DID - June 8, 2007 Issue

Vol. 6 No. 113

House PDUFA Reauthorization Draft Stricter Than Senate Bill

A key House member is circulating a new draft version of legislation to reauthorize the Prescription Drug User Fee Act (PDUFA) that calls for stronger restrictions than the Senate’s version of the bill.

While House Subcommittee on Health Chairman Frank Pallone’s (D-N.J.) discussion draft would increase user fees devoted to postmarketing safety similar to S. 1082, the FDA Revitalization Act, they would create stricter limits on issues including direct-to-consumer (DTC) advertising and disclosure of clinical trial results. The subcommittee will hold a markup on the discussion drafts June 14, after a June 12 hearing, Pallone said.

Pallone’s draft would authorize the HHS secretary to put a temporary waiting period of up to three years on DTC advertisements for new drugs on a case-by-case basis. The Senate bill does not allow the FDA to ban DTC advertisements. In addition, Pallone’s drafts add a one-time user fee to be paid at the creation of the FDA’s voluntary advertisement review program, as well as a fee for each requested review. The fees would total more than $6 million each year, according to Pallone.

The draft would also create a clinical trial registry database and a clinical trial result database. All clinical trials related to the safety and efficacy of drugs and devices would have to report their results to the database and the information would be made publicly available on the internet, Pallone said. The Senate bill would only require some late-stage clinical trials to disclose their results.

In addition, the draft would require the FDA to review data on a product’s use after it has been on the market for seven years, a provision the Senate bill lacks. It also orders the HHS secretary to establish an active postmarketing drug surveillance center.

While S. 1082 would allow the HHS secretary to provide waivers to qualified advisory board committee members so they could participate on the agency panels, Pallone’s draft would limit this authority to one waiver per committee meeting. In addition, the waivers would have to be made public at least 15 days before the advisory committee meeting.

Pallone’s draft also makes the HHS secretary’s authority to require pediatric studies under the Pediatric Research Equity Act (PREA) permanent. S. 1082 reauthorizes PREA but does not make it permanent.

The new draft is a “shot across the bow” similar to the original version of S. 1082, Coalition for Healthcare Communication Executive Director John Kamp told DID. “I would expect serious compromises between the Pallone bill and the bill that will come out of committee,” he added.

The majority of significant actions on the bill will happen during the House Energy and Commerce Committee markup, Kamp said. Committee Chairman John Dingell (D-Mich.) has been calling for a “clean bill” focused on PDUFA reauthorization, he added. “I never underestimate the power of John Dingell to control the details of legislation in his committee,” Kamp said.

The draft discussions can be viewed at energycommerce.house.gov/Public%20Health%20bloc/index.shtml. — Emily Ethridge


GSK Avandia Woes Mount With Intimidation Accusations and Black Box Warning

Allegations of a “high-ranking” GlaxoSmithKline (GSK) employee threatening a scientist for questioning the safety of the company’s Type 2 diabetes drug Avandia has drawn the attention of two long-time agency critics in Congress.

Sens. Chuck Grassley (R-Iowa) and Max Baucus (D-Mont.) 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. Adding further to the company’s Avandia troubles, FDA Commissioner Andrew von Eschenbach has said the FDA wants a black label warning on the product citing its increased risk of heart failure. 

The June 6 hearing focused on how the FDA handles postmarketing drug safety after a study published in the New England Journal of Medicine (NEJM) found that Avandia (rosiglitazone/maleate) increased the risk of heart attack by 43 percent and death from cardiovascular causes by 64 percent (DID, June 6).

At the hearing, Buse said an employee at SmithKline Beecham, now part of GSK, told Buse’s department chair that Buse could be held liable for a $4 billion drop in the company’s stock after he gave a presentation on Avandia’s possible cardiovascular risks. The conversation was “disturbing,” and Buse’s chair told him the employee characterized Buse as “a liar” and “for sale,” Buse said.
After he learned of the conversation, Buse signed a statement the company prepared clarifying his presentation to help the company’s “equity interest,” he said. In a letter to SmithKline Beecham Pharmaceutical Research and Development Chairman Tadataka Yamada, Buse wrote, “Please call off the dogs. I cannot remain civilized much longer under this kind of heat.”

