Biosimilar Development Continues to Challenge FDA and Industry

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Despite considerable investment by biotech manufacturers in developing competitive biologics for the US market, gaining FDA approval of these products has turned out to be a slow and complex process.

Despite considerable investment by biotech manufacturers in developing competitive biologics for the US market, gaining FDA approval of these products has turned out to be a slow and complex process. Now with one approved biosimilar under its belt, and dozens more under review and in development, FDA’s biosimilar regulatory and approval program has moved “beyond the finish line,” says Steven Kozlowski, director of the Office of Biotechnology Products (OBP) in the Center for Drug Evaluation and Research (CDER). But there still is “a lot more road to travel,” he commented, outlining some of these challenges at the October “Biosimilars 2015” conference sponsored by the Drug Information Association (DIA).

As of September 2015, FDA had received six biosimilar applications to reference products, the latest filed in early October, and one has been approved-Sandoz’ Zarxio (filgrastim-sndz). Of equal importance, some 57 biosimilar products for 16 reference products are enrolled in FDA’s Biosimilar Product Development program, and sponsors are seeking preliminary advice on another 27 projects.

Yet only one biosimilar on the market five years after Congress authorized biosimilar marketing seems slow progress to many observers. Several applications have been under review at FDA for nearly a year, raising questions about whether the US program requires more data than necessary to demonstrate product comparability. The European Union has authorized nearly 20 biosimilars since 2006, providing strong evidence that biosimilars can meet regulatory standards and can play an important role in expanding patient access to needed medicines.

A related question is whether CDER and other FDA offices have sufficient resources to provide extensive advisory services for sponsors and to evaluate these products efficiently, following a process that emphasizes analytical comparability of a biosimilar to a reference product. The Biopharmaceutical Products User Fee program is up for renewal in 2017, and FDA is holding an initial public meeting in December to launch negotiations with manufacturers on the fee structure and other aspects of the program; of note is its unique feature of requiring sponsors to pay a portion of the biosimilar application fee upfront to support extensive agency assistance to sponsors on shaping R&D programs.

Emphasizing analytics

Biosimilar development in the US looks for extensive use of analytical tools to demonstrate biosimilarity and an absence of clinically meaningful differences between the proposed product and its reference drug, as opposed to independently documenting safety and efficacy. To this end, FDA has finalized guidances outlining key scientific and quality considerations for manufacturers to document, following a step-wise approach that emphasizes structural and functional product characterization and identification of critical quality attributes. The aim is to limit animal and clinical studies to only those needed to eliminate residual uncertainty in the product’s safety and efficacy, using risk assessment to rank the importance of different measures for ensuring similarity.

FDA officials and industry experts discussed strategies at the DIA conference for reverse engineering the reference product, starting with characterization of primary attributes to develop the expression construct and cell line to match host cell proteins. This approach applies to both upstream manufacturing and downstream purification to develop a formulation with a comparable stability profile. While the current objective is to develop highly similar biological products, an ultimate goal is for products to achieve fingerprint-like similarity, which would set the stage for regulators to determine a new therapy interchangeable with a reference product, a contentious topic that awaits clarification in further FDA guidance.


The agency also plans to publish guidance on appropriate statistical analysis of production data and results from pharmacologic and clinical studies. Kozlowski explained that rigorous statistical analyses will be part of the evidence submitted by a sponsor to document biosimilarity, but that such calculations won’t support yes-no approval decisions by themselves. Sponsors currently find statistical analyses helpful in identifying important product attributes and the impact of batch variability as part of internal development programs.

These analytical strategies should help manufacturers weigh “how close is close enough” for a biosimilar and reference product. Minor differences in protein sequence may be acceptable if sufficiently justified and demonstrated to have no impact on product safety, efficacy, purity, or potency, Kozlowski explained. Further analysis may help determine if it is acceptable, say, for expression systems to have different impurities or for excipients to vary. Risk assessment is important in assessing which quality attributes are most important for ensuring product quality and similarity, and those that do not matter as much.

Global alignment

In addition to refining US requirements for biosimilar development, FDA officials are engaging with regulatory colleagues in establishing common standards and regulatory proposals to support global biosimilar development. A Biosimilars Cluster seeks “scientific alignment” of policies and development issues for FDA, the European Medicines Agency (EMA), Health Canada, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Similarly the Biosimilars Working Group of the International Pharmaceutical Regulators Forum (IPRF) periodically discusses issues and challenges in regulating biosimilars in these countries plus South America, Asia, and other regions.

These efforts are important in facilitating development of biosimilars in multiple markets, as manufacturers seek to use certain data generated outside the US to support FDA product approval. A main issue for FDA is whether sponsors may use a non-US-licensed comparator in studies to support US licensure, noted Leah Christl, associate director for therapeutic biologics in CDER’s Office of New Drugs, at the DIA conference. Manufacturers may seek “parallel scientific advice” from FDA and EMA, says Christl. For now, FDA and other authorities are striving for “alignment” of scientific concepts, as it may not be possible to “harmonize” policies and advice to sponsors in many cases.