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 a November 2010
FDA hearing 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 hearing provide a good starting point for any biotechnology company to assess its strategy
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. 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.
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 Sen.
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.
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—that is, postmarket 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.