DID - July 15, 2009 Issue

Vol. 8 No. 136


Immunosuppressant Makers Required to Update Infection Warning

The FDA told makers of several immunosuppressant drugs to update labeling of their products to adequately warn about the risk of opportunistic infections, considered serious adverse events, in kidney transplant patients.

Wyeth’s Rapamune (sirolimus), Roche’s Cellcept (mycophenolate mofetil), Novartis’ Sandimmune (cyclosporine), Neoral (cyclosporine modified) and Myfortic (mycophenolic acid), and generic formulations pose an increased risk of infections with latent viruses including BK virus-associated nephropathy, the FDA says in a statement Tuesday.

The FDA’s decision is based on a review of reports to the agency’s Adverse Event Reporting System. A separate immunosuppressant drug, Astellas’ Prograf (tacrolimus), already includes information about the increased risk for opportunistic infections in its prescribing information.

The agency also sent a MedWatch to healthcare providers about the drugs’ risk. The information sheet on immunosuppressant drugs for healthcare professionals is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm171654.htm. — David Belian


House Healthcare Legislation Requires Drugmaker Discounts, Rebates

Three House committee chairmen introduced healthcare overhaul legislation that would require drugmakers to pay increased rebates for single source drugs, provide greater discounts to consumers and publicly report financial relationships with physicians.

The 1,018-page bill was produced by the House Committees on Education and Labor, led by Rep. George Miller (D-Calif.), Ways and Means, led by Rep. Charles Rangel (D-N.Y.), and Energy and Commerce, whose chairman is Rep. Henry Waxman (D-Calif.). The legislation contains at least seven sections that directly affect drugmakers.

Sections 1181 and 1182 of the bill introduced Tuesday eliminate the drug coverage gap for Medicare Part D beneficiaries in stages, beginning in 2011. The “doughnut hole” would be closed by progressively increasing the initial coverage limit and decreasing the annual out-of-pocket threshold. A Senate version of healthcare reform legislation, the Affordable Health Choices Act, is being marked up by the Health, Education, Labor and Pensions Committee (DID, July 6).

The bill would reduce the doughnut hole by $500 in 2011; eliminate it completely within 15 years, using drug manufacturer rebates to cover the cost; and have drugmakers provide 50 percent discounts on brand-name drugs during the phase-out period.

Other sections of the House legislation that affect drugmakers include:

  • Section 1232, which expands Medicare coverage for kidney-transplant drugs;
  • Section 1451, which requires physicians and drugmakers to report their financial relationships. The Physician Payments Sunshine Act, S. 301, introduced by Sen. Chuck Grassley (R-Iowa) establishes similar requirements but has stalled in the Senate Finance Committee (DID, June 22). A House version, H.R. 3138, was introduced July 9 by Rep. Baron Hill (D-Ind.);
  • Section 1742, which requires prescription drug rebates. New formulations of existing solid oral dosage drugs would be subject to an additional rebate and single source drugs would be subject after Dec. 31, 2009, to a minimum 22.1 percent rebate;
  • Section 1743, which extends prescription drug discounts to Medicaid managed-care enrollees; and
  • Section 1802, which establishes financing for comparative-effectiveness research.

“This bill is among our highest legislative priorities this year,” Waxman says in a statement posted on the Energy and Commerce committee website Tuesday. “I am confident that we will succeed in enacting this landmark reform into law.”

The committees will begin marking up the bill this week. The America’s Affordable Health Choices Act of 2009, which had not been assigned a number at press time, is available at energycommerce.house.gov/Press_111/20090714/aahca.pdf. — Martin Berman-Gorvine


Protalix Plans NDA Filing for Gaucher’s Drug This Year

Less than a month after the FDA sought a treatment protocol for the Protalix Gaucher’s disease treatment, the company confirmed the clinical, nonclinical and chemistry requirements for its NDA with the agency and plans to file the application by year’s end.

The FDA requested treatment protocols for Protalix’s PrGCD and Shire’s separate experimental Gaucher’s drug to offset expected shortages of Genzyme’s Cerezyme (imiglucerase) based on the company’s temporary plant closure (DID, July 7).

