Biosimilars are new versions of existing biopharmaceuticals whose patents have expired. Currently, much debate is taking place in the industry over the efficacy and safety of biosimilars compared with the original products. In general, questions are expected from patients and physicians, who will need to be convinced about a biosimilar’s bioequivalence before they will agree to switch from a proven branded product. Regulations are clearly needed, as even minuscule differences in impurities, breakdown products or molecular conformation can have serious health implications. Biosimilars must go through clinical trials to address concerns that they might perform differently to the original product. Biosimilars need to demonstrate comparability to the original product, not be a “reinventing of the wheel.” Any differences to the reference drug that arise must be adequately explained.
In November 2010, the U.S. FDA held a two-day public hearing on the Approval Pathway for Biosimilar and Interchangeable Biological Products. Consumer advocates and patient support groups, pharmaceutical innovator companies, biosimilar drug development companies, drug distribution entities, clinical research organizations (CROs) and academics participated in the hearing, through which the FDA aimed to obtain input on specific issues and challenges associated with the implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The Act establishes an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) to, or “interchangeable” with, an FDA-licensed biological product. The BPCI became law in the U.S. with the passage of the Affordable Healthcare for Americans Act in March, 2010.
The hearing highlighted a diverse array of approaches and opinions on the development and licensure of biosimilars. While all parties generally agreed on the benefits of lower cost biologics, there seemed to be two differing positions on how to accomplish that. One position focused on the need to obtain sufficient preclinical and robust clinical data to ensure safety and efficacy, while the other position favored more emphasis on the demonstration of analytical similarity. Consumer groups were particularly concerned about safety and efficacy issues. It also became apparent that innovative trial designs would likely be needed to allow for a reasonably sized clinical program to be accomplished. The goal of biosimilar development is to front-load the development program with as much preclinical information as possible. This is more economical in terms of the cost of program development and also more ethical, as this approach can reduce the number/size/duration of biosimilarity clinical trials designed to show comparability rather than specifically for patient benefit. It was acknowledged that the biosimilar drug development/approval in Europe has been smooth and generally without problems, so the question was raised as to why those approved biosimilars could not enter the U.S. market with minimal additional development effort.
Emphasis was placed on the need to broaden access to proven and reliable analytical techniques and to train scientists and regulators on how to use the resulting data. Achieving these goals can be a rather challenging task, especially given the scientific and technical complexities associated with the larger and often more complex molecular structures of biosimilars. CROs are ideally positioned to address these challenges through the carefully managed application of industry expertise.
While the details of the regulatory pathway are still to be determined, the opinions expressed during the hearing should help the FDA develop guidance going forward. Special focus will likely be placed on patient safety as a top priority.
Following the FDA hearing, the European Medicines Agency (EMA) released for consultation a draft guideline on biosimilar medicines containing monoclonal antibodies. The guideline defines the requirements for medicines containing monoclonal antibodies that claim to be similar to another such medicine already marketed. The Agency has also released for consultation a related guideline on the immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. Over time, we may see the EMA release mAb guidelines for specific indication areas, such as oncology and anti-inflammatory. Carefully designed clinical trials will prove crucial in adequately defining the biosimilar’s safety profile, with guidelines offering maneuverability on the design of trials and the EMA appearing to be receptive to novel trial designs.