Vol. 6 No. 115
Sen. Chuck Grassley (R-Iowa) asked FDA Commissioner Andrew von Eschenbach to respond to allegations that a senior agency scientist was punished for recommending a black box warning on GlaxoSmithKline’s (GSK) Type 2 diabetes drug Avandia in 2006.
The FDA announced last week it would be recommending black box warnings for Avandia (rosiglitazone) and Takeda’s diabetes drug Actos (pioglitazone) because of increased risk of congestive heart failure (DID, June 8). A recent study in the New England Journal of Medicine found that Avandia increased the risk of heart attack by 43 percent and death from cardiovascular causes by 64 percent (DID, May 22).
However, in the Senate Committee on Finance’s investigation into Avandia, the committee received a memorandum from the FDA showing staff members had recommended changes to Avandia’s label in 2006, Grassley said. While the FDA’s delay in action was concerning, the allegations that an FDA staff member was punished for supporting a black box warning on the drug are far worse, he said.
In a Feb. 22, 2006, memorandum, a “very seasoned” safety evaluator from the agency’s Division of Drug Risk Evaluation (DDRE) said Avandia’s label should have a black box warning for congestive heart failure, he added. The DDRE evaluator also called for macular edema to be included as a serious adverse event on the drug’s label.
Grassley, the committee’s ranking member, said he had heard allegations that the DDRE deputy director was reprimanded for signing the 2006 memorandum recommending the black box warning. The Office of New Drugs (OND) did not agree that Avandia needed a label change and punished the deputy director for not consulting with the OND before signing the recommendation, Grassley said.
In addition, the deputy director was advised she could not “sign off” on any Avandia-related matters in the future and could not sign any recommendations for major regulatory actions without first checking with the DDRE director, Grassley said. He called the allegations “unconscionable.”
The Avandia case is another example of the FDA allowing the OND to “call all the shots regarding the postmarket surveillance of drugs, despite the expertise that’s contained within the FDA’s office that is responsible for postmarket surveillance,” Grassley added.
The FDA’s Office of Surveillance and Epidemiology (OSE) can recommend how to manage drug risks but the OND decides what action to take. The Senate rejected a Grassley amendment to S. 1082, the bill reauthorizing the Prescription Drug User Fee Act (PDUFA), that would have given the OSE more authority so it would have equal standing with the OND on certain issues (DID, May 10).
Grassley said he hoped Congress would revisit his legislation to make
the OSE “an equal partner” with the OND. The House Subcommittee on
Health will hold a hearing on its version of legislation renewing PDUFA
FDA employees “should be able to express their opinions in writing and independently without fear of retaliation, reprimand or reprisal,” Grassley added. He asked von Eschenbach to correct the agency’s situation.
Grassley and Sen. Max Baucus (D-Mont.) also recently sent a letter to GSK and the University of North Carolina at Chapel Hill in response to university professor John Buse’s testimony before the House Committee on Oversight and Government Reform (DID, June 8). Buse testified that a “high-ranking” GSK employee threatened him for publicly questioning Avandia’s safety. — Emily Ethridge
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will consider the safety of sanofi-aventis’ weight loss drug Zimulti (formerly known as Acomplia) during its upcoming meeting scheduled for June 13.
In committee briefing documents posted on the FDA’s website, the agency said although the 20-mg dose of Zimulti (rimonabant) was effective for weight management, incidence of psychiatric adverse events observed in clinical trials, including suicidality and seizures, led the FDA to request more safety data in an approval letter issued last year (DID, Feb. 21, 2006).
At the agency’s request, sanofi obtained a formal assessment of the potential suicidality of the product from Columbia University researchers.
The researchers identified 91 cases classified as either possibly or definitely suicidal events in Zimulti clinical data. Of the 2,909 subjects on placebo, 13 (0.45 percent) experienced suicidal thoughts. In comparison, of the 6,802 patients dosed with 20 mg of Zimulti, 39 (0.6 percent) experienced suicidal thoughts. However, seven subjects on placebo attempted suicide while only four in the Zimulti group did, according to the analysis.
“Roughly 50 percent of the subjects in the rimonabant and placebo groups withdrew early from the trials, with more rimonabant subjects doing so due to depression, anxiety, mood alteration with depressive symptoms and the need for antidepressant medication,” the FDA said.
