Regulation of Follow-on Biologics: Ensuring Quality and Patient Safety

In the wake of health care reform legislation, there continues to be widespread concern about the upward spiral of the cost of prescription pharmaceuticals, par- ticularly for biologic products used to treat patients with debilitating conditions that are unresponsive to tradi- tional therapies. We in the medical community share this concern and have taken a keen interest in The Patient Pro- tection and Affordable Care Act (PPACA 2009) with re- spect to generic biologics, also called follow-on biologics (FOBs) or biosimilars.

Although the PPACA is clear about periods of exclu- sivity for innovator biologics and the first-approved FOB products, it is less prescriptive about the regulatory path- ways and approval criteria for these agents. In fact, the U.S. Food and Drug Administration (FDA) has been given considerable latitude and flexibility in fashioning these processes; for example, the PPACA has no requirement for the publication of guidance (i.e., serious scientific re- view) with respect to the interchangeability of biosimi- lar products.

Moreover, although the PPACA requires FDA applica- tions to demonstrate the similarity of FOBs with reference products in terms of safety, purity, and potency in treat- ing one or more of the conditions for which the reference product is licensed, it permits the Secretary of Health and Human Services to determine that elements in the application, such as clinical studies, are unnecessary. Given the myriad unresolved scientific issues (e.g., ther- apeutic equivalence, bioequivalence, pharmaceutical equivalence, immunogenicity) surrounding these very complex products, these potential loopholes raise some concerns.

Uncharacteristically, the United States lags behind the rest of the world in the regulation of FOBs. There are al- ready some excellent prototypes. The European Medi- cines Agency (EMEA) is the front-runner, and its ap- proach makes a great deal of sense. The EMEA has adopted a set of general guidelines and developed specific criteria for each distinct biologic class as opposed to a sin- gle FOB process. All guidelines and criteria are dissemi- nated for public comment before rulings are issued. The EMEA has produced guidance for five to six specific prod- uct classes that are currently approved in the United

States as drugs (e.g., insulin, epoetin alfa, low-molecular- weight heparin). Rather than “reinvent the wheel,” the FDA would be wise to give the EMEA model serious consideration as it hammers out the details of processes in the United States.

From my standpoint as a physician, the most impor- tant caveat for any regulation concerning FOBs is that pa- tient safety must always be the top priority. Since biologic drugs are extremely complex, making them difficult (and, in some cases, impossible) to replicate, isn’t it in every- one’s best interest — especially patients’ — to require that all FOBs be clinically tested for safety before introducing them to the marketplace?

I believe that the FDA should commit to focusing on the science of FOBs as opposed to seeking bureaucratic expediency. In keeping with its responsibilities for patient safety and public health, the FDA must ensure that the approval process for FOBs is science-based and trans- parent, with reasonable input from stakeholders in the scientific, clinical, consumer, payer, and health policy arenas. My advice would fall into three general domains:

• Avoid overly prescriptive regulations
• Ask everything that needs to be asked
• Make certain that the criteria adopted are appro-

priate for the specific type of therapeutic class (i.e., requiring clinical trials for safety and efficacy of FOBs in recognition that these products are not re- ally substitutable or interchangeable)

In late April 2009, I had the privilege of facilitating a policy forum at the National Press Club in Washington, D.C., entitled “Regulation of Follow-on Biologics: En- suring Quality and Patient Safety.” The forum, spon- sored by the Jefferson School of Population Health, brought together an impressive group of experts from the fields of medicine, science, economics, and health policy to discuss the quality and safety issues involved in creat- ing a regulatory pathway to bring FOBs to market in the United States. Several of the forum speakers partici- pated in a follow-up congressional briefing on the topic in November 2009.

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