DID - July 31, 2007 Issue

Vol. 6 No. 149

FDA Advisory Committees Recommend Keeping Avandia on Market

Two FDA advisory committees voted late yesterday to recommend keeping GlaxoSmithKline’s (GSK) Type 2 diabetes drug Avandia on the market, although the committee also agreed that the drug appears to increase the risk of adverse cardiovascular events.

The committees voted 22-1, with no abstentions, to keep Avandia (rosiglitazone maleate) on the market. The members did not make any recommendations about what else the FDA should do, although most suggested adding warnings to the product’s labeling. 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 committees also voted 20-3 to agree that the drug increased the risk of cardiac ischemic events. However, members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee disagreed about the quality of all the Avandia studies, including meta-analyses, observational studies and large, randomized controlled studies. 

Some of the members called for more long-term studies and studies that focused on specific patient groups, such as those taking insulin and older diabetic patients.

The advisory committees held the joint meeting to discuss diabetes drug class thiazolidinediones, with a focus on Avandia. 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).

An FDA official said Avandia should be taken off the market because it lacked documented health benefits and increases cardiovascular risks. It is a “well-accepted fact” that Avandia increases the risk of heart failure, the FDA’s Office of Surveillance and Epidemiology (OSE) Associate Director for Science and Medicine, David Graham, said.

Several studies, including a meta-analysis the FDA conducted, show that Avandia increases cardiovascular risk and has no major clinical health benefits, according to Graham.

However, Takeda’s Actos, the other drug in Avandia’s class, appears to lower the risk of cardiovascular events compared with both placebo and other diabetes drugs, Graham added.

“There are no definitively documented health benefits of rosiglitazone to justify its continued marketing,” Graham said. He added that although his comments did not represent the views of the entire OSE, OSE Director Gerald Dal Pan agreed with his assessment.

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

GSK defended its drug and criticized the data from several of the studies. “The number of myocardial infarctions is small … and there is no overall evidence rosiglitazone is different from any other oral anti-diabetes agent,” GSK’s Senior Vice President and Chief Medical Officer, Ronald Krall, said.

GSK’s Vice President for Clinical Development Murray Stewart agreed, adding that Avandia’s risk for myocardial infarction was similar to other diabetes drug and the same as with Actos.

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


CMS Issues Final Coverage Determination for ESAs in Cancer Settings

The Centers for Medicare & Medicaid Services’ (CMS) final coverage determination for the use of erythropoiesis-stimulating agents (ESAs), issued yesterday, does not deny reimbursement for the products when used by patients in conjunction with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) anti-cancer agents.

The agency originally said the use of ESAs is not reasonable for patients being treated with antibodies that target the EGFR, such as Amgen’s Vectibix (panitumumab) and ImClone’s Erbitux (cetuximab). Erbitux and Vectibix are both used in conjunction with chemotherapy (DID, May 16).

In addition, the CMS said it has made no determination regarding the use of the products for myelodysplastic syndrome, a precursor to acute myeloid leukemia. “In cases where no determination is made, Medicare local contractors have the discretion to make reasonable and necessary determinations regarding ESA use,” the CMS said.

However, the “final [national coverage determination] provides coverage with restrictions for the treatment of anemia secondary to myelosuppressive anti-cancer chemotherapy in certain cancer conditions, such as solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia,” the agency said.

These restrictions include limiting initiation of ESA therapy to when a patient’s hemoglobin levels are less than 10g/dL, limiting the ESA treatment duration to a maximum of eight weeks after a chemotherapy session ends, limiting the starting dose to the FDA-recommended starting dose and limiting dose escalation levels, the agency said.

The coverage determination became effective yesterday, the agency said. — Christopher Hollis


Governors Association Supports Follow-On Biologics Pathway

Comprehensive Medicaid reform should include establishing patient access to affordable biosimilar pharmaceuticals, according to a newly adopted National Governors Association (NGA) policy position.

At its annual meeting this month, the association updated its position on Medicaid reform, which includes a call for Congress to forge a pathway for follow-on biologic approval.

The Deficit Reduction Act of 2005 (DRA) was a step in the right direction, according to the association. Under the DRA, the Centers for Medicare & Medicaid Services (CMS) recently published a new final rule defining a federal upper limit for Medicaid reimbursements for multiple-source drugs as 250 percent of the average manufacturer price (AMP) (DID, July 9). However, the governors remain concerned that Medicaid is still not receiving the most competitive prices, and more reforms are needed, the NGA says.

Since the CMS published its rule, House lawmakers have introduced a bill, the Saving Our Community Pharmacy Act of 2007, that would replace AMP with retail acquisition cost and encourage generic drug use (DID, July 25).

The NGA’s policy position also encourages Congress to establish a way for the FDA to approve follow-on biologics. “By taking such action, lower-cost biopharmaceutical products could be available to Medicaid recipients, as well as other healthcare consumers,” according to the association.

The support for a follow-on biologics approval pathway is echoed in letters sent by governors and other state lawmakers to Congress in recent months.

A bipartisan group of governors sent a letter to Senate and House leaders in April calling for the passage of follow-on biologics legislation. “While some believe the FDA could approve generic versions of biopharmaceuticals under existing law, the FDA apparently does not believe it has the authority,” they wrote.

“The FDA is even delaying the release of guidances for insulin and human growth hormone, where it clearly has authority,” they continued. “Based on that example, we believe there is little hope that Americans will have the benefit of generic versions of other biopharmaceuticals until Congress passes legislation authorizing the FDA to create an efficient and effective abbreviated pathway for approval of generic versions of biopharmaceuticals.”

