DID - July 30, 2007 Issue

Vol. 6 No. 148

Lawmakers Push for Final Passage of PDUFA Reauthorization

The top Republican on the Senate Health, Education, Labor and Pensions (HELP) Committee has written the majority and minority leaders, encouraging them to appoint conferees to the committee that will finalize pending legislation reauthorizing the Prescription Drug User Fee Act (PDUFA) and enhancing the FDA’s drug safety efforts.

“Appointing conferees now would send a powerful message that Congress is working as hard as FDA is,” HELP Committee Ranking Member Mike Enzi (R-Wyo.) said in the July 27 letter. The Senate passed its version of the bill, S. 1082, in May, while the House passed its version, H.R. 2900, earlier this month (DID, July 12). Since there are a number of differences, a conference committee made up of members of the House and Senate must reconcile the two bills before the legislation can be voted on again and sent to the president.

Members of the HELP Committee and their staffs are working on the bill, but the conference committee has not yet been assembled, a minority staff spokeswoman told DID.

In the letter, sent to Majority Leader Harry Reid (D-Nev.) and Minority Leader Mitch McConnell (R-Ky.), Enzi warned that if PDUFA is not reauthorized before the Senate recess that begins Aug. 6, the FDA will have to send layoff notices to hundreds of agency employees, who could find jobs elsewhere. PDUFA expires Sept. 30.

“A staff exodus would be a disaster for this agency and for the public health it safeguards so zealously,” Enzi said. He added that the Senate leadership should consider its priorities in the limited time before recess.

Sen. Chuck Grassley (R-Iowa) also recently encouraged the Senate to make progress on the bills in a statement he made on the Senate floor July 26. He added that one bill is not superior to the other, but each addresses some issues better.

Grassley discussed an amendment he had introduced to S. 1082 to give the FDA’s Office of Surveillance and Epidemiology (OSE) equal standing with the Office of New Drugs (DID, May 10). The amendment failed by one vote.

Although neither bill gives postmarketing drug surveillance enough focus, H.R. 2900 contains a provision that would require the FDA to report to Congress on drug safety recommendations from OSE. If the FDA does not take OSE’s recommendation, the agency would be required to justify the action to Congress, Grassley said.

In addition, Grassley said he approved of H.R. 2900’s provisions requiring more clinical trials to be publicly available and allowing the HHS secretary to require manufacturers to conduct postapproval studies.

However, Grassley said it was crucial to keep a provision in S. 1082 that states the scientific reviews of a new drug application cannot be changed once it is final. The provision will stop FDA safety reviewers from being coerced into changing their findings, he added.

More information on H.R. 2900 can be found at thomas.loc.gov/cgi-bin/bdquery/z?d110:h.r.02900:. S. 1082 can be found at thomas.loc.gov/cgi-bin/bdquery/z?d110:SN01082:. — Emily Ethridge


House Ways and Means Committee Passes Bill Limiting ESA Reimbursements

The House Ways and Means Committee late Thursday night passed H.R. 3162, the Children’s Health and Medicare Protection Act of 2007, by a 24-17 vote. The legislation was slightly modified during the committee markup, however, provisions that will likely have a negative effect on pharmaceutical manufacturers remained intact.

Although much of the support for the legislation revolves around reauthorization of the State Children’s Health Insurance Program, H.R. 3162 includes sections to increase rebates manufacturers pay for drugs dispensed under Medicaid and reduces Medicare reimbursement rates for erythropoietin-stimulating agents (ESAs) administered to patients with end-stage renal disease (ESRD) (DID, July 27).

Safety concerns surrounding the use of ESAs in both ESRD and certain cancers have already taken their toll on product sales. U.S. sales for Amgen’s Aranesp (darbepoetin alfa) decreased 18 percent to $578 million during the second quarter of 2007, compared with the same period last year. However, international sales of the product increased 8.5 percent to $371 million, the company said. Earlier this year the FDA added new warnings to physician labeling for the products (DID, March 12).

The bill also requires the HHS Office of Inspector General (OIG) to submit a report to Congress by January 2009 detailing the use of ESAs in dialysis centers and how it conforms to FDA-approved labeling.

Despite the negative aspects of the bill, it will not likely become law, as President Bush will veto the legislation, according to a July 26 letter HHS Secretary Michael Leavitt sent to Ways and Means Committee Chairman Charles Rangel (D-N.Y.). The House Energy and Commerce Committee is also considering H.R. 3162, although no action on the bill was taken by press time.

The legislation, which was introduced July 24, also alters how the Centers for Medicare and Medicaid Services (CMS) calculates the volume-weighted average sales price (ASP) for drugs reimbursed under Medicare Part B. According to a Ways and Means Committee summary of the bill, the intent of the change is to “appropriately weight ASPs based on actual sales volume.”

The proposed law specifically states the CMS should use OIG’s formula for calculating volume-weighted ASPs, identified in a February 2006 report to Congress. According to the report, if the CMS used OIG’s calculation in 2005, the Medicare program and its beneficiaries would have paid an estimated $115 million less in 2005, excluding minimal under-payments due to the CMS’s formula.

Further, the establishment of a Center for Comparative Effectiveness Research under the Agency for Healthcare Research and Quality is included in the bill. The center would evaluate the clinical effectiveness of healthcare treatments, including pharmaceuticals, medical devices and other medical interventions.

