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Feb 6, 2012

EMA’s Draft Rules for Interferon Beta Biosimilars Include Clinical and Nonclinical Studies

Guidance is now open to comments, and a final rule is expected by the middle of this year.

EMA’s Draft Rules for Interferon Beta Biosimilars Include Clinical and Nonclinical Studies

EMA created its first biosimilar guidance in 2005; FDA is still working on such guidance for the U.S. market. [© Eclipse Digital - Fotolia.com]

  • Interferon beta drugs have been approved for treating multiple sclerosis (MS) since the 1990s. While no biosimilars to those drugs are yet on the market, EMA released a draft guidance on January 23 covering clinical and nonclinical requirements for developing interferon beta biosimilars.

    The agency has opened the document up for comment, and the deadline for comments is May 31. EMA says its timeframe for reviewing the feedback will depend on the number of comments received as well as on the need to involve or further consult other entities. “The process, which involves consultation between scientific committees and working parties, can take several months,” Monika Benstetter, a spokeswoman for the EMA, told GEN. “Therefore we expect the guideline to be released toward the middle of 2012.”

    Interferon beta drugs account for about half the treatments approved for MS by FDA. In the EU and the U.S. there are two interferon beta-1a drugs: Biogen Idec’s Avonex and Merck Serono’s Rebif. Additionally, there are two interferon beta-1b drugs, Betaseron (also called Betaferon) made by Bayer HealthCare and Novartis’ Extavia, a copy of Betaseron. Novartis got the rights to launch a copy of Betaseron and pays Bayer royalties.

    A recombinant interferon beta-1a drug, CinnoVex, is manufactured as a biosimilar in Iran. It has not been approved in Europe or the U.S. “Certainly the guidance that EMA is providing would represent probably the first foray really in the MS space for a biosimilar,” Timothy Coetzee, Ph.D., chief research officer for the National MS Society, pointed out to GEN. “That is an important first step in the evolution of biosimilars for MS.”

  • Nonclinical Expectations

    “Generally the trigger for the development of a new product-class specific guideline is the number of requests for advice received by the agency in a particular field,” Benstetter explained. “This relates mainly to requests for scientific advice but could also come from other requests for information.”

    EMA’s concept paper for interferon beta biosimilars advises drug developers to start with nonclinical in vitro studies that “should be comparative in nature and should be designed to detect differences in the pharmaco-toxicological response between the similar biological medicinal product and the reference medicinal product and should not just assess the response per se.”

    EMA expects data from a number of comparative bioassays (e.g., receptor-binding studies, antiviral effects in cell culture). “Analytical methods should be standardized and validated according to relevant guidelines, e.g., evaluation of antiviral effects in cell culture in accordance with the provisions of the European Pharmacopoiea,” the guidance states.

    If the in vitro studies raise concerns, the guideline suggests also conducting in vivo pharmacological studies and/or general repeated-dose toxicity studies. If researchers can justify that further studies in a pharmacologically responsive animal species would not likely provide relevant additional information, then such studies may be omitted.

  • Patient Trials

    As for clinical investigation, the draft guideline suggests starting with pharmacokinetic and pharmacodynamic studies and then continuing with efficacy and safety studies. The pharmacokinetic properties should be compared in a crossover study for the route of administration applied. Healthy volunteers are considered an appropriate study population.

    Researchers should select a dose in the sensitive part of the dose concentration curve and justify their use of a single or repeated dose. Pharmacokinetic parameters that should be considered include area-under-the-plasma or blood concentration time curve (AUC), the maximum level of a drug in a patient’s blood (Cmax), and half-life times (T1/2) or total clearance from serum (CL/F).

    To measure pharmacodynamics, the draft guideline suggests using myxovirus resistance 131 protein A (MxA) and any of several other markers of interferon beta’s biological activity, including serum (2’–5’) oligo-adenylate-synthetase activity, neopterin, beta2–130 microgloblin, interleukin 10, and TNF-related apoptosis inducing ligand (TRAIL).

    “A comprehensive comparative evaluation of some of these markers could be used to support the similarity of the biosimilar and reference products,” the draft stated, calling it the fingerprint approach. It added that MxA “is currently considered as one of the most sensitive markers of the biological activity of interferons type I and should be one of the selected markers.”

    To prove clinical efficacy the draft guideline suggests an adequately powered, randomized, parallel group equivalence clinical trial, preferably double-blind, with a similar route of administration as the reference product. Relapse rate has been used as a primary endpoint in relapsing MS trials using interferon beta. But such clinical studies are not necessary for biosimilars, the guideline notes, since the focus is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se.

    “For demonstrating clinical similarity of a biosimilar and reference product, magnetic resonance imaging (MRI) of disease lesions in relapsing MS may be sufficient. In addition, clinical outcomes such as relapse rate or percentage of relapse-free patients should be used as secondary endpoints in support of the MRI outcomes,” the draft stated.

    Regarding the study design, assay sensitivity could be shown by a three-arm trial including a placebo arm for a short period of time (e.g., four months) sufficient to demonstrate superiority of both the biosimilar and reference products over placebo using an MRI endpoint. An alternative design could be a three-arm trial with the reference product and two doses of the biosimilar product.

    However the study is designed, the trial should run at least 12 months or longer. The most sensitive patient population, which would enable detection of differences between the biosimilar and reference products, should be selected.

    As for clinical safety, the draft guideline noted that comparative safety data from the efficacy trial should be sufficient for the required premarketing safety database. Adverse events of specific interest include influenza-like symptoms, injection reactions, and laboratory test abnormalities. EMA will, however, seek a comparison of the immunogenicity profile of the biosimilar and reference products over time. The draft calls for sponsors to submit a minimum of 12-month comparative immunogenicity data pre-authorization, with further assessment to be continued post-approval for at least six months for the biosimilar product.

    “A strategy that includes serum sampling at baseline and at regular intervals is necessary for assessing the comparability of the dynamics of antibody development during therapy, e.g., every month in the beginning of the treatment followed by every three months,” according to the draft guideline.

    EMA would require a validated, highly sensitive antibody assay, capable of detecting all antibodies of varying affinities, classes, and subclasses. After confirming antibody positive samples, researchers would also be required to further characterize them, including determining their ability to neutralize the biological activity of interferon beta and cross-reactivity: “It is recommended that the standardized MxA protein nAb assay or a nAb assay that has been validated against the MxA protein nAb assay is used.”

  • The Drive for Biosimilars

    The concept paper covering interferon beta biosimilars marks the latest step by EMA toward developing a regulatory framework for widespread use of various types of biosimilars. The agency has steadily developed guidelines for 10 categories of medicine, progressing from smaller to larger molecules. It created its first guidance in 2005 and approved its first category of biosimilars a year later. FDA by contrast has yet to introduce a pathway for getting biosimilars on the U.S. market.

    “The good part about the EMA is that they actually have a mechanism and a system to methodically go through class by class, drug by drug if you will, and explain what it will take to get a product on the market, so then you can design clinical trials with less risk,” Richard Tinsley, a partner with Putnam Associates, told GEN.

    Containing costs is a challenge drug developers must surmount if the aim of commercializing biosimilars is to provide patients with cheaper alternatives. Based on current guidelines, it looks like developers will need years to prove biosimilarity and launch these drugs. That presents a third hurdle for biosimilar firms to surmount: managing patient expectations regarding biosimilars that biosimilars will deliver faster cures at less cost.

    How satisfied are you with progress toward bringing biosimilars to the U.S. market?


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