DID - July 16, 2009 Issue

Vol. 8 No. 137


Senate Panel Approves Healthcare Bill With 12-Year Biosimilar Exclusivity

A healthcare overhaul bill that would give innovator biologics 12 years of data protection and create two comparative-effectiveness research centers was passed by the Senate Health, Education, Labor and Pensions (HELP) Committee.
The Affordable Health Choices Act, which passed by a 13–10 vote Wednesday, is the first congressional healthcare overhaul bill to advance out of committee.

The bill 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 (DID, July 15).

It also would establish two centers to compare the effectiveness of healthcare services and procedures. The Center for Health Outcomes Research and Evaluation, which would be run by the FDA, would “coordinate, conduct, support, and synthesize research relevant to the comparative health outcomes and effectiveness of the full spectrum of health care treatments,” including drugs and biologics, according to the bill (DID, June 12).

An Office of Women’s Health in the FDA commissioner’s office would consult with drugmakers on women’s issues, estimate the funds needed to monitor clinical trials, and track women’s participation in clinical trials that analyze information on treatments with drugs and biologics.

Despite its passage, the bill did not receive the support of the committee’s Republican members, with Sen. Mike Enzi (R-Wyo.), the committee’s ranking member, saying it will drive up healthcare costs, increase the national deficit by more than $1 trillion and force millions of Americans to lose the healthcare they have.

“The HELP Committee bill is a complete failure that would make our health care system even sicker than it is today,” Enzi says in a statement Wednesday.

In the House, the Education and Labor committee began marking up its own healthcare legislation, the America’s Affordable Health Choices Act of 2009.

The House bill — also under consideration by the Energy and Commerce and Ways and Means committees — would require drugmakers to pay increased rebates for single-source drugs, provide greater discounts for Medicare Part D beneficiaries, and publicly report financial relationships with physicians, among other requirements (DID, July 15).

The Senate bill can be found at help.senate.gov/BAI09A84_xml.pdf. The House bill can be found at energycommerce.house.gov/Press_111/20090714/aahca.pdf. — David Belian


Apotex Warned by FDA for GMP Deficiencies

The FDA has warned Canadian generic-drug maker Apotex that products manufactured at its Etobicoke, Ontario, plant may be refused entry into the U.S. unless “multiple, serious deficiencies” in good manufacturing practices (GMPs) are corrected.

The FDA acknowledges that the company has corrected or soon will correct some of the violations in a Form 483 that followed a Dec. 10–19, 2008, inspection of the plant. But the GMP deviations listed in the June 25 warning letter posted to the FDA website this week will cause Apotex drug products to be adulterated, the agency says.

Apotex did not investigate batch failures and, in two cases since December 2006, affected batches of the drug acyclovir may have been shipped to the U.S., according to the warning letter. The agency asks the company to clarify questions including whether portions of the batches with passing testing results were shipped to the U.S.

“The list of rejected products includes multiple batches of therapeutically significant drug products such as cyclosporine, gabapentin, topiramate, divalproex and carbidopa-levodopa,” the warning letter says. “This unusual[ly] high number of rejected batches demonstrates a lack of adequate process controls and raises significant concerns regarding the capability and reliability of your processes to consistently manufacture drug products meeting predetermined specifications.”

The company also is cited for its conduct of out-of-specification investigations, which the FDA says “illustrate problems in the quality control unit’s ability to conduct thorough investigations.”

The FDA adds that the company failed to submit NDA Field Alert reports (FARs) to the agency as required in any case of bacteriological contamination; significant chemical, physical or other change or deterioration in the distributed drug product; or any failure of one or more distributed batches of drug product to meet specifications. According to the company’s own work instructions, the reports must be submitted to the FDA within three working days of confirmation that there might be a concern.

However, the FDA says, the company submitted FARs late in several instances, including one case involving ketoconazole tablets in which the report was submitted after 15 months had passed.

The company has 30 days to respond. Apotex did not respond to a request for comment by press time. The warning letter can be seen at www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm170912.htm. — Martin Berman-Gorvine


Eshoo Plans to Offer Biosimilars Bill as Part of Larger Package

Rep. Anna Eshoo (D-Calif.) plans to offer her biosimilars legislation as part of a larger healthcare overhaul package that the House Energy and Commerce Committee will begin marking up Thursday.