Of the patients that discontinued treatment with the 20-mg dose of rimonabant, 26 percent withdrew because of adverse events, the FDA said.
Eleven adverse events were classified as either likely or possible seizures in eight patients on the drug and three patients on placebo. The agency said a statistical analysis of seizure data would be presented during the upcoming advisory committee meeting.
Last year, rimonabant, still marketed as Acomplia in Europe, was approved by the European Commission for the treatment of obesity (DID, June 23, 2006). As of November 2006, the firm sold 3.9 million tablets outside of the U.S., with the vast majority of sales in the UK and Germany. For the first quarter of 2007, sanofi recorded $20 million in revenue for Acomplia.
ImClone Systems and Bristol-Myers Squibb (BMS) said the FDA has accepted a supplemental biologics license application (sBLA) for priority review of their cancer drug Erbitux.
The companies want to put evidence of improved overall survival in “third-line treatment” of patients with metastatic colorectal cancer on the product labeling for Erbitux (cetuximab). The data are based on results from a large, randomized, multi-site Phase III clinical trial.
Due to the priority status, the companies said the FDA will likely decide on the sBLA in early October. If the sBLA is approved, Erbitux will become “the only biologic therapy to demonstrate overall survival as a single agent in patients with metastatic colorectal cancer,” ImClone and BMS said.
The U.S. District Court for the District of New Jersey vacated a temporary restraining order that it had issued last month, which had prevented Teva Pharmaceutical Industries from selling its generic version of Novartis’ hypertension drug Lotrel (DID, May 22).
Following the ruling, Teva announced that it intends to resume commercial shipments of its generic amlodipine besylate/benazepril HCl products immediately, and Novartis announced that it will immediately launch its own generic version of Lotrel in the U.S. through its Sandoz division.
The court turned down Novartis’ motion for a preliminary injunction against Teva and found that Novartis is not likely to succeed in its allegations of patent infringement. However, Novartis said that it “will continue pursuing its defense of intellectual property rights for Lotrel, since its U.S. patent is still valid until 2017.”
Novartis said that in 2006 its sales of Lotrel totaled $1.35 billion. Lotrel is a combination product that is available only in the U.S. The two active ingredients in the drug no longer have U.S. patent protection by themselves.
Teva’s amlodipine besylate/benazepril HCl products were approved by the FDA on May 18, and the company immediately commenced commercial shipment, only to be hit by the temporary restraining order.
As the first company to file an abbreviated new drug application with a Paragraph IV patent certification, Teva was awarded 180 days of marketing exclusivity from the date of initial shipment. — Martin Gidron
Medivation’s experimental Alzheimer’s disease treatment Dimebon stopped mental decline for up to a year in clinical trials, the longest benefit observed for any Alzheimer’s drug in clinical trials, the company announced.
Patients receiving Dimebon scored better in five mental areas than those taking placebo, the company said. The 12-month Phase II clinical trial involved 183 patients with mild to moderate Alzheimer’s disease. Patients were tested for cognition, clinical function, ability to carry out daily tasks and behavioral problems.
The benefits in cognitive ability and daily living tasks appeared to be stable or greater after 12 months, according to the company. Dimebon works by blocking a new target involving mitochondrial pores, which may play a role in the cell death associated with neurodegenerative diseases, Medivation said.
In addition, patients taking Dimebon had fewer serious adverse
events than patients who took placebo and had a similar dropout rate as
the placebo group, according to the company. The most frequently
reported adverse events with Dimebon were dry mouth, depressed mood and
sweating. The side effects were generally mild and did not result in
patients discontinuing the study, Medivation said.
Approximately 26 million people worldwide have Alzheimer’s disease, and the number is expected to quadruple by 2050, according to a study from researchers at Johns Hopkins University.
The company plans to begin six-month Phase III clinical trials of the drug in 2008, Medivation CEO and President David Hung said. If the trials are successful, the company will submit new drug applications in the U.S. in 2010.
Medivation’s shares rose 25 percent following the announcement. If Dimebon receives FDA approval, it will be the company’s first marketed product. — Emily Ethridge
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