In their letter to GSK President Christopher Viehbacher, Baucus and Grassley requested “a direct response” to their concerns about GSK employees silencing medical professionals who attempted to publicize the potential cardiovascular risk associated with Avandia. Buse’s testimony was reminiscent of a similar incident where Merck attempted to silence a scientist who raised concerns about Vioxx (rofecoxib), the lawmakers wrote. Baucus and Grassley requested a response by June 11.

“If credible research exposes the risk of death for patients taking a drug, then any drug company attempt to squelch that information would be morally reprehensible,” Baucus said in a statement.

In addition, the lawmakers requested copies of all documents, contacts and communications regarding Avandia between GSK and the University of North Carolina by June 29 in their letter to University Chancellor James Moeser.

At the same hearing, von Eschenbach announced that the agency had requested a black box warning for Avandia and diabetes drug Actos (pioglitazone/HCl) because of the increased risk of congestive heart failure.

An interim analysis of an ongoing GSK study published in the June 5 online edition of the NEJM showed Avandia was associated with an increased rate of heart failure. However, the drug did not show a link to an increase in death from heart attack and stroke. The black box warning does not reflect an increased risk for heart attacks.

GSK has not yet agreed to the wording of the black box warning. Takeda, which manufactures Actos, said it is working with the FDA on the labeling revision. The company is confident in Actos’ safety and efficacy when used according to the label, Senior Medical Director of Takeda’s Diabetes and Metabolism Division Robert Spanheimer said.

In addition, Sen. Sherrod Brown (D-Ohio) and Reps. John Dingell (D-Mich.) and Bart Stupak (D-Mich.) joined Baucus and Grassley in sending another letter to von Eschenbach about the agency’s policy on hiring staff directly from pharmaceutical companies. The letter followed a May 24 email an agency consultant sent journalists from his FDA email address criticizing the Avandia study in the NEJM. The email blurs the line between “the actions of the FDA and those that might come from a drugmaker it’s regulating,” Grassley said. The employee’s drug company connections may have led him to criticize the study’s author and “settle old scores,” the letter says.

The lawmakers requested information on the FDA’s hiring and email policies and on any income the employee may receive from companies who make FDA-regulated products.

The FDA has not decided whether to take any further regulatory action on Avandia, von Eschenbach added. Two FDA advisory committees will meet July 30 to discuss the drug. — Emily Ethridge


FDA Proposes Banning Ozone-Depleting Inhalers

The FDA, , in a decision reached in consultation with the Environmental Protection Agency (EPA), is proposing to ban the use of oral pressurized metered-dose inhalers (MDIs) in self-pressurized containers that contain ozone-depleting substances.

The proposed amendment to current FDA regulations would remove the “essential use” designations from MDIs containing flunisolide, triamcinolone, metaproterenol, pirbuterol, cromolyn, nedocromil, and albuterol and ipratropium in combination.

Products that would be banned under the proposed change include Forest Laboratories’ Aerobid and Abbott Laboratories’ Azmacort, used to treat asthma in patients as young as 6. These are the only currently marketed products containing flunisolide and triamcinolone, respectively. However, alternatives are available, the proposal notes.

Under the Clean Air Act, the FDA, in consultation with the EPA, is required to determine whether an FDA-regulated product that releases ozone-depleting substances is an “essential use” item. Since therapeutic alternatives without these substances are available on the market and “appear to provide all of the important public health benefits of the listed drugs,” the FDA is proposing to ban the ozone-depleting products after a 60-day public comment period, an open public meeting and a transition period. The FDA said it will hold the public meeting soon, but did not provide a date.

The notice of the proposed regulatory change can be found at www.fda.gov/OHRMS/DOCKETS/98fr/06n-0454-npr0001.pdf. — Martin Gidron


GPhA Urges Senators to Act Quickly on Follow-On Biologics Bill

A generic drug industry coalition seeks quick action on a pending Senate bill that would create an approval pathway for follow-on biologics to ensure its passage before the end of the year.

A recent letter signed by the Generic Pharmaceutical Association (GPhA) and several generic drug companies asks Sens. Edward Kennedy (D-Mass.) and Mike Enzi (R-Wyo.), chairman and ranking member of the Committee on Health, Education, Labor and Pensions (HELP), to push through a bill that will strike a balance between encouraging innovation and promoting generic drug access.

The proposed legislation, the “Access to Life-Saving Medicine Act,” S. 623, and its companion bill, H.R. 1038, would create an abbreviated approval pathway for products proven to be biosimilar to existing biologic drugs.

