DID - June 7, 2007 Issue

Vol. 6 No. 112

House Committee Questions FDA’s Response to Postmarketing Safety Studies

Witnesses at a House committee hearing questioned the FDA’s role in monitoring postmarketing drug safety and whether the agency needs more authority to require clinical trials to investigate particular risks.

The House Committee on Oversight and Government Reform held the hearing June 6 after a study published in the New England Journal of Medicine (NEJM) found that GlaxoSmithKline’s (GSK) Type 2 diabetes drug Avandia increased the risk of heart attack by 43 percent and death from cardiovascular causes by 64 percent (DID, May 22).

The study was a meta-analyses of published results from 42 clinical trials comparing the risk of heart attack and cardiovascular-related deaths in patients taking Avandia versus patients taking other diabetes drugs or placebo.

Committee Chairman Henry Waxman (D-Calif.) said the FDA “ dropped the ball” on requesting a long-term study focused on cardiovascular risks after Avandia’s primary reviewer recommended one. There were a “number of missed opportunities,” he said.

However, FDA Office of New Drugs Director John Jenkins defended the study GSK conducted after approval, saying it was what the FDA’s primary review called for. The study did not appear to suggest a difference in cardiovascular risk between Avandia and other common diabetes drugs, but the FDA is still reviewing the data, Jenkins added.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee will meet July 30 to discuss Avandia, FDA Commissioner Andrew von Eschenbach said.

The agency either did not request the right type of study to track cardiovascular risks or GSK did not want to conduct that kind of study, University of Washington Cardiovascular Health Research Unit Co-Director Bruce Psaty said. The agency needs the authority to demand postmarketing study design and study completion, and Congress can include it in Prescription Drug User Fee Act (PDUFA) legislation, he added. Waxman agreed, saying the drug serves as a good “case study for the need of reform of the FDA’s safety review.”

When asked if he supported legislation allowing the FDA to require postmarketing safety studies, von Eschenbach replied that he would support a regulation that provided “resources to get those tools to focus on postmarketing safety.” The Senate’s version of the PDUFA reauthorization would give the agency that authority. The House is expected to hold hearings on its version of PDUFA in mid-June (DID, May 29).

The FDA should have conducted a study focused on cardiovascular risks in 1999, following the FDA’s approval of Avandia, NEJM article author Steve Nissen said. GSK needs to do one now, even though it could take seven years to complete and review, he added.

GSK’s current ongoing long-term study, the RECORD trial, will not give a definitive answer on Avandia’s cardiovascular risks even when it is completed in 2009, University of North Carolina at Chapel Hill’s John Buse said. The NEJM published an interim analysis of the RECORD study in its June 5 online edition. The study said the data was “inconclusive,” but GSK Chairman for Research and Development Moncef Slaoui defended the results.

“If I were a diabetes patient, I would be thrilled with the results of the RECORD study,” Slaoui said. None of GSK’s long-term clinical trials show an increased cardiovascular risk, he added. However, smaller meta-analyses the company conducted in between larger trials often showed a possibility of increased risk. This shows meta-analyses, such as the one Nissen conducted, can be incorrect, Slaoui said.  Meta-analyses are only as good as the studies included in them, and the studies Nissen used were not designed to look for cardiovascular events, he added.

Rep. Darrell Issa (R-Calif.) said Nissen’s study “looks like it was an anecdotal concoction” designed to attack GSK. Issa, along with other lawmakers, said Nissen was politicizing science by going to Congress with the data from his study before presenting it to the FDA.

It could seem as though “disgruntled” FDA staff, members of Congress and Nissen collaborated to create a drug scare to humiliate the agency, Rep. Virginia Foxx (D-N.C.) said.

Nissen admitted he showed members of Waxman’s staff a preliminary analysis of his data before it was published, but said he did not have to share the results with the FDA because the agency already had access to all the data he used and more.

Psaty agreed with Nissen, saying the FDA had all the information, but did not act on it until Nissen’s article was published. “I don’t know why it takes so long for the FDA to release information,” Psaty said, adding that releasing information in August 2006, when GSK gave the agency results from its trial, would have been appropriate. — Emily Ethridge


BIO Calls for Changes to Patent Reform Bill

The biotechnology industry yesterday made its case to Congress for changes to comprehensive patent reform legislation, saying the bill as currently drafted favors patent challengers and could make it harder to attract investors.

The remarks came at a hearing held by the Senate Judiciary Committee on S. 1145, the Patent Reform Act of 2007. Alkermes Senior Vice President Kathryn Biberstein, who testified on behalf of the Biotechnology Industry Organization (BIO), told the committee that BIO opposes many of the bill’s provisions, including a proposed new post-grant opposition system that would “create an essentially limitless opportunity to broadly challenge a patent.”

Jon Dudas, director of the U.S. Patent and Trademark Office (PTO), said that while his office may not even have the resources to carry out the process, the proposed procedure, if revised, would be a cheaper and more effective alternative to patent litigation.

The system would allow a petitioner to request a review of a patent within a year of its issuance upon receiving a notice of infringement or if the petitioner can prove the patent causes significant economic harm, Dudas said.

The “second window,” or second chance to challenge a patent after the first year, as outlined in the bill “will diminish patent value and therefore discourage investment,” Biberstein countered, adding that biotech investors rely on the strength of patents when choosing to invest in investigational products.

Another point of contention for BIO is the provision that would limit damage awards in patent infringement suits. According to the bill, a court would have to consider the value of any prior art and deduct that value, so that the damages represent “the patent’s specific contribution over prior art.”

Biberstein asked the committee to consider the example of an inhaled insulin product that Alkermes is developing, which is fundamentally based on “two things that already existed as ‘prior art,’ insulin and small, hand-held inhalers.”

