greater risk of suicide. Doctors couldn’t see the results of tests that drug companies had done with children, even as prescriptions for the young ballooned. In June, New York State Attorney General Eliot Spitzer sued GlaxoSmithKline PLC, alleging that the company concealed efficacy and safety in tests done with children and the company’s blockbuster drug Paxil for treating depression. The lawsuit is continuing.

To quell the furor, several drug makers have pledged broader disclosure. Glaxo released all its Paxil data on its Web site (the company says the move was not in connection with the lawsuit) and said it would disclose data from trials of all its marketed products. Glaxo is still hashing out what kind of information will be disclosed and declined to comment on its plan. Merck & Co. has indicated that it would support a government-run listing system, and pledged more openness — but only about late-stage clinical trials or postapproval tests. Johnson & Johnson also said it supported the idea of a clinical trials registry.

Federal law requires drug companies to list all studies done in serious or life-threatening illnesses on the public Web site ClinicalTrials.gov. The site does not provide any results of trials because it is geared to people looking to enlist in studies.

Lilly says it will release historical information for all of the drugs it now sells going back 10 years. Dr. Breier says that such retrospective data on drugs already on the market immediately help doctors in prescribing medication for patients. Despite ongoing litigation, Lilly plans to release historical data on Zyprexa, the blockbuster antipsychotic that brings in a third of the company’s revenues. Zyprexa was at the center of a debate last year over whether antipsychotic drugs cause weight gain and increase the risk of diabetes. Lawsuits involving Zyprexa are getting under way in federal and state courts. Lilly’s Dr. Breier says the company isn’t concerned that it’s giving plaintiffs’ lawyers an edge in the litigation because much of the data already has been published.

In another new approach, Lilly says it will rely on a third-party auditor to monitor its adherence to the policies, something no other company has said it would do. Lilly also pledged to notify the public when it begins a trial that will later be included in the application submitted to the Food and Drug Administration for approval or when it will conduct a postmarketing study that explores using the drug for another disorder — both moves aren’t common practice in the industry.

That move would make it easier for patients to locate clinical trials to join, and as act an “accountability check” to ensure that Lilly actually publicized all results when the trial ended. Some lawmakers and associations of medical journal editors and doctors have called for all companies to disclose such information.

After a drug comes to market, companies aren’t required to publish or give the FDA further test results on a drug’s effectiveness for other conditions or if it was studied on special populations, such as children. Lilly will publish its clinical trial results for unapproved uses. Lilly’s antidepressant Prozac was the only one that received FDA approval for use in children with depression. Dr. Breier says Lilly will release its tests of Prozac in kids on its Web site.

Since doctors frequently prescribe drugs for unapproved uses, more information would help them in treating patients. For example, Lilly’s antipsychotic drug, Zyprexa, is widely prescribed for hard-to-treat cases of depression and dementia in the elderly. Yet there haven’t been any large-scale studies to determine whether Zyprexa works in those disorders. A clinical trial registry along the lines of Lilly’s plan would let doctors know if the company had ever done tests of Zyprexa for unapproved uses — and what the results were.

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