As many commentators have pointed out, the biosimilar legislation enacted last year (“the BPCIA”) is short on detail, and puts the burden on the Food and Drug Administration to determine the proper regulatory procedure and standards for approval of biosimilar drugs.  The FDA has since reached out to stakeholders via hearing and requests for written comments.  Those hearings and requests have elicited a disparate — yet predictable — set of attitudes and specific proposals.  Those favoring the introduction of biosimilars emphasize the FDA’s previous experience in comparing biologics and the competitive benefits of biosimilars, whereas the developers of approved biologics emphasize instead the FDA’s duty to protect public safety at all costs.  This post discusses some of the parties’ positions in more detail.

FDA held a 2-day public hearing on November 2-3 to discuss implementation of the Biologics Price Competition Innovation Act of 2009.  The hearing announcement can be found at Fed. Reg. 75 FR 61497.

Among the issues on which FDA sought comments:

• Scientific standards for biosimilarity
• Scientific standards for interchangeability
• Specific approaches to pharmacovigilance for biosimilars
• Use of comparative data from non-licensed comparator products
• FDA definitions for “protein” and “chemically synthesized polypeptide”
• What guidances are needed by industry
• Implementation of the 12 year exclusivity period for pioneers
• The transition period under the statute for products formerly regulated under Section 505 of the FD&C Act
• User fees

Subsequent to the meeting, FDA received detailed letters from the three major trade organizations impacted by the BPCIA addressing these topics:

• The Generic Pharmaceutical Association (GPhA)
• The Pharmaceutical Research and Manufacturers of America (PhRMA)
• The Biotechnology Industry Organization (BIO)

Unsurprisingly, the GPhA’s positions would serve to minimize the burden on biosimilar applicants, while PhRMA’s and BIO’s letters argue for very rigorous standards for approval under Section 351(k).  Some of the most interesting points from these letters are summarized below.

Clinical testing for biosimilarity.  The innovator and generic communities are miles apart on the need for clinical testing to establish biosimilarity.  Neither BIO nor PhRMA acknowledges there could be any circumstances where a biosimilar could be approved without clinical testing:

BIO: “We foresee no circumstances in which an applicant of a 351(k) application would not submit non-clinical studies and clinical studies.”

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“Even if no structural differences have been detected it will be important to confirm the similarity of the biologic to the reference product using functional assays and appropriate non-clinical and clinical evaluations of the behavior of the biologic.”

PhRMA: “Given the limits of current scientific knowledge and for reasons of patient safety, PhRMA cannot envision a biosimilar product or class of products for which comparative clinical studies would be unnecessary for approval.”

In stark contrast, the GPhA opines that clinical testing “may be entirely unnecessary” if the biosimilar product is proved highly structurally similar to the reference product:

As a general principle, clinical testing should not be required to any greater extent that it is required for originator products under-going manufacturing changes, and should reflect the extent of “high similarity” demonstrated at the analytical level.  This would match the clinical experience accumulated in the literature, by the medical community and by the FDA, in the very same review divisions, from the use of the reference product over at least 12 years. ... Biogeneric sponsors, just like originators of products today, will be using highly-sophisticated analytical and validation tools that allow for detailed confirmation of the similarity of biological products.

The GPhA’s principal point is that the standard for determining biosimilarity, and indeed interchangeability, should be identical to the preexisting comparability standard used by the FDA in assessing whether changes to an approved biologic product’s manufacturing process are acceptable:

Fortunately, biologics and comparative product assessment is an area where FDA has significant experience. FDA has been evaluating originator products for biosimilarity, including the assumption of interchangeability . . . for years. This is done every time a branded biologic manufacturer changes its manufacturing process, such as making a piping modification, moving processes between buildings or adding new facilities (locally or even internationally), substituting an ingredient or even changing the master cell line. Some of these changes are quite extensive, including the case with Betaseron and Avonex where the FDA use of comparability was challenged and upheld by the courts. FDA worked with the biopharmaceutical industry to develop the original and now well established protocol for evaluating all these kinds of changes based on a time honored standard “Comparability”, and led the world into the discussion by the publication of the 1996 Guidance.

