On November 2 and 3, 2010, the FDA held a public hearing to obtain input on implementing the Biologics Price Competition and Innovation Act of 2009 ("BPCIA"). The BPCIA establishes an abbreviated approval pathway for biological products that are deemed "biosimilar" or "interchangeable" to previously approved reference products. Speakers at the hearing included representatives from Reference Products Sponsors ("RPS"), potential Follow-On Applicants ("FOA"), patient groups, trade groups, pharmacies, universities, and law firms. The FDA welcomed comments from stakeholders on any aspect of its implementation of the BPCIA, but specifically requested input on biosimilarity, interchangeability, patient safety and pharmacovigilance, the use of supportive data and information, the definition of a biological product, published guidance, exclusivity, transition provisions, and user fees. The hearing is posted on the FDA website (http://www.fda.gov/Drugs/NewsEvents/ucm221688.htm).

Although many would have welcomed more definitive statements from the FDA concerning its thoughts on the implementation of the BPCIA, the questions and statements from the panel of FDA representatives were neutral in content and tone. Stakeholder comments made clear, however, that there is a great deal of disagreement regarding the proper process for approving follow-on biologics. The FDA has its work cut out for it in the months ahead as it works to implement the BPCIA in the face of the widely diverging perspectives of the various stakeholders.


Not surprisingly, many speakers discussed the critical "highly similar" standard. One speaker argued that the standard applied for a manufacturing change by an RPS should also be applied for follow-on products. Another argued that a product should be considered highly similar if it falls within the range of variation observed in samples from the reference product. A third offered a more specific alternative: same amino acid sequence, same host, highly similar glycosignature, same major isoforms, and no new isoforms. In contrast, an RPS argued that the standard should be "as similar as is reasonably achievable."

The concept of "drift" also featured prominently. RPSs expressed concern that the composition of both the reference product and the biosimilar could change over time. RPSs urged the FDA not to "lock in" the reference product at a single time point.


Patient advocacy groups were generally critical of full interchangeability. One patient organization asked the FDA to bar this pathway until more was known about follow-on biologics. The group noted that biosimilars can have significantly different safety profiles, citing reports of an increased rate of aplasia in a follow-on erythropoietin product relative to the branded product. The group argued that selection of a particular biological product for a patient should be left to the patient’s doctor rather than physicians’ organizations. A general consumer advocacy group, however, argued that safety concerns might be exaggerated and outweighed by the potential public health benefits of access to cheaper biological products.

Some RPSs questioned the concept of interchangeability, arguing that interchangeability might only be feasible for small, homogeneous, functionally similar biologics. RPSs also echoed the patient advocacy groups in urging the FDA to proceed cautiously when implementing the interchangeability provisions. They asked the FDA to focus on whether the follow-on would have the same result in any given patient, and to only allow interchangeability if there were no risks inherent in alternating between the reference product and the follow-on. On this point, RPSs also advocated for extensive comparative clinical and non-clinical testing. They urged that such testing is necessary, because patient safety should be the FDA's paramount concern.

In contrast, FOAs argued, based on experiences in Europe, that patients can be routinely switched without problem. A contract research organization and at least one FOA suggested that switching safety could be demonstrated in a four-arm trial. The FDA, however, noted that such a trial would only test the effects of switching once, which appeared out of line with both the statute and current U.S. health care practices.

Clinical Testing

While most agreed that some clinical testing will be necessary for any follow-on application, many FOAs argued that the purpose of the BPCIA would be frustrated unless the clinical trial burden were substantially reduced relative to an BLA. Senator Bernie Sanders expressed similar concerns, indicating that the FDA would violate medical ethics by requiring duplicative trials. In a letter read to the FDA panel, Senator Sanders discussed his proposed bill, S3921, which would mandate that applicants be allowed to rely on existing clinical trial data, subject to paying a share of the costs that the RPS incurred in producing the data.

Some FOAs proposed that non-inferiority clinical studies with surrogate (biomarker) endpoints would be appropriate for biosimilars approval. However, at least one RPS argued that demonstrating equivalency within a predefined margin, rather than non-inferiority, should be required, at least for complex biologics such as monoclonal antibodies. There was some consensus, however, that head-to-head trials would be necessary.

The speakers diverged again on the possibility of extrapolating from one approved indication to another. FOAs urged that extrapolation should be allowed if the two indications are based on the same mechanism of action. On the other hand, multiple RPSs and at least one patient group called for a clinical trial for each key indication. One RPS conceded that extrapolation might alleviate the need for a full-blown clinical trial but maintained that treatment through the same mechanism of action should be considered a necessary, but not sufficient, condition for extrapolation.

Patient Safety and Pharmacovigilance

Patient advocacy groups and RPSs strongly advocated for a unique proprietary name for each product. They pointed to the fact that patients do not look at lot numbers but can list the names of the drugs that they are taking. Therefore, it was their position that tracking side-effects would simply not be possible unless a patient could clearly identify the biologic by a unique name. Patient advocacy groups and RPSs also asked that labels clearly state all indications for which the product is approved and all indications for which it is not.

There was disagreement over the application of International Nonproprietary Names ("INN") to follow-on products. A RPS suggested that each biologic should have a distinct INN for pharmacovigilance and tracking purposes. The speaker suggested, for example, that the name of each biosimilar could have the same stem as the reference product and have a unique suffix to distinguish it from the reference product and other follow-ons. FOAs, on the other hand, supported using the same INN for the reference product and any follow-on but using distinct trade names to differentiate the products. They argued that using different INNs would be confusing and might limit potential improvements in patient access. The FDA indicated that there could be confusion either way, i.e., whether the INNs were the same or different.

Use of Supportive Data and Information for Approval

FOAs urged the FDA to allow them to avoid duplicative trials by relying on studies comparing follow-on candidates against non-U.S. licensed products. FOAs argued that if the quality of these studies is otherwise acceptable and the foreign comparator is highly similar to the U.S.-licensed reference product, FOAs should be able to rely on them. RPSs, on the other hand, noted that "similarity" is not a transitive property: even if the non-U.S. product is similar to both the U.S. reference product and the follow-on, the latter two may not be similar to each other. One RPS conceded that such data might be acceptable for establishing biosimilarity but not interchangeability.

Published Guidance

Although the BPCIA permits the FDA to approve biosimilar applications without issuing guidance, RPSs and industry organizations urged the FDA to provide clear and general guidance as a first priority, followed by specific guidance by product class. In contrast, at least one FOA argued against general guidance, suggesting that all products should be considered on a case-by-case basis. The European Generic Medicines Association and others noted that because Europe has a four-year head start in biosimilars regulation, the FDA should use the European Medicines Agency guidelines, at least as a starting point.