Last summer four of the governors who signed the April letter — Minnesota Gov. Tim Pawlenty, Wisconsin Gov. Jim Doyle, Vermont Gov. Jim Douglas and Kansas Gov. Kathleen Sebelius — filed a citizen petition with the FDA asking the agency to release long-awaited guidances on approval requirements for generic insulin and human growth hormone (HGH) products (DID, Aug. 4, 2006). Proponents say the FDA has created the guidances but has not yet released them publicly.

Recently, numerous members of the Pennsylvania House of Representatives wrote to U.S. lawmakers to voice their support for follow-on biologics legislation, and to urge Congress to mandate that the FDA release the insulin and growth hormone guidances.

“The FDA has acknowledged that generic biologics are inevitable. In fact, the FDA has repeatedly and publicly indicated that finalized guidance on the approval process for generic forms of biologics would be forthcoming and began the process of issuing guidances on insulin and HGH in 2001,” Reps. Frank Oliver (D) and George Kenney (R) wrote in a June 26 letter to U.S. House members.

“Meanwhile, state Medicaid costs for drugs continue to rise,” they continued. “For this reason, we are urging you to take action and support legislation creating a regulatory pathway to ensure these drugs are brought to market quickly, safely and effectively in the United States.”

The Pennsylvania House of Representatives Southwest Caucus sent a similar letter June 21 to U.S. Sens. Arlen Specter (R-Pa.) and Bob Casey (D-Pa.).

The Senate Health, Education, Labor and Pensions Committee June 27 passed S. 1695, the Biologics Price Competition and Innovation Act, which would allow the FDA to approve products that are biosimilar to existing biologics (DID, June 28). The agency could also determine that a product is interchangeable with the innovator biologic.

Committee Chairman Edward Kennedy (D-Mass.) has said the bill would be attached to the Prescription Drug User Fee Act (PDUFA) reauthorization legislation, which has passed in both the Senate and the House. The Senate version of the PDUFA bill, S. 1082, contains a placeholder to insert follow-on biologics legislation, while the House bill, H.R. 2900, does not.

Earlier this month a group of House lawmakers sent a letter to the chairmen and ranking members of the Senate HELP Committee and the House Energy and Commerce Committee asking them not to add follow-on biologics legislation to the bill, saying it could delay PDUFA reauthorization and force the FDA to issue notices of employee reductions (DID, July 24). — Breda Lund


Proposed Bill Would Allow State Negotiations for Prescription Drugs

Rep. Chris Van Hollen (D-Md.) plans to introduce legislation this week that would give states the authority to negotiate for prescription drugs for poor citizens with limited or no insurance coverage, according to the lawmaker’s office.

Specifically, the bill would allow states to set up programs and utilize their negotiating authority with drug companies to garner the same kinds of savings they do for participants in the Medicaid program. The only criteria would be state citizenship for participants with income levels up to 300 percent of the poverty line, Marilyn Campbell, Van Hollen’s press secretary, said.

Under the proposed bill, participants would receive discount cards to use at pharmacies. In addition, states could encourage industry participation by conditioning company participation in the state’s Medicaid program on that same company’s participation in the state discount prescription drug plan, Campbell said.

According to Campbell, most people with existing coverage will get a better deal on their prescription drugs and would likely not choose to participate in the program the bill would create. “But lack of insurance coverage is not an eligibility requirement under our bill for the reason that some citizens in some circumstances could benefit — think Medicare Part D beneficiaries who fall into the doughnut hole, for example,” she added.

The Pharmaceutical Research and Manufacturers of America (PhRMA) expressed opposition to the bill, saying it failed to address the root problem. PhRMA Senior Vice President Ken Johnson said prescription drug cost savings could be better addressed through greater coverage from competing private insurance plans.

“Proposals calling for government imposed price controls on medicines — like the one Rep. Chris Van Hollen may soon introduce — could potentially restrict patient access to medicines and do not address the underlying issue of insurance coverage, and the lack of it, for millions of patients in America,” Johnson said. 

No specific date has been set for the bill’s introduction. — Steve Brown


Impax Loses Generic Rilutek Case

A district court has ruled against Impax Laboratories in patent litigation involving Aventis Pharmaceutical’s patent for Rilutek, Impax announced last week.

The U.S. District Court for the District of Delaware ruled July 19 that Aventis’ ’814 patent related to the use of Rilutek (riluzole) for treating amyotrophic lateral sclerosis is valid, Impax said.

This decision comes after the U.S. Court of Appeals for the Federal Circuit remanded the case in November 2006, vacating the district court’s ruling of validity, Impax said.

The company had filed an abbreviated new drug application (ANDA) with the FDA in March 2001 seeking approval to market generic Rilutek 50-mg tablets. At the time there was no riluzole patent listed in the FDA’s Orange Book, according to appeals court documents.

Impax filed suit in 2002 seeking a declaration that it had not infringed on the ’814 patent. The company argued that the claims of the ’814 patent were invalid due to prior art and alleged inequitable conduct. In December 2002, the Delaware district court granted Aventis’ motion for a preliminary injunction against Impax, preventing it from marketing its product. In August 2004, the court ruled that Aventis’ patent is valid and enforceable (DID, Sept. 7, 2004). Impax appealed the ruling.

In its decision, the appeals court affirmed the district court’s determination that there was no inequitable conduct but ruled that the district court had erred in finding the ’814 patent valid. It vacated that ruling and sent the case back to the lower court.

The FDA had approved Impax’s ANDA in January 2003, but the company said it has never marketed the product due to the injunction.

Aventis accepted an offer to merge with Sanofi-Synthelabo in 2004, forming sanofi-aventis (DID, April 24, 2004). The company’s Rilutek patent isn’t set to expire until June 2013, according to the FDA’s Orange Book.

Rilutek had U.S. sales of $39 million during the 12-month period that ended in May, Impax said, citing Wolters Kluwer Health. — Breda Lund

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