By James DeGiulio --
Earlier this month, we reported that a major issue discussed at the Food and Drug Administration's public hearings on the implementation of the Biologics Price Competition and Innovation Act (BPCIA) concerned the standards that the FDA will require for clinical testing of biosimilars (see "Clinical Trial Requirements Are Top Issue at FDA Hearings on Biosimilars"). Balancing patient safety with allowing biosimilars to enter the market without cost-prohibitive extensive testing will likely be a major issue for the FDA to unravel going forward. However, other topics at the hearings materialized as innovators, biosimilar advocates, and patient groups argued their positions, hoping to influence the FDA panel charged with the arduous task of figuring out how to implement the BPCIA.
Reviving a form of the data exclusivity debate that raged prior to passing of the BPCIA, patient and consumer groups warned that strict interpretation of the 12-year exclusivity provision would create a problem similar to the "evergreening" phenomenon observed under the current Hatch-Waxman scheme. At issue is the interpretation of the scope of the exclusivity provision, specifically how broadly or narrowly it should be read to cover inevitable changes to the biologic. Innovators argue that the exclusivity provision should be read literally, thus granting a new data exclusivity period to products with any structural differences that result in any change in potency, purity, or safety. Patient groups warn that some flexibility must be applied or the new exclusivity period for minor alterations would continue to be a barrier to biosimilar market entry.
Naming issues and pharmacovigilance were also a matter of debate at the FDA hearings. Innovators supported the approach of the European Medicines Agency (EMA), which endorses an International Nonproprietary Name (INN) system that requires biosimilar products be assigned a unique name that is globally recognized as distinct from the reference product. Although the EMA does not have authority to require unique INNs, innovators noted that the system which combines unique INNs and use of trade names has resulted in unique naming. Patient groups did not suggest any specific approach to approval standards and naming for biosimilars, instead emphasizing the need for patient and doctor education about product differences so as to avoid confusion and enable informed choices. Biosimilar proponents argued that the current FDA National Drug Code and lot numbers could be better used to track adverse events than INNs, and INNs would make insurer coverage more difficult because they are unnecessary and confusing. While there were decisive splits of opinion on naming issues, both sides agreed that harmonization with foreign regulations should be accommodated whenever possible, not just with pharmacovigilance and naming systems but with all aspects of the new regulatory standards.
Also of concern to the FDA panel was the issue of "drift," or post-market changes to the reference product due to changes in manufacturing. Since the reference product and the biosimilar would experience drift separately, the panel expressed doubt regarding whether interchangeability would ever be totally feasible. Batch-to-batch variation, differences in manufacturing methods, and the use of different cell lines could lead to a departure from biosimilarity and clinical equivalence over the life of the products. Innovators suggested that the problem of drift could be best controlled by high interchangeability standards. Biosimilar proponents argued that drift could still be addressed with lower interchangeability standards, as the FDA already performs comparability studies to approve process changes for currently marketed reference products. Use of a parallel system could be used to approve biosimilars.
Neither the standards for clinical trials or these secondary issues seem to be close to resolution by the FDA. When asked for a prediction for decisions on the new biosimilars regime, FDA Commissioner Margaret Hamburg was non-committal. "It's a complex challenge. I can't put dates on our timelines for implementation." Indeed, according to a recent Reuters report, most experts agree it could take at least five years for new biosimilars to emerge. It may take months or years for the FDA to finalize its approval pathway, and the earliest guidelines will likely to be issued on a case-by-case basis. As the issues addressed in the FDA hearing are still far from resolution, the companies who are aggressively advocating their positions to the FDA are most likely to influence favorable implementation of the new pathway. Some of the industry stakeholders voicing their opinions at the FDA hearings included Pfizer, Roche, Merck, Novo Nordisk, Novartis, Amgen, Shire, and Teva.
Readers who are interested in reviewing the recordings or transcripts of the two-day FDA hearings in their entirety can do so here.