The Biologics Price Competition and Innovation Act (“BPCIA”), which was intended to provide an abbreviated pathway for FDA approval of “follow-on,” or “biosimilar,” biological products, has encountered many hurdles since its passage in 2010. Perhaps the largest of these hurdles derived from the fact that the BPCIA was buried within the Patient Protection and Affordable Care Act (“PPACA”), colloquially known as “Obamacare.” On June 28, 2011, however, the Supreme Court rejected a constitutional challenge to the PPACA in a 5 to 4 decision. See Nat’l Fed’n of Independent Business et al. v. Sebelius, 567 U.S.___(2012). While the Supreme Court had other issues than biologics/biosimilars in mind when it upheld the PPACA, the Court’s ruling nevertheless clears the way for renewed interest in this area.

Another hurdle to implementation of the BPCIA was cleared on February 9, 2012, when the FDA issued three documents providing Guidance for Industry regarding the BPCIA. These are draft guidances only, and are subject to revision following a public comment period that ended on April 16, 2012. FDA held a public hearing to discuss the guidance documents and comments on May 11, 2012, at which patient advocates, along with representatives of biosimilar and innovator companies, voiced their comments, criticisms and suggestions regarding FDA’s proposals. In their current form, the three guidance documents leave many important questions unanswered, yet they also provide a first glimpse into how FDA will approach its task of approving applications for biosimilars under the BPCIA.

Pursuant to the BPCIA and the proposed FDA guidance, biosimilar applicants in the U.S. must consider a number of factors when determining whether this allegedly “abbreviated” approval pathway makes sense, including:

• Approval date of the Biologics License Application (BLA) for the reference product sponsor
• Marketing exclusivity expiration for the reference product
• Patent(s) expiration for the reference product
• Structural complexity of the reference product and the ability to properly characterize it from an analytical standpoint
• Immunostimulatory and clinical effects of the reference product, including side effects
• Existing and anticipated regulatory barriers, with inherent risks and costs, including the existing threshold for establishing “biosimilarity” (and perhaps, at a later date, interchangeability”)¹
• Manufacturing costs
• Transferability across indications
• Market approval of the reference product and/or biosimilar versions of the reference product in other countries
• Use of data (especially clinical data) from an equivalent non-U.S. licensed biosimilar product
• Anticipated competition, whether in the U.S. or globally
• Launch of second- or third- generation products in the same class.

The relevance of these factors will differ depending on the biological product at issue. For this reason, we believe it is helpful to categorize biosimilars into three rough classes: (1) Existing Biosimilars; (2) Emerging Biosimilars; and (3) Late-Stage Biosimilars.

Existing Biosimilars
At least initially, it seems logical that the BPCIA approval pathway will be most attractive for companies intending to make biosimilar products that correspond to “older” reference products. These biologics, such as erythropoietin (EPO) and granulocyte colony stimulating factor (G-CSF), typically received market approval in the 1980s or 1990s, and many are already off patent, at least with respect to the active ingredient and first-generation products. For molecules within this class, a BLA was typically sought and obtained by the reference sponsor many years ago, and thus any remaining regulatory exclusivity, even under the BPCIA, is likely to be minimal or nonexistent.

Furthermore, while complex relative to small molecule drugs, these particular biologics are generally considered to be well understood and readily characterizeable. Thus, the financial burden of establishing biosimilarity is expected to be low as compared to more complex molecules, and presentation of robust comparative structural data from the biosimilar applicant will likely obviate the need for expensive animal or clinical studies. As FDA has stated in its recent guidance, “The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies.” Thus, if there is little “residual uncertainty” about a biosimilar from an analytical standpoint, the need for extensive animal or clinical studies will be significantly reduced, and, in some select cases, perhaps eliminated altogether.