The center would have the power to “secure directly” from any government agency information necessary to carry out its duties. — Christopher Hollis


FDA Concerned With Avandia Heart Attack Risk, Agency Says

Two FDA advisory committees meet today to discuss the future of GlaxoSmithKline’s (GSK) Avandia — whether the agency should remove it from the market, restrict it to certain patients or add warnings to its labeling, according to documents on the FDA website.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee are holding the joint meeting to discuss diabetes drug class thiazolidinediones, with a focus on Avandia (rosiglitazone maleate). The agency convened the meeting after a meta-analysis appeared in the New England Journal of Medicine (NEJM) in May showing that Avandia increased the risk of death from cardiovascular causes by 64 percent (DID, May 22).

Although the various datasets present “an array of somewhat inconsistent findings” with regard to Avandia’s effect on cardiac ischemic events, the agency has “considerable concern” that the drug increases heart attack risk, according to briefing documents posted to the FDA website July 26.

Last month, the FDA requested a black box warning for Avandia and diabetes drug Actos (pioglitazone HCl), citing the increased risk of congestive heart failure (DID, June 8).

The agency issued a waiver for conflicts of interest for the meeting to the author of the NEJM meta-analysis, Steven Nissen (DID, July 17). However, Nissen’s meta-analysis will not be a focus of the meeting because results from both GSK and FDA analyses “do not greatly differ” from Nissen’s results, the agency said.

“Current available information points to an increased risk of cardiovascular adverse events such as heart failure and death from heart problems,” FDA Division of Drug Risk Evaluation scientists Kate Gelperin and Lahn Green said in a memo included in the posted documents.

GSK submitted a nearly 200-page document covering Avandia’s background and results from several clinical trials. Its reports showed that Avandia did not increase the cardiovascular risk more than other drugs, the company said. The company has previously published reports that the incidence of heart attack with Avandia is the same as with placebo (DID, June 1).

Although Nissen can answer questions about his study and meta-analysis, he cannot participate in the committee’s discussions, deliberations or voting. Five other members of the advisory committees also received conflict-of-interest waivers, and four of them can vote.

Sens. Chuck Grassley (R-Iowa) and Max Baucus (D-Mont.) have questioned the composition of the FDA advisory committees and criticized the agency for allowing its Office of New Drugs to control the meeting instead of the Office of Surveillance and Epidemiology (DID, July 26).

Sales of Avandia fell 22 percent in the second quarter to $715 million after the NEJM meta-analysis was published, according to GSK.

The FDA briefing documents can be viewed at www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-fda-backgrounder.pdf. — Emily Ethridge


FDA to Allow Limited Use of Zelnorm

The FDA has decided certain patients will be able to take Novartis’ Zelnorm, despite the fact that Novartis withdrew the drug from the market at the agency’s request in March due to an increased risk of cardiovascular events.

Novartis had conducted an analysis of clinical trial data, which found that Zelnorm (tegaserod maleate) raised the risk of heart attack and stroke compared with placebo, prompting the withdrawal (DID, April 2). However, no causal relationship between Zelnorm and cardiovascular ischemic events has been demonstrated, according to Novartis.

At the time of the withdrawal, the FDA said there might be patients for whom the benefits of Zelnorm outweigh the risks and for whom no other treatment options are available. After working with Novartis, the FDA has established an investigational new drug (IND) protocol that would allow certain patients to be treated with Zelnorm.

The IND protocol for Zelnorm stipulates that women under 55 whose physicians decide the drug is medically necessary may be prescribed Zelnorm to treat irritable bowel syndrome combined with constipation or chronic idiopathic constipation, the agency said. Patients will have to sign consent materials to ensure they are informed of the drug’s risks.

CDER Director Steven Galson said only patients who are in “critical” need of the drug and have no pre-existing heart problems will be eligible.

Novartis said it is continuing to discuss the risks and benefits of Zelnorm with the FDA. — Breda Lund


Patient in Gene Therapy Study Dies; Clinical Trial Halted

A patient in a gene therapy clinical trial died after suffering an unspecified serious adverse event (SAE), and the trial has been halted, the sponsor announced.

Targeted Genetics said it decided along with the FDA to shut down the trial of its flagship product after the patient suffered the SAE, but before the death.

The company’s Phase I/II study was designed to assess the safety and efficacy of different doses of tgAAC94, an investigational gene therapy for the treatment of inflammatory arthritis. The investigational product is administered directly into patients’ affected joints using a viral vector that delivers the gene to the cells.

What happened to the deceased patient “has, to our knowledge, never been seen as a consequence of exposure to adeno-associated viral (AAV) vectors or naturally occurring AAV,” Stewart Parker, president and CEO of Targeted Genetics, said. “We continue to work closely and diligently with the FDA and the study’s independent data safety monitoring board to determine the cause of the SAE as quickly as possible.”

The company said that subjects already enrolled in the study will continue to be followed and monitored. Since the trial began in October 2005, 127 adult subjects have received an initial dose of active drug or placebo, 74 out of these patients have received a second dose of active drug and 55 people out of that group have received two doses of the active drug.

This is the second recent high-profile shutdown of a gene therapy trial due to SAEs. In the other case, a Phase I study of a gene therapy product called TGN1412 was halted after six healthy volunteers became critically ill within hours of taking their first dose. In July 2006, the sponsor of that trial, TeGenero, filed for bankruptcy. These events led the European Medicines Agency to issue a new draft guideline earlier this year advising sponsors testing high-risk new drugs for the first time on human subjects to undertake additional preliminary studies in some circumstances (DID, March 28).

Targeted Genetics did not reply to requests for comment by press time. — Martin Gidron

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