Articles Posted in Biologics

Thumbnail image for Thumbnail image for Thumbnail image for FDA.jpegLast week, the U.S. Food and Drug Administration published the Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022.  Commonly referred to as the “goals letter” or “commitment letter,” the publication represents discussions among FDA, the regulated industry, and public stakeholders regarding reauthorization of the Biosimilar User Fee Act (“BsUFA”).



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Written by Scot B. Pittman

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BsUFA authorizes FDA to collect user fees for the review of biosimilar biological product applications.  The current legislative authority for biosimilar user fees expires in September 2017, and FDA cannot continue to collect user fees without reauthorization.  Relatedly, on Monday, FDA announced that it will hold an upcoming public meeting to discuss proposals for reauthorization.  The proposals include enhancements to the existing biosimilars user fee program in four key areas: (i) review performance; (ii) meeting management; (iii) guidance development, and (iv) fee/program administration.

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On September 9, 2016, Apotex Inc. filed a petition for a writ of certiorari in the Amgen Inc. v. Apotex Inc.[1] case decided by the Federal Circuit on July 5, 2016.  Apotex’s petition was placed on the Supreme Court’s docket on September 14, 2016 as No. 16-332.  Amgen’s response is due on October 14, 2016.

There are two issues raised in Apotex’s petition: (1) whether a biosimilar applicant must provide notice of commercial marketing when it complied with the patent dance; and (2) if notice of commercial marketing is required, whether notice can be effective prior to FDA approval of the biosimilar application.  The Federal Circuit held that notice of commercial marketing is mandatory and not effective until after the biosimilar application is approved.  Amgen, 2016 U.S. App. LEXIS 12353, at *36 (“We conclude that an applicant must provide a reference product sponsor with 180 days’ post-licensure notice before commercial marketing begins, regardless of whether the applicant provided the (2)(A) notice of FDA review.”).

Apotex makes two arguments in its petition: (1) the notice of commercial marketing provision provided by the Biologics Price Competition and Innovation Act (“BPCIA”) is not mandatory, especially where the biosimilar applicant engaged in the patent dance; and (2) even if notice is required, it can be provided before a biosimilar application is approved.

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Congress passed the Food and Drug Administration Amendments Act of 2007 (“FDAAA”) to give the U.S. Food and Drug Administration (“FDA”) new authority to regulate the safety of marketed drugs. As part of this authority, FDA may require drug companies to propose and implement Risk Evaluation and Mitigation Strategy (“REMS”) for certain drugs whose risk- benefit profiles warrant safety measures beyond professional labeling. FDA may require REMS as part of the approval of a new drug or biologic (brand or generic), or for an approved product when new safety information arises. If FDA determines that a drug has been shown to be effective but is associated with an adverse drug experience, the FDA will require that the REMS have elements to assure safe use (“ETASU”). An example of an ETASU is that health care providers who prescribe the drug have particular training or experience or are specially certified.

The FDA, Federal Trade Commission, and generic drug manufacturers have raised concerns that branded drug manufacturers could be using REMS to impede generic competition. One concern is that branded companies may use REMS distribution restrictions to deny generic companies the drug samples they need to conduct necessary testing and otherwise meet the requirements for generic drug approval. Another concern is that branded drug firm may abuse situations where FDA approval of a generic drug is conditioned on the utilization of a single, shared ETASU by both the generic and branded companies. Essentially, the concern is that branded firms are impeding negotiations of a single, shared ETASU in order to delay generic entry.

To address these concerns, the Senate Judiciary Committee introduced Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act of 2016 on June 14, 2016. The bill—co- sponsored by Senators Grassley (R-IA), Klobuchar (D-MN), Leahy (D-VT), and Lee (R-UT)— permits a generic manufacturer to sue the branded manufacturer if: (1) the branded manufacturer fails to “provide sufficient quantities of [a drug sample] on commercially reasonable, market- based terms”; or (2) branded and generic manufacturers are unable to develop single, shared ETASU after 120 days of initiating a request to develop a shared ETASU. The relief contemplated in the bill is (1) a court order that the brand company provide the drug sample or the brand and generic develop single, shared ETASU or generic firm join a pre-existing ETASU; and (2) monetary award.

leerink.pngOn February 12 and 13, 2014, Leerink Partners LLC (“Leerink”) held its annual Global Healthcare Conference at the Waldorf-Astoria Hotel in New York, New York. Each year the Conference includes emerging themes in healthcare, where Leerink’s equity analysts moderate discussions with MEDACorp specialists to provide unique and timely insights.

