Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Agency sought to answer various procedural questions that could come up during presubmission meetings.

EMA recently pulled into one document its answers to regulatory and procedural questions biosimilar developers are likely to ask before submitting marketing applications. The answers that comprise the “EMA Procedural Advice for Users of the Centralised Procedure for Similar Biological Medicinal Products Applications” were all already in public domain, so there are hardly any surprises. Equally unsurprising, the generic drug segment generally supports the published product, which should keep EMA out front among the world’s regulatory agencies when it comes to biosimilars.

“The timeframes are the same as before the publication of this guidance and appear in general satisfactory to the EU biosimilar medicines industry using the centralized procedure,” Suzette Kox, senior director, scientific affairs for the European Generic Medicines Association (EGA), told GEN.

As Kox correctly notes, the potential for a biosimilar to gain approval lies with the scientific establishment of biosimilarity with the reference product. Interestingly, EMA answers the first of the document’s 43 questions—What is a similar biological medicinal product?—with a definition less burdensome to biosimilar makers than FDA’s. EMA defines biosimilars as “similar to a biological medicine that has already been authorized, the so-called reference medicinal product.”

FDA proposes using slightly stricter wording, declaring that in order to be considered a biosimilar, the biological product must be “highly similar to the reference product notwithstanding minor differences in clinically inactive components.” By minor differences, the agency states that there should be no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Evaluating Similarity

Despite differing definitions of biosimilarity, EMA’s standard for assessing differences between biosimilars and their reference products is similar to FDA’s, which says both “are expected to have the same safety and efficacy profile and are generally used to treat the same conditions.”

The EMA document directs biosimilar drug developers to provide results of preclinical tests or clinical trials. “The comparability exercise should be a robust head-to-head comparison between the similar biological medicinal product and the reference medicinal product performed at the levels of quality, safety, and efficacy.”

FDA’s clinical comparability language notes that the clinical comparability exercise “is a stepwise procedure that should begin with pharmacokinetic (PK) and pharmacodynamic (PD) studies followed by clinical efficacy and safety trial(s) or, in certain cases, PK/PD studies for demonstrating clinical comparability.” FDA recommends comparing the proposed product and the reference product on structure, function, animal toxicity, PK/PD, clinical immunogenicity, and clinical safety and effectiveness.

Data Exclusivity

EMA grants eight years of data exclusivity in an EU member state for reference products whose marketing authorization was submitted as of October 30, 2005, under national, mutual-recognition, and decentralized procedures, and as of November 20, 2005, under the centralized procedure. That is followed by two years of marketing exclusivity plus an additional year for a new indication. EMA offers the commonsense advice that when a biosimilar application is submitted, the data protection period of the reference medicinal product should have already expired so that applicants can rely on its dossier.

The biosimilar exclusivity period follows the same 8+2+1 formula in effect for branded small molecule drugs, an extension from the old six-year exclusivity periods granted by several member countries before 2005. EMA believes this timeframe will encourage biosimilars, something EU members want because of the potential to contain drug costs for their largely state-run health systems.

EMA’s biosimilar exclusivity falls just short of the 12-year exclusivity period proposed in the U.S. (four years for data and eight years for market exclusivity), though it is lower than the seven-year exclusivity proposed by President Barack Obama this year in his fiscal 2013 budget proposal. While President Obama claims the measure will save Washington $4 billion over 10 years, most of the branded-drug industry, led by the Biotechnology Industry Organization and Pharmaceutical Research and Manufacturers of America, are heavily opposed, arguing the change would discourage development of the very biosimilars that exclusivity is supposed to catalyze. House and Senate committees backed the 12-year period last year.

The current U.S. exclusivity is an innovator-friendlier alternative, but not by much. That may explain why industry groups have not spoken out against the EMA document.

Interchangeability and Manufacturing

After defining biosimilarity, EMA poses the next logical question—Will my similar biological medicinal product be considered interchangeable with the reference medicinal product?—then refers readers to the end of the document for the answer: It’s up to national drug regulators.

When it comes to interchangeability, EMA should make its own decisions. Leaving it up to individual countries creates a serious burden for biosimilar developers, who are forced to pursue two tracks of reviews for approvals: EMA’s Committee for Human Medicinal Products (CHMP) and its centralized procedure for authorizing biosimilar products and allowing direct access to the single EU market; and the regulators of each country where they wish to sell their treatments, who must decide on interchangeability.

Fortunately the system requires European rather than individual national authorization for several production processes governing biosimilars. Under EMA’s guidelines, biosimilars are subject to the same level of GMP supervision and GMP standards as any other medicinal product. That includes inspections verifying manufacturing and control activities related to applications.

A second inspection is required for plants outside the European Economic Area (EEA)—which comprises the 27 EU nations plus Iceland, Liechtenstein, and Norway—where no mutual recognition agreement with the EU is in effect and where a plant has not been inspected for GMP compliance in the last three years by “an EEA-competent authority.”

That rule will likely hinder new biosimilar activity in nations outside the EEA: Albania, Belorussia, Bosnia and Herzegovina, Croatia, Kosovo, Macedonia, Moldavia, Montenegro, Serbia, and Ukraine. While these nations may lack the EU’s volume of drug activity, they are hardly out of the business. Generic drugmaker Actavis, set to be acquired by Watson Pharmaceuticals for €4.25 billion (around $5.6 billion), is Serbia’s third-largest manufacturer thanks to a production plant there. In January, Actavis won an exclusive license to commercialize recombinant human insulin developed and manufactured by Polish firm Bioton in the EU and several outside-EEA countries.

EMA’s Path

EGA’s Kox believes that the procedural guidance will not further complicate the already long and complex process of biosimilar development in terms of the time and expense involved, which by her estimate is seven to 10 years and between $70 million and $200 million. EMA’s development of solid guidelines almost a decade ago followed by specific rules for different drug classes helps explain why Europe is much further along than the U.S. in bringing biosimilars to market.

EMA’s directive gives biosimilar developers more certainty and thus more of an incentive than FDA’s approach. While the U.S. agency says that it will make decisions on a product-by-product basis, it hasn’t issued specific guidelines—even in a draft format—for each product type.

Since developing a biosimilars pathway in 2005 and approving its first category of biosimilars a year later, EMA has developed biosimilar guidelines for nine categories of medicines. It progressed from recombinant human insulin to larger molecules including recombinant erythropoietins, mAbs, recombinant interferon beta, recombinant follicle stimulation hormone, and most recently, interferon beta.

FDA, by contrast, is still reviewing comments on its first draft guidance. Today, the agency is holding a public hearing on the matter. Big pharma has already come out as opposed to FDA’s proposals: Abbott has petitioned FDA to reject biosimilar applications for reference products approved before President Obama’s health law took effect on March 23, 2010. It argues that approval would be an unconstitutional taking of trade secrets involved in reference products. When the draft guidances are finalized, the U.S. will start playing catch-up on biosimilars. Till then, Europe will remain ahead of the U.S.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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