As we enter the brave new world of biosimilars, the first obstacle for FDA and the industry will be developing the approval standards. Although the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) creates an approval pathway for biosimilar and interchangeable biological products, it provides little guidance as to its implementation. As the FDA hearing this past November made clear, there is no general consensus as to the proper standards for biosimilarity and interchangeability, or even a consensus as to how and when those standards should be created (1).

Given the significant safety and efficacy issues involved in biologics, these standards will determine the impact the BPCI Act has on the biologics industry. Those biosimilar companies who go to FDA early and often and who can effectively advocate for the desired approval standards for particular products will be the ones who are initially successful in this nascent industry.

The issues highlighted by the November 2010 hearing provide a good starting point for any biotechnology company to assess its strategy going forward.

First, and perhaps most significant, FDA seems to be undecided in its approach to issuing guidance documents for approval standards. Specifically calling back speakers to answer the question, the November panel sought opinions on whether it should seek to first issue guidance documents of a more general nature rather than of a product-specific nature. "Innovators"—that is, the companies that make the original reference product—advocated for issuance of broadly-applicable guidance documents and a stay of approvals until such documents are issued. On the other hand, those companies interested in seeking biosimilar approvals advocated for product-specific guidances as well as standards on a case-by-case basis. FDA's willingness to accept suggestions in this area shows that early advocacy for the desired approval standards will likely influence the ultimate biosimilars landscape.

Exclusivity

Possibly equally significant, FDA sought comments at the November hearing on interpretation and implementation of the exclusivity provision of the BPCI Act. The representative from Knowledge Ecology International as well as a representative for US Senator Bernard Sanders (I-VT) pointed out that the provision may violate Article 20 of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects by forcing duplicative studies instead of allowing reliance on innovator data. Consumer groups and biosimilar proponents expressed worries of the potential for evergreening, encouraging stringent standards for determining when a modification to the structure of a reference product results in "a change in safety, purity, or potency" sufficient for eligibility for a second 12-year exclusivity provision. This position was directly contradicted by innovators who argued that any change in safety, purity, or potency (improvement or otherwise) is sufficient for new exclusivity under the Act.

If the BPCI Act generously grants new exclusivity to minor structural changes in reference products, this could effectively negate the provisions of the Act allowing for follow-on biosimilar products. If innovators use this provision, as the hearing suggests they might, to keep on-the-market products under successive 12-year exclusivity, biosimilars will not be able to effectively come to market as a follow-on product.

Interchangeability

The most stark line of division with regard to approval standards between innovators and biosimilar proponents at the hearing was the respective views on the appropriate standards for interchangeability. Innovators stressed "product is process" to argue that interchangeability was simply not feasible at this time. They also asserted that interchangeability should be demonstrated for all indications, given that doctors and insurers would likely treat interchangeability in that manner. The panel expressed concern about the problem of drift—post-market changes to the reference product caused by manufacturing changes. The panel asked whether interchangeability could ever work given that the two products would change separately.

While innovators shared this worry, biosimilar proponents used drift to advocate for lower interchangability standards —because FDA already does comparability studies to approve process changes for already marketed reference products, it should be able to similarly approve biosimilars. One interesting proposition put forward was the possibility of a postmarket system for interchangeability, which would rely on strong pharmacovigilance and reporting to allow biosimilars to achieve interchangeable status after the product can be observed on the market.

The issues underlying interchangeability were emphasized by the concerns of patient-interest groups. These groups stressed opposition to allowing substitution of reference product for "interchangeable" biosimilars at any point prior to the patient-doctor decision. Above all, they stressed the importance of patient and doctor education, and the ability to make informed choices.

The issues presented at the hearing regarding interchangeability suggest that this is going to be the biggest battle for biosimilar proponents. Those who plan on seeking interchangeable status need to focus their efforts on advocating for approval of interchangeability and may choose to stress product-specific interchangeability before advocating for more general standards. The key for companies planning to develop products to meet interchangeability standards will be to develop robust scientific data to support such a determination by FDA.