Finally, many of the “existing biosimilars” are so named because they have already received approval as biosimilars in other countries or regions, particularly Europe. As of this writing, for example, the EMA has approved two biosimilar somatropin products (recombinant human growth hormone), five biosimilar epoetin alfa or zeta products (red blood cell stimulating factor), and seven biosimilar filgrastim products (white blood cell stimulating factor). FDA’s recent guidance indicates that data derived from animal or clinical studies comparing a proposed biosimilar product with a non-U.S. licensed product may be used if the sponsor can provide “adequate data or information to (1) scientifically justify the relevance of the comparative data to an assessment of biosimilarity and (2) establish an acceptable bridge to the U.S.-licensed reference product.” Furthermore, FDA “encourages” applicants to discuss whether the use of such data is appropriate for a given product. Thus, if FDA holds true to its word, BPCIA applications for this class of “existing biosimilars” are likely to be an attractive option.

Emerging Biosimilars
Unlike the category of existing biosimilars described above, “emerging biosimilars” have few or no approved biosimilar counterparts in Europe or other countries. Examples of such products include insulins² and interferons. Consequently, while there may exist biosimilars guidelines for these products in other countries, they have yet to be successfully utilized by follow-on companies. Nor is there any immediately accessible comparative clinical data for these products in Europe that might help facilitate FDA approval for a U.S. biosimilar applicant.

The reference products for emerging biosimilars also frequently have a substantial remaining patent term and/or have only recently received FDA approval. Companies considering biosimilar applications for this category of products must therefore perform a cost-benefit analysis in light of the BPCIA framework. In particular, applicants will need to consider how much data exclusivity remains on the reference-listed product. Under the BPCIA, a follow-on biologic application may be submitted four years from the date on which the reference product was first licensed by the FDA, but no follow-on biologic application may be approved until 12 years from that date. In addition, “emerging biosimilar” applicants must be aware of the possibility of patent term extensions obtained by the innovator.

For emerging biosimilars, then, important questions to consider include:

• Can the patents covering this class of biologics be avoided by developing alternatives to the originator product?
• Is it possible to manufacture the biosimilar product in a different system than that of the reference product to circumvent innovator patents?
• If patent obstacles are circumvented, might that also make it more difficult to establish biosimilarity for these products?
• Should a full-blown BLA be filed in lieu of pursuing the abbreviated regulatory pathway?

If FDA requirements for emerging biosimilars turn out to be too onerous (especially in the area of clinical and immunogenicity testing), then the BPCIA route may be viewed as less attractive — and not much less expensive — than the more established BLA route. Further, the time restrictions for filing a Section 351(k) application under the BPCIA, as compared to a BLA, may also make the BLA more desirable. A BLA can be filed at any time, whereas an “abbreviated” application under the BPCIA cannot be filed until four years after the first approval date for a reference product. Equally important, a new BLA would avoid the patent identification/litigation “dance” currently built into the abbreviated pathway, a dance which few seem to understand or believe will be manageable as currently structured. Follow-on companies must remember, however, that filing a BLA will not eliminate patent challenges altogether, nor will it necessarily guarantee that FDA will consider the application a “true” BLA instead of a follow-on application under the BPCIA.

Developers of emerging biosimilars already appear to be alleviating the financial and time constraints associated with approval by collaborating with, on the one hand, large pharmaceutical companies that can provide financial support, and on the other, specialty biotechnology companies that can provide technical expertise, for example, with respect to manufacturing. Ultimately, companies pursuing emerging biosimilars will likely choose market entry in developing countries – such as India or China – before embarking on the BPCIA pathway in the United States. See, e.g., Ranbaxy Puts Biosimilars Into Gear, available at http://reut.rs/MfS88W (last accessed August 3, 2012). In those countries, given significantly lower regulatory barriers and development costs, biosimilar development is and will remain very attractive.