Cerezyme is the only enzyme replacement therapy approved by the FDA for Gaucher’s disease, a rare inherited disorder. PrGCD, Protalix’s lead product candidate, is a proprietary plant-cell expressed recombinant form of glucocerebrosidase, the company says in a statement Tuesday.

Protalix hopes to report results from an ongoing Phase III trial of the product in October and submit the NDA before the end of the year, spokeswoman Marcy Nanus told DID.

Protalix President and CEO David Aviezer says in the statement, “This meeting gives us confidence that we will be able to submit the NDA as planned.”

Shire could not be reached for an update on its Gaucher’s disease treatment by press time. — April Hollis


Senate Committee Backs 12 Years Data Exclusivity for Biologics

Innovator biologics makers scored a win when a Senate committee approved an amendment that would give them 12 years of data protection for biologics as part of a healthcare overhaul package.

The Senate’s Health, Education, Labor and Pensions (HELP) Committee voted 16–7 to pass an amendment offered by Sens. Orrin Hatch (R-Utah), Mike Enzi (R-Wyo.) and Kay Hagan (D-N.C.) this week that gives innovator companies longer periods of exclusivity than what has been backed by President Barack Obama and Rep. Henry Waxman (D-Calif.). 

The vote came before the House Judiciary Committee Subcommittee on Courts and Competition Policy’s hearing Tuesday on biosimilars.

The HELP committee amendment would allow an innovator product only one period of data exclusivity to prevent innovators from making minor changes to a product to obtain another 12-year period of exclusivity.

During the debate, Hatch said it is critical to get a biosimilars bill passed this year and pointed out that the committee passed legislation giving innovators 12 years of exclusivity in 2007 but the bill went no further (DID, June 28, 2007). He added that he personally worked to get innovator companies to agree to this number.

Not everyone backed the Hatch-Enzi-Hagan amendment. Sen. Sherrod Brown (D-Ohio) discussed a separate amendment he had offered that would give innovators seven years of data exclusivity. Providing longer protection would stifle innovation, Brown said, pointing to the FTC’s recent report that concludes 12 years of exclusivity is too long (DID, June 11). For example, a manufacturer of a biologic given by injection wouldn’t be inspired to create an aerosol application for the drug, he added.

Brown maintained that things had changed since 2007, when the committee agreed on 12 years of exclusivity. The political profile of the Senate is different, Brown said, adding that manufacturers raise prices unchecked. He pointed to Obama’s support for a seven-year period of exclusivity (DID, June 26). The committee rejected Brown’s amendment.

“As health reform legislation moves through Congress, I will continue to fight for more competition and cheaper biologic drugs for patients who need them,” Brown says in a statement following the vote. “Drug companies should be able to recoup their research and development costs, but they are not entitled to open-ended monopolies and unlimited windfall profits.”

Stakeholder Reaction

Stakeholders had varying reactions to the committee’s vote. “Our amendment puts patients first by striking the right balance between saving money and preserving incentives to develop new, life-saving drugs,” Enzi says in a statement.

Hatch says in a statement, “It’s unfortunate that we had to spend so much time re-litigating this issue again, especially since this amendment is almost the same language embodied in the 2007 Committee compromise (S. 1695), which was voted out of the HELP Committee by unanimous consent. I am happy in the end, though, that committee members agreed with what I have been pushing for years and that Sens. Enzi and Hagan could join me on such an important piece of legislation.”

Innovator groups such as the Biotechnology Industry Organization (BIO) praised the committee’s vote. The language of the amendment “strikes the appropriate balance among ensuring patient safety, expanding competition, reducing costs and providing necessary and fair incentives that will provide for continued biomedical breakthroughs,” BIO President and CEO Jim Greenwood says in a statement.