In addition to the company presentations, this year’s line up featured the following panels or keynote speakers with some observed comments or trends:

• Panel: The Future of Medical Devices in an Evolving Landscape: A Shifting Emphasis to Patient Monitoring and Customizable Solutions

  • Patients view surgeons that incorporate robotics in their practice as the better doctors, driving more surgeons to utilize them in their practice. As surgeons become more familiar with these devices, patients may have more options for surgical procedures and implants.
  • Larger companies are looking at controlling infections caused by implanted medical devices with special coatings–either anti-infectives or antibiotics, particularly for use in higher-risk patients. There is an increasing need, however, for implants to have built-in tools for monitoring the devices. But as medical devices become more complex, such as hip, knee, or total joint replacements, these devices will require preapproval marketing applications (“PMAs”) with clinical data rather than less costly and time-consuming 510(k)-type premarket clearance applications. Since PMAs cost companies more than 510(k) applications, these newer devices will cost third party payors and patients more.
  • Hospitals continue to be under a lot of pressure not to lose patients, so they may seek lower margins by having surgeons add anti-infective coatings or antibiotics rather than purchasing more costly versions with the coatings or by importing “generic” implants from other countries that may not be as rugged as the versions cleared for use in the U.S. FDA’s new unique device identifiers and improved monitoring, however, may reduce use of such imported devices with unclear pedigrees.

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On Sunday, February 16, BioCentury This Week television examined the policies surrounding the expected competition of innovator biologic products with biosimilar versions. Featured in the program were interviews with:

  • Geoffrey Eich, Executive Director of R&D Policy at Amgen Inc.
  • Craig Wheeler, President & CEO of Momenta Pharmaceuticals Inc.

BioCentury This Week.pngSunday, February 16: The Battle Over Biosimilar Business Models.

Biosimilars — lower-cost versions of expensive biologics — are coming to pharmacy shelves in the U.S. But biosimilars players disagree about how they should compete.

Should biosimilars be sold like inexpensive generic drugs? Or should they be sold at higher prices like branded drugs?

DNApurple.jpgOn February 4, 2014, the U.S. Federal Trade Commission (“FTC”) held a Workshop entitled: “Follow-On Biologics Workshop: Impact of Recent Legislative and Regulatory Naming Proposals on Competition“. The Workshop was well attended and sought to solicit a variety of views on the marketing of follow-on biologics, currently referred to as “biosimilars” under the Biologics Price Competition and Innovation Act (“BPCIA”).

Briefly, the BPCIA defines “biosimilarity” as “[T]he biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” A biosimilar is submitted as a 351(k) application, which must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies, animal studies, and a clinical study or studies, unless FDA determines, in its discretion, that certain studies are unnecessary. To meet a higher standard of “interchangeability,” an applicant must provide sufficient information to demonstrate biosimilarity, and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. According to the BPCIA, interchangeable biosimilar products may be substituted for the reference product without the intervention of the prescribing healthcare provider.

As explained by Edith Ramirez, FTC Commissioner, many state legislatures have either passed or are considering legislation to explain how to handle biosimilars that are not interchangeable (and sometimes including interchangeable biosimilars), which may affect competition for the market at this juncture before even one biosimilar has been approved. In particular, many of the state laws or bills include provisions for prescriber notification of possible biosimilar substitution for the referenced innovator biologic product. FDA and other regulatory bodies are still considering universal nomenclature for biosimilars, which may either create the same or similar names for biosimilars and their referenced innovator biologic products. The FTC sees similarities between biosimilars and how generics were first perceived and opportunities to either facilitate or hinder acceptance of biosimilars in the market that they wanted to explore in this Workshop.
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Jnj.jpgJohnson and Johnson (“J&J”) recently joined the discordant chorus of stakeholders and commentators who have weighed in on the issue of naming for biosimilar products. On the one hand, some advocate for shared International Non-Proprietary Naming (“INN”) system names between a biologic approved under Section 351(k) of the Biologics Price Competition and Innovation Act of 2010 (“BPCIA”) and the reference protein product (“RPP”). Conversely, others argue that biosimilars and RPPs should be assigned unique INNs. Whether biosimilar products are given the same or unique names matters: biosimilar products with unique names will likely require independent marketing and detailing (i.e., automatic substitution will not be available). For its part, J&J requests that FDA “require biosimilars to bear nonproprietary names that are similar to, but not the same as, those of their reference products or other biosimilars.”

