On March 23, 2010, some four decades after the modern US healthcare reform debate began, comprehensive reform provisions were
signed into a law. Among thousands of pages of legislative text are the most extensive and potentially farthest-reaching amendments
to the statutory provisions governing biologics in the 65-plus-year history of Section 262 of the Public Health Service Act
(PHSA), pursuant to which the US FDA approves biologic license applications (BLAs). Those PHSA amendments—set forth in Title
VII, Subtitle A, of the healthcare reform law and known as the Biologics Price Competition and Innovation Act (BPCIA)—are
the culmination of a 14-year debate. That debate began in earnest in 1996, when the FDA adopted its original comparability
guidance and, three weeks later, issued its pioneering approval of the first comparable biologic, Biogen Idec's Avonex (interferon
β-1A). In licensing Avonex, the FDA allowed Biogen to rely on the results of a clinical trial of another company's interferon
β product manufactured from a different cell line in a different facility in another country—reliance that the FDA's expert
reviewers determined was scientifically justified based on Biogen's demonstration that the products were "biochemically and
functionally equivalent"—without requiring Biogen to conduct any clinical trials on Avonex.
John M. Engel
Fourteen years later, the BPCIA is designed to leverage what has long been recognized as the next logical step—flowing directly
out of the Avonex comparability determination and hundreds of other comparability determinations that the FDA subsequently
rendered—by establishing a new regulatory pathway for biosimilars. Thus, under the BPCIA, a biosimilar is a biological product
demonstrated to be "highly similar" to a reference biologic from another company that the FDA previously licensed. By adopting
this approach to biosimilarity, Congress could be considered to have codified the FDA's longstanding comparability standard.
For many years, comparability has been
"[A] conclusion that products have highly similar quality attributes before and after manufacturing process changes and that
no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred. This conclusion can be
based on an analysis of product quality attributes. In some cases, nonclinical or clinical data might contribute to the conclusion."
Against this historical regulatory backdrop, the BPCIA establishes a biosimilar pathway that adds explicit, albeit waiveable,
mandates to the BLA-licensure provisions of the PHS Act for the first time in their 66-year history. Most notably, the law
establishes an express requirement that a biosimilar application include "a clinical study or studies (including the assessment
of immunogenicity...)." This contrasts with the very broad, longstanding statutory regime, which was in place throughout the
biotech revolution and that was aptly summed up in the Federal Court decision affirming the FDA's comparability determination
"Biogen and FDA acknowledge FDA's past insistence upon clinical trials of each drug being considered for approval, but they
contend that no statute or regulation requires it and submit that the use of data on "comparable" drugs is within FDA's discretion....
Neither the PHSA itself nor FDA's regulations issued under the PHSA provide that the clinical study offered to demonstrate
the safety, purity and potency of a new biological product shall have been conducted on that very product.... FDA conceded
that it had never before approved a new biological drug on the basis of a clinical study of a "comparable" drug, but FDA demonstrated
by reference to public documents that the principle of comparability was not unknown and that, in fact, it had been previously
applied in other situations."
Under the BPCIA, the statutory regime that the FDA must apply to a "highly similar" biosimilar differs significantly from
the very broad and straightforward provisions governing traditional BLAs, which make no reference to clinical trials or other
studies, and simply require a demonstration of safety, purity, and potency to secure BLA approval for an originator biologic.
Although Congress greatly amplified the detail of the requirements for what must be included in a biosimilar application,
Congress nonetheless delegated scientific responsibility for implementing those requirements to the FDA. In doing so, Congress
established what can be, on a product-by-product basis, a self-implementing pathway and one that, in all cases, defers to
the expert scientific judgment of the FDA's career reviewers in the same review divisions having responsibility for the counterpart
reference biologic BLA.