Creating a pathway for biosimilars approval is not the centerpiece of healthcare reform but is a key element, Eshoo said during a press briefing Wednesday at the Center for Medicine in the Public Interest (CMPI).

Rep. Mike Rogers (R-Mich.) also has endorsed Eshoo’s bill, which would give biologics innovators 12 years of data exclusivity and has 131 co-sponsors. The legislation competes with Rep. Henry Waxman’s (D-Calif.) bill, which provides seven years of exclusivity for innovators and has 13 co-sponsors.

“The next few weeks are going to be a pivotal time in Congress as health care takes top billing in the House and the Senate,” Robert Goldberg, CMPI’s co-founder and vice president, says in a statement. It is critical to support Eshoo’s bill, he added.

Eshoo testified this week before the House Judiciary Committee on balancing the incentives for innovation with the need for biosimilars. She praised the Senate Health, Education, Labor and Pensions Committee’s 16–7 vote to approve an amendment offered by Sens. Orrin Hatch (R-Utah), Mike Enzi (R-Wyo.) and Kay Hagan (D-N.C.) that would give innovator biologics makers 12 years of exclusivity. She also noted her bill has been endorsed by a number of groups, including the Biotechnology Industry Organization, the Association of American Universities and the National Venture Capital Association (DID, July 15 ).

Waxman’s bill, H.R. 1427, Promoting Innovation and Access to Life-Saving Medicine Act, is available at energycommerce.house.gov/Press_111/20090311/hr1427.pdf. Eshoo’s bill, H.R. 1548, the Pathway for Biosimilars Act, is available at www.fdanews.com/ext/files/Drug_Industry_Daily/Pathway%20for%20Biosimilars%20Act%2020091.pdf. — Elizabeth Jones


FDA Advisory Panel Raises Toxicity Concerns With J&J Drug

The FDA’s Oncologic Drugs Advisory Committee voted 14–1 not to recommend approval of Johnson & Johnson (J&J) and Zeltia’s Yondelis to treat relapsed ovarian cancer.

The committee cited risks of heart and liver toxicity with Yondelis (trabectedin) during the Wednesday meeting, J&J spokesman Jeff Leebaw told DID.

J&J believes Yondelis has an important role in the treatment of recurrent ovarian cancer, the company says in a statement Wednesday. It adds that it will work with the FDA to address the committee’s concerns.

Separately, an FDA decision on rivaroxaban to prevent pulmonary embolism and deep vein thrombosis has been delayed until mid 2010 (see related story). — April Hollis


Abbott to Seek New Humira Indications Next Year

Abbott Laboratories plans to submit additional indications for its blockbuster Humira rheumatoid arthritis drug next year, to treat ulcerative colitis and pediatric Crohn’s disease.

The company expects to submit applications for the indications to the FDA and the European Medicines Agency, John Thomas, Abbott’s vice president of investor relations, said on an earnings call Wednesday.

Humira (adalimumab) is in Phase III development for the indications. The inflammatory disease treatment, which competes with Johnson & Johnson’s Remicade (infliximab), had U.S. sales of $635 million in the second quarter, up 20.9 percent, according to a company statement.

Abbott also plans global regulatory submissions next year for a psoriasis treatment — ABT-874, an anti-IL 12/23 biologic. The treatment is in Phase II development to treat Crohn’s disease.

The company is collaborating with Roche on two oncology candidate drugs — ABT-869, a multitargeted kinase inhibitor and a Bcl-2 family protein antagonist. Abbott anticipates beginning a pivotal study for ABT-869 this year.

Abbott has three hepatitis C compounds in human clinical trials, including protease inhibitors and polymerase inhibitors, which have the potential to shorten treatment duration and increase cure rates, Thomas said.

The company is awaiting an FDA decision on cholesterol drug Certriad (rosuvastatin calcium/fenofibric acid). The drug is a fixed-dose combination of Trilipix (fenofibric acid) and Crestor (rosuvastatin calcium) that Abbott is developing with AstraZeneca. — April Hollis


J&J to Meet With FDA on Rivaroxaban NDA

Ortho-McNeil, a Johnson & Johnson subsidiary, plans to meet with the FDA over the next few months to discuss its reply to a complete response letter on its rivaroxaban NDA for the prevention of pulmonary embolism and deep vein thrombosis.