J&J cites to its experience with Eprex®/Erypo® recombinant human erythropoietin (epoetin alfa), to inform its position on biosimilar naming. In particular, J&J identified four considerations that arose from its experience: (1) reliable pharmacovigilance mechanisms are necessary for postmarket safety; (2) products may undergo clinically-meaningful changes over time; (3) effective pharmacovigilance can only occur when it is possible to identify the product administered to a patient; and (4) switching products can interfere with determining which product is responsible for any given adverse effect. For example, J&J received reports of erythopoetin antibody-mediated pure red cell aplasia in Thailand between 2004-2007 but were unable to pinpoint the adverse event reports to a specific epoetin product due to incomplete documentation and frequent product switching.

Based on this experience, J&J argues that giving a biosimilar product the same name as the RPP would interfere with pharamacovigilance. For example, J&J states that, “to the extent that adverse event reports identify a product solely by nonproprietary name, shared names would complicate if not prevent tracing a safety signal to a specific product.” J&J also states that physicians may submit adverse event reports that incorrectly identify the responsible product if switching occurs without the knowledge of the physician.
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genetherapy.jpgOn February 25-26, 2014, FDA will hold a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee. A majority of the meeting will concern oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility. While FDA will post meeting materials at least two business days before the meeting, one item that will likely be discussed is a workshop held in September 2002 on Evidence Based Assisted Reproductive Technologies (ART) that concerned oocyte modification. Approximately half of the second day will focus on considerations for the design of early-phase clinical trials of cellular and gene therapy products, which was the topic of a revised guidance published on July 2, 2013. This meeting was originally scheduled for October 22-23, 2013 but was postponed “due to resource constraints arising from the government shutdown.”

The July Draft Guidance provided recommendations to assist in designing early-phase clinical trials of cellular therapy (“CT”) and gene therapy (“GT”) products, collectively referred to as “CGT products”, which covers most Phase 1 trials and some Phase 2 trials. FDA considers clinical study designs for CGT products to be different because of the way the products work and the potential for substantial risk. In the past, FDA halted CGT therapies due to experiences that included: (1) multiple-organ failure and death of a subject receiving a GT product for ornithine transcarbamylase deficiency, (2) late-onset T-cell leukemia in subjects who received a GT product for X-linked severe combined immunodeficiency, and (3) the development of tumors in the brain and spinal cord of a patient who received intrathecal allogenic stem cells for ataxia telangiectasia.

FDA’s Guidance on early-phase clinical trials explained that unlike many small molecule drugs, there is much less experience across a broad population with CGT products, leading to more uncertainty with clinical study design and controls. Some CGT products persists in humans for an extended time period and the administration may involve surgery or other invasive procedures that may require use of an investigational medical device. Allogenic CT products, GT vectors, and proteins that may be produced by CGT products have the potential to produce an immune response that may produce an unintended adverse reaction or sensitivity to a CGT product in the future. CGT products are cellular products and so mimic the complex, dynamic nature of living cells, which can migrate within the recipient’s body.
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Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for dna.jpg[Update: The Workshop was cancelled on December 10, 2013, due to weather-related closure of the federal government. On December 30, 2013, FTC announced the Workshop would be held on February 4, 2014, at the FTC Conference Center at 601 New Jersey Avenue, NW, Washington, D.C. and will be webcast. FTC will publish an updated agenda and list of speakers. The comment period is unaffected by the rescheduling of the event, i.e., due by March 1, 2014.]

On December 10, 2013, the Federal Trade Commission (“FTC”) will host a Workshop on the Competitive Impacts of State Regulations and Naming Conventions Concerning Follow-on Biologics. FDA has yet to receive its first biosimilar application filed under the Biologics Price Competition and Innovation Act of 2010 (“BPCIA”). Despite this, the FTC believes that some state legislatures have already passed laws that may affect substitution of biosimilars for their referenced innovator biologic products. As a result, the FTC is concerned that these laws may deter the development of biosimilars and raise the costs for consumers without biosimilar options.

FTC’s Workshop plans to cover some of the following questions:

  • How would the new state follow-on biologic substitution laws passed this year, or similar proposals pending in other states, affect the competition expected between or among biosimilar, interchangeable and reference biologic medicines?
  • What are the rationales behind new state proposals and laws for regulating follow-on biologic substitution?

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