The GPhA goes on to observe that many manufacturing changes are deemed by FDA to produce a comparable product without any clinical testing.  BIO, however urges caution regarding the applicability of an analogy to comparability determinations:

Product comparability testing for intra-manufacturer changes can yield meaningful results because the innovator begins from its intimate and exhaustive knowledge of a process that has proven capable of producing a high quality, safe, and effective finished product over a period of time. Specifically, over the course of time, the innovator accumulates extensive historical data to which the biosimilar manufacturer generally would not have access. The experience of a biological products manufacturer with manufacturing a particular product provides the context within which comparability protocols – as that term is currently used by FDA – can legitimately be used.  Absent such context, the impact of any changes to the product or the process by which it is produced must be assessed differently. It is therefore incorrect to use the term “comparability” to describe the relationship between innovator and biosimilar products, as there is less assurance of continuity in process and testing methods when a different manufacturer is involved.

Moreover, there is an additional difference between when an approved product is subjected to manufacturing changes and when a potentially biosimilar product is proposed for approval.  Generally only one or a limited number of variables is changed between an approved manufacturing process, as opposed to manufacture of a biosimilar product (a) from a new DNA construct, (b) in a new cell line (c) by a new production and purification technique (d) in a new factory (e) which is assessed in a new testing environment.

Clinical testing for interchangeability.  Similar to its arguments concerning the quantum of proof to show biosimilarity, the GPhA argues that “interchangeability” as used in Section 351(k) should be addressed identically to comparability determinations that FDA now makes when innovator products undergo manufacturing changes.  Its arguments are based on fairness and economic policy:

The data burden on sponsors should also be irrespective of the traditional business model of the applicant, and an assumption of a greater degree of clinical assessment for biogenerics than is expected of originator sponsors making manufacturing changes is unfair and scientifically inappropriate.

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Without an FDA willingness, when justified with data, to designate biogeneric biologics as interchangeable to the same extent as they do today pre- and post-manufacturing changes, we can expect to see detailing wars that are a net cost for all sponsors and that must be passed on to the payors and their patients. The expectation of Congress, in enacting legislation, was for biogeneric sponsors, including both GPM members and traditional originator companies, to put price pressure on originators whose patents and exclusivity have expired, thereby forcing prices down for consumers and the government, and ensuring savings in the billions over the next decades.

Again, the originators take the opposite view.  While BIO acknowledges that with rigorous clinical testing it may be possible to grant interchangeability status, it warns that it might not always be feasible.  Taking a more extreme tack, PhRMA presents the view that proof of interchangeability under the statute is impossible given current technology:

In order to protect patients who might be prescribed biologics for which there are interchangeable biosimilars, Congress intended the interchangeability standard to be an exceptionally high standard that could be met only with an additional showing beyond that which is required to establish biosimilarity. PhRMA does not believe that this high standard can be met given the current state of the science.

 Nomenclature.  The trade organizations also disagree about the need for unique non-proprietary names for biosimilars.  GPhA argues that since products deemed comparable after manufacturing changes are not required to be separately named from the original approved product, biosimilars should not require a different name either.  BIO and PhRMA take the position that separate names are crucial to avoid inadvertent switching without doctor’s direction between non-substitutable biologics and to ensure accurate post-marketing surveillance on each biosimilar introduced.

Distinction between Sections 351(k) and 351(a).  The innovator groups are clearly worried that generic manufacturers are going to “end around” the exclusivity provisions of Section 351(k) by submitting biosimilar applications under Section 351(a) instead:

BIO: BIO believes that FDA should not allow a sponsor to choose to submit a BLA under Section 351(a) unless it fully meets the data requirements for an innovator product. Doing otherwise would eviscerate the protections for sponsors of first-generation biological products provided by Congress, undermining the careful balance of benefits and burdens that the statute reflects.

PhRMA: FDA has long and consistently taken the position that applications submitted under section 351(a) may not rely on data and findings relevant to another product — i.e., that the section requires original applications demonstrating product safety, purity, and potency. It would upset the careful balance struck by Congress between biosimilar market entry, on the one hand, and incentives for biological product innovation, on the other hand, if FDA allowed section 351(a) applications to rely on prior findings, prior approvals, or previously submitted data without consent.

 Biosimilar manufacturers have, and will probably continue to file under Section 351(a) in order to avoid the 12 year data exclusivity provision of the BPCIA and the uncertainty of the requirements for approval under the new abbreviated pathway.  But it seems unlikely that FDA will let its guard down and lower the standards for approval of a full Section 351(a) BLA.