“Assuming that courts and juries could even apply a prior art subtraction standard in a reasonable accurate manner, … the resulting residual royalties would be lower than the reasonable royalties calculated under current law,” she said.

In addition, BIO’s testimony called for the addition of provisions to repeal the inequitable conduct defense and the best mode requirement. The proposed changes had been included in last year’s version of the bill.

The inequitable conduct defense, where a party can argue a patent is unenforceable due to misrepresentations in the patent application, is “a key driver in the cost and length of patent litigation,” BIO said.

The PTO also supported an amendment to repeal inequitable conduct, saying that would improve the quality of patent submissions. Applicants often “fear that the legal doctrines of inequitable conduct and unenforceability may unfairly punish them with draconian penalties for innocently omitting information,” which prompts them to send along thousands of pages of supporting material for the PTO to review.

As for the best mode requirement of current patent law, under which patent applications must contain a detailed description of the best way to produce the product, BIO said it is “used in modern patent litigation to attack the subjective state of mind of the inventor at the time the patent application was filed.”

The generic drug industry, on the other hand, has praised the absence of provisions to eliminate the inequitable conduct defense or the best mode requirement. The Generic Pharmaceutical Association says the inequitable conduct defense is an important way to bring generic drugs to market, and the best mode requirement is “crucial to promoting efficient use of scientific resources” (DID, June 6).

The bill is available at thomas.loc.gov/cgi-bin/bdquery/z?d110:s.01145:. The companion legislation under consideration in the House is H.R. 1908. — Breda Lund


Court Reverses Generic Norvasc Ruling

A federal court has reversed a district court ruling that had found in favor of Pfizer in generic Norvasc patent litigation.

The U.S. Court of Appeals for the Federal Circuit granted Mylan Laboratories’ motion for reversal of a Feb. 22 ruling by the U.S. District Court for the Western District of Pennsylvania that upheld Pfizer’s claims that the ’303 patent covering Norvasc (amlodipine/besylate) is valid and enforceable (DID, March 12). The court said Mylan’s generic version of the drug would infringe on Pfizer’s patent.

Mylan immediately appealed the ruling and decided to launch its product following a March 22 U.S. Court of Appeals for the Federal Circuit ruling — in a separate patent challenge brought by Apotex — that the ’303 patent is invalid and unenforceable (DID, March 26). The company launched amlodipine besylate in 2.5- and 10-mg tablets March 23.

In April the FDA decided to deny approval to all other applications for generic Norvasc that had been submitted, but reversed its decision last month by approving Apotex’s 2.5-, 5- and 10-mg amlodipine besylate tablets after a court ruled in the company’s favor (DID, May 25).

The hypertension drug had U.S. sales of approximately $2.7 billion in 2006, according to IMS Health. — Breda Lund


FDA Issues Draft Guidance on Malaria Clinical Trials

There is a need for new products to treat drug-resistant forms of malaria, but any new treatments should be tested in randomized, double-blinded clinical trials on ethnically diverse male and female subjects of all ages in different geographical regions, according to a draft guidance from CDER.

Anti-malarial therapy can take the form of a single anti-malarial drug, a combination of drugs or more than one drug used sequentially, the draft guidance notes. As in other therapeutic areas, two or more adequate, well-controlled studies generally are appropriate for approval of a malaria drug.

Sponsors should compile a safety database of at least 1,000 subjects of both sexes and all ages and racial groups in Phase I, II and III studies, the draft guidance says. Drug interaction studies should be included where appropriate.

If the study cannot be fully blinded for technical reasons, attempts should be made to blind as many of the study personnel as possible, such as microbiologists interpreting malarial smears.

Sponsors should include appropriate formulations for children, who are at heightened risk of contracting the disease. Pediatric dose recommendations should be established early in the drug development program so that children can be included in Phase III studies, the draft guidance says.

In reviewing new drugs to treat drug-resistant malaria, CDER will consider a combination of various types of data, including:

  • Evidence of superior efficacy when the investigational malaria drug is compared with another approved drug to which the microbes have become resistant;
  • Epidemiological evidence of clinical drug resistance to another approved malaria drug in the area where the study is to be performed. High clinical failure rates provide the strongest evidence for drug resistance in a given region;
  • Evidence of clinical response in patients who have failed alternative treatments because of drug resistance;
  • In vitro evidence of activity against isolates with genetic markers of resistance to other malaria drugs; and
  • In vitro evidence of activity against isolates resistant to other approved malaria drugs in drug sensitivity assays.

The draft guidance can be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/07d-0212-gdl0001.pdf. CDER is accepting public comments until Sept. 5.  — Martin Gidron


Amgen to Pay $300 Million for Alantos Pharmaceuticals

Amgen announced it will pay $300 million in cash for Alantos Pharmaceuticals, a privately held biotech company that develops drugs for diabetes and inflammatory diseases. The deal, which is expected to close in the third quarter, will make Cambridge, Mass.-based Alantos a wholly-owned subsidiary of Amgen.

Amgen said the acquisition will provide it with a clinical-stage dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes, as well as a matrix metalloproteinases platform for osteoarthritis.

Alantos’ investigational drug ALS 2-0426 is a dipeptidyl peptidase IV inhibitor that started undergoing a Phase IIa clinical trial last month. The drug is designed to treat Type 2 diabetes. The clinical trial is being done in collaboration with Servier, which will be responsible for commercializing the drug outside the U.S.

Amgen was dealt a setback last month when the Centers for Medicare & Medicaid Services proposed new limitations on its coverage of erythropoiesis-stimulating agents for cancer patients, which could negatively affect sales of the company’s product, Aranesp (darbepoetin/alfa) (DID, May 16). — Martin Gidron

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