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Jun 26, 2013

Latest Biosimilar Guidance Raises More Questions

Quick FDA action just as unlikely as last year, when agency issued original policy advice.

Latest Biosimilar Guidance Raises More Questions

FDA issued three draft guidances on biosimilars more than a year ago, but has been unable to show industry and others much progress since then. [© Eclipse Digital - Fotolia.com]

  • Testifying before Congress in April, FDA Commissioner Margaret A. Hamburg, M.D., sought to reassure lawmakers: “We are developing a science-based process for bringing safe and effective biosimilar and interchangeable products to market, which should increase competition and create substantial savings for patients, healthcare providers, and insurers.”

    More than a year after issuing three draft guidances on biosimilars, however, FDA has been unable to show industry and others little progress beyond a fourth draft guidance issued in March on formal meetings between the agency and biosimilar sponsors. And judging from comments by drug developers during a comment period that ended May 31, industry has numerous questions it wants FDA to address.

    Those questions are unlikely to be addressed quickly, given that more than a year has passed since FDA came out with its initial biosimilar guidances, designed to address scientific and quality considerations, as well as answer common questions on biosimilar development. Those guidances sparked mostly good marks, but also requests from a dozen biopharmas in letters and a public hearing for greater flexibility in defining proteins, and tighter standards in naming and labeling follow-on biologics.

    “FDA is currently reviewing and considering all comments received from the May 11, 2012 public hearing docket and those from the draft guidance dockets as we move forward to finalize the draft guidances and determine plans for developing future policies on biosimilars, including guidance on clinical pharmacology data to support a demonstration of biosimilarity to a reference product,” FDA spokeswoman Lisa Kubaska, Pharm.D., told GEN on June 19.

    Dr. Kubaska said FDA’s Center for Drug Evaluation and Research (CDER) continues to meet with sponsors interested in developing biosimilars. As of June 19, CDER received 56 meeting requests for initial gatherings to discuss biosimilar development programs to 12 different reference products, and held 40. CDER has also received 17 INDs for biosimilar development programs, but additional development programs are proceeding under a pre-IND.

    “You might expect that building a new approval program of this complexity takes much time and deliberation, and that certainly has been the case,” Dr. Hamburg said, understating matters in a March 15 address to the Massachusetts Biotechnology Council.

    FDA will need more time and deliberation, six drug developers and two industry groups concluded in comments on the agency’s “Draft Guidance for Industry on Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants.”

    “Given the complexity of the issues involved in developing, manufacturing, and approving biosimilars, we hope that FDA will continue to seek stakeholder input openly and transparently in order to best protect patients and to ensure implementation is based on sound science,” the Pharmaceutical Research and Manufacturers or America (PhRMA) advised FDA, in a letter written by Kristin Van Goor, Ph.D., RAC, the industry group’s senior director, scientific, and regulatory affairs.

  • Exploring Options

    Dr. Van Goor and PhRMA urged FDA to commit to providing feedback on sponsors’ pre-meeting materials at least five business days in advance; and ensure different pathways for “Section 351(k)” biosimilars and “Section 351(a)” biologics license applications.

    “Allowing a Section 351(a) applicant to submit an abbreviated application (as a result of reliance on a prior approval) would give the applicant the benefits of an abbreviated pathway without imposing the corresponding obligations that accompany the 351(k) pathway,” Dr. Van Goor said—such as waiting for data-protection expiry, and being subject to pre-market patent litigation.

    FDA’s latest draft guidance envisions five types of meetings with biosimilar developers:

    • An initial advisory meeting with general discussion on whether biosimilar licensure may be feasible, and general product development advice, within 90 calendar days of FDA receiving a written meeting request and meeting package.
    • Biological Product Development (BPD) Type 1—required for stalled BPD programs to proceed, within 30 calendar days of receipt.
    • BPD Type 2: Discussion of specific issues such as proposed study design or endpoints, where FDA will provide targeted advice, within 75 calendar days of receipt.
    • BPD Type 3: In-depth data review and advice meeting regarding an ongoing BPD program, within 120 calendar days of receipt.
    • BPD Type 4: Discussion of format and content of a biosimilar biological product application or supplement, within 60 calendar days of receipt.

    “The timelines established in this draft guidance are too protracted and complicate the Agency’s advice to sponsors to have a step-wise approach to biosimilar development,” Boehringer Ingelheim told FDA in a letter from Joanne Palmisano, M.D., FACP, vp-regulatory affairs.

    Dr. Palmisano suggested FDA allow submission of packages for BPD3 meetings closer than 120 days in advance. “While the normal four-week period may not be sufficient for review of a biosimilar meeting package, we feel that 120 days is perhaps more than should be required,” she noted. The agency can split the difference by proposing 60 days, which should allow industry more time it wants while still allowing for careful review.

    FDA should also consider Teva Pharmaceuticals’ advice to spell out how the agency will review meeting packages, and how much data it will want before initial advisory and BPD3 meetings. “Any details the agency may provide at this time would be appreciated, and would further the industry understanding of the review timelines for the various meetings,” Teva stated in a letter from Penny S. Levin, director, global regulatory intelligence & policy.

    While companies typically start their biosimilar applications with free initial advisory meetings, FDA can in cases substitute BPD3s, which require user-fee payments within five days.

    “The sponsor may wish to re-evaluate its meeting request entirely, and should be given an opportunity to do so before incurring a payment obligation,” Carol Haley, Ph.D., Pfizer’s director, U.S. regulatory policy & global intelligence, told FDA.

    The agency should heed Pfizer’s advice, provided re-evaluation is limited to a few days, to avoid needless delay.

  • Seeking Safeguards

    FDA last year expanded its user-fee collection to biologics and biosimilars, setting the same fees as, while committing to longer decision timeframes than, new prescription drugs. Mylan suggested BPD3 meetings be held within 60 rather than 120 days of requests, same as Type B meetings for reviewing new drugs.

    AbbVie called for additional efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “AbbVie is deeply concerned that FDA has not yet described publicly, or to our knowledge implemented within the agency, any safeguards to prevent the impermissible use or disclosure of reference product sponsor trade secrets during these meetings,” Mark J. Goldberger M.D., AbbVie’s divisional vp, regulatory policy & intelligence, told the agency.

    AbbVie cited instances where FDA acknowledged reviewers either cited nonpublic data from reference drugs in 505(b)(2) applications that can rely in part on data from existing reference drugs, or compared that data to data from biosimilars. One such instance, the company said, came when FDA approved Teva’s testosterone gel, for which AbbVie AndroGel 1% was the reference product.

    “We remain concerned that agency scientists may unintentionally, inadvertently, but nevertheless impermissibly use and/or disclose to a biosimilar applicant innovator trade secrets during the BPD program,” Dr. Goldberger wrote.

    One safeguard AbbVie seeks would bar “employees who were significantly involved in reviewing particular reference product BLA and who have meaningful knowledge of the trade secrets in the BLA.” The company also wants FDA to create an electronic database of such employees, and block reviewers electronically from accessing BLAs or review documents for reference products.

    Also responding to FDA’s latest guidance were Generic Pharmaceutical Association and Apotex.

    FDA has two challenges ahead on biosimilars. One is finalizing the four guidances. Then comes the harder task of playing catch-up to Europe, where 14 biosimilars have been approved since 2006. Many more are expected once the European Medicines Agency finalizes new guidelines on approving biosimilars with biotechnology-derived proteins as active ingredients; a draft was released June 10. All the more reason why FDA needs to modify, then finalize the draft guidances before another year elapses without a biosimilar pathway in the U.S.


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