Kennedy has said he planned to attach it as an amendment to S. 1082, the Prescription Drug User Fee Act reauthorization bill recently passed in the Senate (DID, May 4). The HELP Committee would first need to hold a markup on S. 623, which Kennedy’s office said could happen June 20.

The letter asks the lawmakers to ensure that the final version of the bill lets the FDA “use its expertise to determine on a case-by-case basis what scientific data [it needs] to approve comparable and interchangeable products.”

FDA Commissioner Andrew von Eschenbach has said the FDA is already capable of approving some simple follow-on biologics (DID, May 1). The agency also released a white paper saying it has developed a “scientifically based, case-by-case approach” to approve follow-on biologics without extensive clinical trials, although some trials would be necessary for the follow-ons to be deemed interchangeable with the original products (DID, April 25).

The coalition also requests that the bill “provide a clear framework for interchangeability that … does not require additional congressional action,” along with a timeline for when follow-on products could enter the market.

In addition, the letter asks that the bill contain a provision to prohibit “frivolous” patent litigation, while providing a clear method for resolving legitimate lawsuits.

Other bills have been introduced in Congress to create an approval pathway for follow-on biologics, including H.R. 1956, the “Patient Protection and Innovative Biologic Medicines Act of 2007.”

Sens. Richard Burr (R-N.C.), Judd Gregg (R-N.H.) and Tom Coburn (R-Okla.) recently announced the introduction of the “Affordable Biologics for Consumers Act of 2007.” In addition to establishing a follow-on biologics approval pathway, the bill would allow 14 years of data exclusivity for innovative biologic products and create a streamlined patent dispute-handling process. — Breda Lund


High Court Denies Pfizer Appeal to Halt Generic Norvasc

A Supreme Court judge’s decision to deny Pfizer’s request to halt Apotex’s sale of generic Norvasc will “result in irreparable harm to Pfizer,” the company said.

Justice John Paul Stevens denied Pfizer’s motion June 6, which the company had filed in response to a March 22 ruling by the U.S. Court of Appeals for the Federal Circuit that invalidated Pfizer’s ’303 patent covering amlodipine besylate, the active ingredient in Norvasc.

Apotex filed the appeal after a lower court had found the patent to be valid and enforceable. The company launched its generic product May 24 (DID, May 25).

Norvasc, which is off-patent, is still technically protected by a pediatric-exclusivity period, according to Pfizer. But according to a company statement, since Pfizer can’t seek damages for the violation of pediatric exclusivity, “a remedy down the road is likely to be a hollow victory at best.”

Stevens also denied Pfizer’s petition for a writ of certiorari to reconsider the ruling that invalidated the ’303 patent, which was “based on a flawed theory of obviousness that … will have profoundly negative consequences for pharmaceutical patent protection,” the company said.

Earlier this week the same federal appeals court granted Mylan Laboratories’ motion for reversal of a Feb. 22 ruling by the U.S. District Court for the Western District of Pennsylvania that had upheld Pfizer’s patent (DID, June 7). Mylan launched its product March 23. — Breda Lund


Nonvoting Industry Reps Sought for Advisory Committees

The FDA is requesting nominations for nonvoting industry representatives to serve on CDER’s public advisory committees. Industry organizations interested in participating in the selection of these nonvoting representatives are also requested to inform the FDA.

The nominations are for nonvoting vacancies on 16 CDER advisory committees dealing with pharmaceutical science and clinical pharmacology, reproductive health drugs, anesthetic and life-support drugs, anti-infective drugs, antiviral drugs, arthritis, cardiovascular and renal drugs, dermatologic and ophthalmic drugs, drug safety and risk management, endocrinologic and metabolic drugs, gastrointestinal drugs, nonprescription drugs, oncologic drugs, peripheral and central nervous system drugs, psychopharmacologic drugs and pulmonary-allergy drugs.

The FDA is requesting that the nominations, which can be self-generated but must contain a current curriculum vitae, be submitted within 30 days. Within another 30 days after that deadline, the FDA will send a letter to each organization that has expressed an interest, attaching a complete list of all such organizations and a list of all nominees, along with their current resumes.

The organizations will then be requested to vote for one industry representative, or write in a new candidate, within 60 days.

For more information, email jayne.peterson@fda.hhs.gov. — Martin Gidron

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