The Generic Pharmaceutical Association (GPhA) expressed disappointment but vowed to continue to fight. “It is surprising that in the wake of the recent [FTC] report explicitly stating that 12 years of exclusivity would discourage innovation, the HELP Committee voted in favor of profits over patients. This unprecedented action strikes a huge blow to consumers,” GPhA President and CEO Kathleen Jaeger says in a statement.

In the House, Waxman and Rep. Anna Eshoo (D-Calif.) have offered competing biosimilars legislation. Eshoo’s Pathway for Biosimilars Act, H.R. 1548, which has 131 co-sponsors, includes 12 years of exclusivity  (DID, March 18). Waxman’s bill, H.R. 1427, Promoting Innovation and Access to Life-Saving Medicine Act, provides for seven years of exclusivity and has 13 co-sponsors.

House Hearings

The House Judiciary Committee held a hearing on balancing the incentives for innovation on biosimilars Tuesday, during which Eshoo praised the Senate HELP Committee action. She noted her bill has been endorsed by a number of groups, including BIO, the Association of American Universities and the National Venture Capital Association (NVCA).

Bruce Leicher, Momenta Pharmaceuticals’ senior vice president and general counsel, spoke out in favor of Waxman’s bill during the hearing, adding that data exclusivity and other barriers shouldn’t be used to reward inefficient and noninnovative R&D.

Jack Lasersohn, general partner at the Verticle Group speaking for the NVCA, said adopting a biosimilar approval pathway similar to the one proposed by the FTC would result in a Pyrrhic victory with very cheap older biotech drugs and an empty pipeline for new drugs.

Lasersohn’s testimony came a week after the NVCA, which represents about 460 venture capital companies in the U.S., released a study that concluded prior attempts to identify factors driving investment in new drug development have failed to recognize the high cost of capital for small, innovative biotech companies that comprise the majority of the industry (DID, June 13). NVCA backs Eshoo’s bill. — Elizabeth Jones


FDA Seeks Watson Manufacturing Details in Complete Response

The FDA has asked Watson Pharmaceuticals for more information on manufacturing and clinical testing of its long-acting form of the Trelstar prostate cancer treatment before deciding whether to approve the drug.

The agency’s complete response letter requested more information on the chemistry, manufacturing and controls (CMC) of the product, and third-party manufacturing, Watson says in a statement Tuesday. The agency also asked for clarifications related to the clinical testing. Watson says it is working to provide the requested information quickly.

Watson has responded to many of the questions raised about Trelstar’s (triptorelin pamoate) CMC but cannot provide any additional details on the FDA’s concerns or its response, company spokeswoman Patty Eisenhaur told DID.

Trelstar 22.5-mg is a 24-week formulation for the palliative treatment of advanced prostate cancer. The new formulation is designed to continuously suppress the production of testosterone in men with advanced prostate cancer for 24 weeks, the company says. The treatment already has established efficacy and safety in two formulations — Trelstar Depot, a four-week formulation, and a 12-week long-acting form. — April Hollis


Expert: Draft Guidance May OK Adaptive Design in Confirmatory Trials

The FDA is expected to tell clinical trial sponsors later this year that adaptive clinical trial designs can be used in confirmatory studies, an expert says.

The advice will appear in a draft guidance the agency plans to release in this year’s fourth quarter, Judith Quinlan, vice president for adaptive trials at Cytel, said Tuesday during ExL Pharma’s annual conference on trial design innovation.

“We’d hoped it would be out by now,” Quinlan said. She is a member of PhRMA’s Adaptive Design Working Group, which met with the FDA in November 2006, July 2007 and April 2008.

The working group’s definition of adaptive trial designs encompasses those that use the data that accumulate during a study to decide how to modify certain aspects of the trial without undermining its statistical validity and integrity. PhRMA plans to publish its “good adaptive practices” in September, Quinlan said.

The FDA draft will be “quite extensive,” Quinlan said. The agency’s public consideration of how to handle adaptive trial designs began five years ago with the Critical Path Initiative. Since then, other health regulators have also considered the question, including the European Medicines Agency (EMEA), which has issued a guideline in which sponsors are advised to provide adequate justification for any adaptive design.