The company also met with the FDA in June, spokesman Ernie Knewitz told DID. The next talks probably will be a key factor in determining the company’s reply to the agency’s letter, Ortho-McNeil’s partner Bayer says in a statement this week. Bayer adds that it doesn’t expect Ortho-McNeil to complete its reply until at least the fourth quarter. The NDA was submitted July 28, 2008.

The FDA asked the company to submit additional data from completed and ongoing studies of the drug and from market surveillance in countries outside the U.S. to further assess the risk-benefit profile, Bayer says. The FDA also requested more information on study sites for RECORD trials, which assessed the drug’s efficacy in reducing risk of deep vein thrombosis and pulmonary embolism in major orthopedic surgery. No new studies were requested on the efficacy or safety of rivaroxaban, Bayer says.

“We are fully convinced of the positive risk-benefit profile of rivaroxaban, which has been approved in more than 60 countries worldwide in its first indication, and there are no new data in the clinical trials database that would change this assessment,” Bayer Schering Pharma Chief Medical Officer Kemal Malik says in the statement. The product is sold as Xarelto outside the U.S.

Rivaroxaban is a novel, oral anticoagulant under review as a daily tablet for the prevention of deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. In March, an FDA advisory committee voted 15–2 that the available clinical data demonstrated a favorable risk-benefit profile, Bayer adds.

If approved, Ortho-McNeil would commercialize rivaroxaban in the U.S. Bayer HealthCare is responsible for the marketing of rivaroxaban outside the U.S. — April Hollis


Expert: Data Integrity Is Key to Adaptive Trial Success

Sponsors must acquire as much clinical trial data as possible, check for errors early and “clean” them out where possible, and protect the data’s integrity to ensure success in adaptive clinical trials, an expert says.

An adaptive trial is one in which the data that accumulate during the study are used to decide how to modify certain aspects of the trial without undermining its statistical validity and integrity. This kind of trial needs a data monitoring committee (DMC), an independent statistical center and an executive steering committee to achieve its goals, Parvin Fardipour, Wyeth’s senior director of adaptive trials, said Wednesday at ExL Pharma’s annual conference on trial design innovation. Materials used in interim reports must be stored in a secure location, she added.

DMCs are independent of the study team but may not be completely independent of the sponsor because its business decisions depend on the trial data, Fardipour said. That means a firewall is essential to insulate sponsor employees on the DMC from communication with the study team.

The independent statistical center, usually operating outside the sponsor framework, prepares a subset of the data and briefing documents for the DMC to analyze with the goal of recommending whether to continue the study. The center must be able to send the selected clinical data to the DMC within 24 hours of receiving it, Fardipour said.

The executive steering committee is comprised of senior managers employed by the sponsor. It reviews DMC recommendations and makes final decisions regarding trial termination.

Creating Firewalls

Firewalls should be established between the few people who have access to the interim study data and the project team to avoid operational bias on committees, Fardipour said. The investigator should be blind to detailed decisionmaking rules, such as the decision algorithm, which should be published in the statistical analysis plan instead of the protocol.

Other issues to be considered in the planning and execution of response-adaptive randomization trials include:

  • Implementation of changes in randomization probabilities;
  • Availability and flow of information required to support adaptive decisionmaking;
  • Availability of a timely and meaningful endpoint to drive adaptation in real time;
  • Composition and role of the DMC to determine who is permitted to see the data and when; and
  • Availability of technical resources and other infrastructure required to implement a logistically complex trial.

Making the Decision

When planning begins, the decision to implement a response-adaptive randomization design as opposed to a more conventional trial design must be based on a rigorous assessment of the scientific basis for the trial, Fardipour said. It is essential to prove the business case for the desired adaptive design by comparing it with a hypothetical conventional alternative.

An adaptive trial design is validated through a combination of independent source code review, analysis of simulation results and back-to-back testing. The latter step involves independently creating a second version of the model or crucial parts of it to help detect programming errors and similar problems.

Fardipour advised sponsors to keep in mind the impact of adaptive design on drug supply. Since a large number of doses is typically assessed in an adaptive trial and dynamic responses are required, the drug supply requirements at each site may be less predictable than in a conventional clinical trial. Thus, drug supply costs are higher for adaptive trials but overall costs are usually lower. — Martin Berman-Gorvine

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Reporters: David Belian, Martin Berman-Gorvine, April Hollis, Elizabeth Jones, Nick Wills

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