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May 15, 2012

FDA’s Hearing for Biosimilars Showcased Issues Ranging From Definitions to Study Requirements to IP

Industry appeared to provide broad support for draft rules but pointed to areas that need tweaking.

FDA’s Hearing for Biosimilars Showcased Issues Ranging From Definitions to Study Requirements to IP

A tough issue for FDA will be how to get biosimilars and interchangeable products to market without sacrificing patient safety. [© Alexander Raths - Fotolia.com]

  • FDA’s draft guidance for biosimilars drew mostly good marks from industry at the hearing held May 11. Executives from a dozen biopharma companies, however, pressed for greater flexibility in the definition of proteins, tighter standards in naming and labeling follow-on biologics, as well as more details on moving drugs through agency approvals.

  • Defining Protein Therapeutics

    FDA promises a risk-based “totality-of-the-evidence” approach to reviewing biosimilars. Novo Nordisk and Pfizer urged FDA to rethink its definition of proteins as excluding alpha amino acid polymers with fewer than 41 amino acids. Jim Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs, noted that the definition clashed with statutes defining biological products as including any polypeptide except for those that are chemically synthesized.

    “We believe they have selected an arbitrary cutoff,” Shehan told GEN. “It can conflict with the statutory language and it really isn’t grounded in science either,” an exception, he said, to the guidance’s overall focus on respect for science and patient safety. “In broad strokes, they met the mark in seeming to have a healthy respect for the need to have data in order for biosimilars to come to market.”

    F. Owen Fields, Ph.D., Pfizer vp, worldwide regulatory strategy, worldwide R&D, suggested a case-by-case review of proteins with 40 or fewer amino acids. He cited Nisin, a 37-amino-acid polypeptide derivative approved by FDA as a food preservative, as an example among natural peptides best treated as proteins because of their potential for use as substrates for new drug development. “There are structures less than 41 amino acids that present regulatory science issues that are more similar to biologically synthesized proteins than to chemically synthesized peptides,” Dr. Fields pointed out at the hearing.

  • Keeping Trade Secrets Secret

    Abbott called for additional FDA efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “Safeguards are needed to ensure that the agency doesn’t unintentionally, inadvertently, but nevertheless impermissibly use or disclose to a biosimilar applicant an innovator’s trade secrets,” Neal Parker, an Abbott attorney, said at the hearing.

    Among safeguards suggested by Parker were FDA developing IT systems tracking employee involvement with BLAs and biosimilar applications, creating policies and procedures and training employees in them, and preventing FDA reviewers “significantly” involved in reviewing specific U.S.-licensed innovator BLA products from any biosimilar application review activities or any communications with biosimilar applicants seeking to rely on those same reference products.

    Abbott recently submitted a citizen’s petition requesting that the agency not consider any applications for biosimilars based on biologic reference products for which a BLA was submitted before March 23, 2010, the date that President Barack Obama signed the Biologics Price Competition and Innovation Act. The request would effectively shield Abbott’s mAb therapeutic and biggest-selling treatment Humira from biosimilar competition. The company is about to spin off its brand-name drug development operations, remaining as a maker of medical equipment and generic drugs.

  • Fine-Tuning Data Requirements

    Kalyan R. Anumala, Ph.D., senior director of Therapeutic Proteins, suggests that the agency should only require Phase II and III trials where it establishes a need after reviewing a submission. He also said the agency should encourage new characterization methods rather than clinical trials.

    Also calling for additional characterization methods is the only U.S. company marketing biosimilar drugs, Hospira. Its products include anemia treatment Retacrit in the EU and biosimilar filgrastim product Nivestim, sold in the EU and Australia for stimulating production of white blood cells in patients receiving cytotoxic chemotherapy.

    Samant Ramachandra, M.D., Ph.D., Hospira’s senior vp, R&D and regulatory and medical affairs and CSO, also urged FDA to account for reference product variability and clarify the required approach to show clinical immunogenicity assessment.

    Dr. Ramachandra and James M. Roach, M.D., svp and CMO of Momenta Pharmaceuticals, urged FDA to permit the use of bridging data in return for allowing non-U.S. reference products. “This is critical if the goal is to implement a global development program that is feasible to conduct,” Dr. Roach added. Eli Lilly’s Gregory C. Davis, Ph.D., pressed FDA for more guidance on the type and extent of bridging data that would be permissible.

    Abbott, by contrast, said data from studies involving a foreign comparator product cannot be considered pivotal if the foreign comparator is different from the U.S. reference product. FDA has stated that clinical comparisons with a non-U.S. licensed product do not provide an adequate basis to support interchangeability.

    Jay P. Siegel, M.D., chief biotechnology officer and head of global regulatory affairs for Janssen Pharmaceutical, echoed many brand-name drug developers by urging FDA to maintain the draft guidance’s standard for interchangeability. Applicants would have to demonstrate biosimilarity and the ability of the biological product to produce the same clinical result as the reference product in any given patient.

    If biosimilarity is established, it should also be extrapolated to pediatric populations, said Karl Heinz Emmert, Ph.D., managing director for Merckle Biotec, a Teva Group member. Dr. Emmert contended that FDA need not require clinical studies of pediatric populations with a biosimilar product. That differs from the thinking of Pfizer, which while supportive of extrapolations between populations within an indication, suggested an exception: diseases where pediatric pathophysiology differs from that of adults.

    With regard to manufacturing concerns, Paul Eisenberg, an Amgen svp, argued in part: “Requiring the maintenance of biosimilarity over time would inhibit manufacturing and quality improvements and unduly burden industry without benefiting patients.” Mark McCamish, M.D., Ph.D., head of global biopharmaceutical development for Sandoz Biopharmaceuticals, disagreed.

  • Determining Label Details

    Amgen did not address manufacturing issues in testimony but focused instead, along with several other companies, on how biosimilars should be identified and labeled to ensure accurate tracking and tracing. Suggestions included biosimilar names sharing a common root but having a unique suffix and/or prefix to denote biosimilarity and interchangeability.

    “Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making,” commented Michelle Rohrer, Ph.D., vp, U.S. regulatory affairs at Genentech.

    Teva’s Dr. Emmert and Ahaviah Diane Glaser, vp for policy and strategic alliances with the Generic Pharmaceutical Association (GPhA), noted, however, that while all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products. Glaser said different INNs would impede market competition because it would likely require a different marketing campaign, thus raising costs, and would also complicate collection of global safety data and could increase medical errors.

  • Embracing Biosimilars

    Further guidance on naming biosimilars and interchangeables was one point agreed upon by industry and patient groups, so it’s likely FDA will oblige. That’s the easy issue for the agency. Tougher will be how to balance shepherding biosimilars and interchangeable products to market without sacrificing patient safety.

    “If FDA issues product-specific guidances with very clear mandates that to get a biosimilar approved, you need to run a Phase III-like trial of X size, evaluating X, Y, and Z, it takes away from the incentive to put that much more time and scientific thought into proving from a structural and functional basis that you have the same compound,” Dr. Roach of Momenta told GEN.

    Years ago EMA developed solid scientific guidelines, then product-specific rules that succeeded in bringing biosimilars to Europe. Sandoz’ Dr. McCamish credited EMA’s consistent standards with health authorities embracing biosimilars. It’s a lesson the U.S. will have to learn as FDA builds the pathway for biosimilars to finally reach the American market.


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