Regulators’ views about adaptive trial designs share some common features that are likely to appear in the FDA draft. They generally consider blinded sample size re-estimation and group sequential designs to be acceptable in a confirmatory setting, Quinlan said. The designs require the sponsor to draw statistical inferences correctly and control for operational bias.

Avoiding Pitfalls

A conference presentation by Robert Hemmings of the Scientific Advice Working Party on adaptive trials at the UK’s Medicines and Healthcare products Regulatory Agency sheds further light on what the EMEA and probably the FDA are seeking.

According to Quinlan, regulators tend to actively discourage proposals that:

  • Are poorly planned, unsubstantiated or undocumented;
  • Fail to offer an acceptable rationale for using an adaptive design;
  • Lead to concerns over the dissemination of interim results;
  • Propose an unacceptably slow patient recruitment rate;
  • Include inadequate pre-specification of the intention to adapt the trial design;
  • May yield results where the totality of the evidence is likely to be inadequate; or
  • Do not address critical methodological concerns such as Type I error (false positive results).

Adaptations once a trial is under way are not true adaptive design and are not acceptable.

Sponsors should not tell regulators that completing the trial quickly is a main rationale for adaptive design, Michael Krams, vice president of applied program strategies and adaptive trials for Wyeth Pharmaceuticals, said.

On the other hand, acceptable adaptive trial design proposals include those with a thorough statistical treatment and those in which the benefits of implementing the adaptive design outweigh any risks, Quinlan said. — Martin Berman-Gorvine


Brookstone Recalls Concentrated Acetaminophen Drops

Brookstone Pharmaceuticals has begun a nationwide voluntary recall at the consumer level of all lots of its concentrated acetaminophen drops in 16-oz. bulk containers.

Brookstone’s product contains more concentrated acetaminophen 80 mg/0.8 ml; regular strength acetaminophen elixir contains 160 mg/5 ml. The firm is recalling its product, which is manufactured by Pharmaceutical Associates, to minimize any confusion and potential risk to patients from dosing errors, according to Brookstone’s recall notice posted on the FDA’s website this week.

The product’s 16-oz. container is comparable to the size used to package regular strength, liquid acetaminophen preparations. The product’s container — coupled with the absence of an integrated dosage-delivery device — is a contributing factor to possible dosing errors, especially inadvertent overdosing, the recall notice says.

Brookstone has distributed 344 bottles nationally and has donated 5,301 bottles to charity for international distribution.

Overdoses of acetaminophen may result in liver toxicity, kidney damage and blood disorders. FDA is aware of several medication error reports that document life-threatening or fatal adverse events in children younger than age 3 because of confusion associated with the concentrated strength compared with regular strength acetaminophen liquid, according to the statement. — Elizabeth Jones


EC Directive Simplifies Amendments to Marketing Authorizations

Drugmakers will be able to amend one or more identical terms in their marketing authorizations across EU member states in a single application once a new directive has been implemented.

European Commission (EC) Directive 2009/53/EC, which takes effect next Monday, requires EU member states and the EC to develop a single application by Jan. 20, 2011, for one or more identical changes made to the terms of a number of marketing authorizations.

The new directive amends directive 2001/83/EC, which stipulates that the processes of granting all marketing auth­orizations for medicinal products for human use should be harmonized within the EU. That did not affect variations on the terms of marketing auth­orizations, the new directive says.

Making vari­ations to all types of marketing authorizations subject to harmonized rules would reduce the administrative burden, aid public health and legal consistency, and strengthen predictability for manufacturers, the directive says.

The rules on variations adopted by the EC should focus attention on simplifying adminis­trative procedures, the directive says, including the development of the single application.

Member states may still apply their own national provisions for amending marketing authorizations if the authorization was granted before Jan. 1, 1998, and is only authorized in that country. If another country approves the authorization, the new EC directive becomes applicable and any further variations would have to be harmonized across the EU.

EC Directive 2009/53/EC can be found at ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2009_53/dir_2009_53_en.pdf. — David Belian

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