Late Stage Biosimilars
Many of the leading biologic drugs currently on the market in the U.S. are monoclonal antibodies, such as Avastin (bevacizumab), Herceptin (trastuzumab), Humira (adalimumab), Remicade (infliximab), and Rituxan (rituximab). Monoclonal antibodies are extremely large molecules with considerable microheterogeneity. Not only does this mean that they are difficult to purify and characterize, but also even small changes in amino acid sequence, local structure, or post-translational modification can have significant functional or immunological consequences.

On May 30, 2012, the EMA issued final guidelines for approval of biosimilar monoclonal antibodies. See Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues, available at http://bit.ly/OUT9m9 (PDF, last accessed August 3, 2012). These guidelines, which go into effect on December 1, 2012, appear to be more stringent than those in place in Europe for other classes of biosimilars. One can expect that the threshold in the U.S. for establishing biosimilarity for a given monoclonal antibody will be equally stringent, if not more so. Furthermore, late-stage biosimilar applicants must be aware that there may be secondary patents for manufacturing and purification processes of monoclonal antibodies that will likely present additional barriers to entry, regardless of which approval pathway is ultimately chosen.

With late-stage biosimilars, use of the BPCIA framework seems unlikely in the immediate future, at least until FDA becomes more comfortable with approving biosimilars generally. The counterweight to this, however, is that many of the monoclonal antibody biologics on the market are precisely the kind of “blockbuster” drugs that follow-on companies feel will be economically worth trying to copy, irrespective of cost. See, e.g., Dr. Reddy’s Plans to Launch Biosimilars in Developed Markets, available at http://bit.ly/Tbuv1t (last accessed August 3, 2012).

The Path Forward
Even in the case of the biosimilars that are most likely to hit the U.S. market first (“existing biosimilars,” described above), applicants will likely seek closure from FDA on a few important topics before moving forward with an application. These topics include: whether they may use non-U.S. reference product data in their applications; whether they can truly submit to FDA a reduced package of human and animal testing; whether they can obtain the same INN name as the innovator product; whether they can skip over any of the “steps” in FDA’s “stepwise” approval process; and perhaps most importantly, whether they can ultimately achieve “interchangeability” status for their product.

Innovators will also likely seek to clarify their rights under the BPCIA, the FDA’s authority pursuant to the Act, and the meaning of FDA’s proposed guidance documents. A good example of this is Abbott’s recent citizen petition challenging FDA’s authority to approve a biosimilar for any product for which a Biologic Licensing Application (“BLA”) was filed before the enactment of the BPCIA on March 23, 2010. See Abbott Asks FDA to Refuse Certain Biosimilar Applications, available at http://bit.ly/RRvilH (last accessed Aug. 3, 2012).

There is no way to escape the competing levers that drive the BPCIA, be they regulatory, economic, patent-law, or policy-based in nature. In the end, however, raw economics should drive the BPCIA inexorably forward so long as it does not stunt innovation — this, after all, is what Congress presumably intended by burying the BPCIA within the “Affordable Care Act” in the first place. 

References

1. Many had wondered whether FDA would include in its guidance documents a roadmap for an applicant to demonstrate that its product is “interchangeable” with the reference product. FDA has largely skirted the issue, however, stating in the guidance that all applicants must first show biosimilarity before they can hope to show interchangeability.
2. Some insulin products do not fit into the BPCIA framework for “biological products” (which is part of the Public Health Service Act), but instead are considered “drugs” under Section 505 of the Federal Food Drug and Cosmetic Act. However, this distinction will expire over time. See BPCIA, Sec. 7002(e).

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Elizabeth Spar, PhD., is also an associate at Edwards Wildman in Boston. Her practice is concentrated on intellectual property and patent law, including drafting patent applications in the fields of molecular and cellular biology, immunology, antibodies, RNAi, biologics, biosimilars and related industries. She can be reached at [email protected]. Tom Wintner, M.A. is an associate at Edwards Wildman Palmer in Boston, where his practice is focused on patent litigation in the life sciences, with emphasis on pharmaceuticals, as well as in the area of biologics. He can be reached at [email protected].