INNsight article by Michael Swit & Alan Klein, August 2014

Although biosimilars, highly similar versions of living cell-based biologic medicines, have been widely available to European patients for close to a decade now, their pathway in the United States has not been equally successful. Spurred by the enactment of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), a route for approving highly similar versions of brand name reference listed biologics became available to those companies – many from the traditional small molecule generic drug industry -- that seek to compete in this higher margin and less crowded marketplace.

In this article, we will report on the recent announcement that FDA has accepted biosimilar applications for two different branded biologics, Neupogen® and Remicade®, and what that development portends, especially on the nature of the data needed to demonstrate that a biosimilar is highly similar to the branded product. We also will review the controversy over the naming of biosimilar products and highlight several recent FDA guidance documents impacting the nascent U.S. biosimilars industry.

FDA Receives First Two Biosimilar Applications

In July, Novartis’ generic drug unit, Sandoz, announced it had submitted an application – and FDA had accepted it for filing – to secure approval of a biosimilar version of Amgen’s Neupogen® (filgrastim), indicated to prevent infections in certain cancer patients. Sandoz’s filgrastim biosimilar already is marketed in dozens of foreign countries under its own brand name of Zarzio®.

Soon after Sandoz announced its application, Celltrion, Inc., a Korean company, proclaimed that FDA also had accepted its application for a biosimilar version of Johnson & Johnson’s blockbuster monoclonal antibody product, Remicade®, used to treat such conditions as ulcerative colitis, Crohn’s Disease, rheumatoid arthritis, and plaque psoriasis. As with Sandoz’s biosimilar product, Celltrion’s is now widely available outside the U.S. under its own trade name of Remsima®.

Unfortunately, many unanswered questions remain about the content of these biosimilar applications as neither the industry nor the public have access to the applications themselves and cannot, for example, determine what kinds of supporting scientific and clinical trial data were submitted to show that the biosimilars were highly similar to the reference products. However, in sifting through available information on the two applications, it appears that the two applications may contain different types of clinical data to prove biosimilarity.

For example, Sandoz had announced in 2012 that its study to support U.S. approval would involve a Phase III study to evaluate the efficacy and safety of its filgrastim versus Amgen’s Neupogen® in breast cancer patients eligible for myelosuppressive chemotherapy treatment. Indeed, a study consistent with that description is listed as completed on ClinicalTrials.gov.

In possible contrast, Celltrion’s August 11 press release on its filed biosimilar application for Remicade® suggests that Celltrion may have taken a different data route to its U.S. biosimilar application, stating that the company:

“ … conducted additional clinical trials (starting on October 2013 and lasting 6 months) to determine the bioequivalency of the originator products with Remsima®. Specifically, Celltrion tested for Pharmacokinetic/Pharmacodynamic (PK/PD) equivalency and safety equivalency for the three distinct products, the originator products sold in the US, the originator products sold in Europe, and Remsima®. These additional clinical trial data, along with Celltrion’s established global clinical trial data, were submitted to the US FDA by Celltrion as part of its application.”

Of course, based on the little public information available, we cannot now reach any clear conclusions about the total data packages included in the two applications and how they differ. For example, Sandoz has not stated – at least publicly to our knowledge – whether its FDA filgrastim biosimilar application contains data similar to that described by Celltrion. And, based on past Celltrion press releases, Celltrion has conducted extensive clinical studies, including Phase III studies, on its Remsima® biosimilar. Thus, those interested in the U.S. biosimilars pathway should continue to monitor future revelations on the contents of these biosimilar applications closely, in particular to see whether and to what extent FDA will grant an approval based more heavily on data first filed in overseas applications and also the nature of any bridging studies that the agency required, as well as under what circumstances FDA will expect a new Phase III study of the biosimilar.

Exclusivity for Branded Biologics Under BPCIA Explored In FDA Draft Guidance

When Congress enacted the BPCIA, the branded biologics industry secured, as both a retroactive reward for past innovation and an incentive to continue to expend the vast resources (both financial, human, and otherwise) required to bring effective biologics to the market, a 12-year period of market exclusivity during which no biosimilar application can be approved by FDA that references the biologics licensing application (“BLA”) enjoying that exclusivity. In addition, a biosimilar application cannot even be submitted to FDA during the first four years of the exclusivity period.

A key issue Congress tried to address in the BPCIA in creating this form of non-patent market protection was fears that the branded industry would attempt to secure additional periods of exclusivity via changes to applications that some might regard as not sufficiently robust as to warrant additional non-patent protection. Perhaps not surprising with the announcement of the filing of the Sandoz and Celltrion biosimilar applications, FDA earlier this month issued a draft guidance on “Reference Product Exclusivity” for branded biologics.

The new draft guidance details FDA’s current thinking, in particular, on how to define the “date of first licensure,” the triggering language for dating the 12-year exclusivity period. To address, this the guidance focuses on whether a later application by the same sponsor represents a significant enough modification in the structure of the original biologic product as to spawn a new 12-year period of exclusivity. In exploring that issue, the draft guidance focuses on two key issues. First, to block a biosimilar application, the current BLA holder either must be the same as the original BLA applicant that secured the first approval or be a successor in interest that FDA recognizes as legitimately entitled to enjoy the original applicant’s exclusivity. Second, to find a new period of exclusivity for that same applicant, FDA will have to find that the structural modification would result in a “change in safety, purity, or potency” of the originally licensed biologic.

With comments on the guidance due by October 6, industry should review the draft guidance with care because, once finalized, while not technically binding on industry, it will represent FDA’s “best advice” on how it will implement the powerful exclusivity provisions of the BPCIA.

“Naming” of Biosimilar Ingredients Remains a Hot, But Unresolved, Topic

With two biosimilar applications under review, FDA, perhaps as soon as the first quarter of 2015 (10 months from about when the Sandoz biosimilar application was likely submitted and assuming no review issues arise delaying FDA’s review), also will need to resolve a very hot issue – “naming” – i.e., what format FDA will allow/require for the non-proprietary name of the biosimilar product.

Biosimilar applicants generally are advocating for FDA to use the same non-proprietary name as the innovator. The branded industry, not surprisingly, opposes this for many reasons including the simple assertion that, because the biosimilar ingredient is not the same, but highly similar, to the brand name, it would be misleading for the biosimilar to use the same non-proprietary name as the innovator. Other factors cited by opponents of identical naming conventions include complications in processing adverse events and the potential that a biosimilar would be substituted for an innovator at the pharmacy level even though FDA had not found the two products interchangeable under the BPCIA.

So far, FDA has not tipped its hand on this issue and, if past practice in other arenas is an indication, the agency may not announce its decision until the same day as it approves a biosimilar as FDA is under no duty to act until then. However, as the INN, the international body responsible for naming of drugs, is also reviewing the question of biosimilar naming. If the INN reaches a conclusion before FDA approves either of the two pending biosimilars, the INN’s approach could put pressure on FDA to reach a similar decision (although FDA has not always followed foreign approaches on similar issues).

FDA Issues its Guidance on Immunogenicity Assessments for Therapeutic Protein Products

Earlier this month, the FDA issued a final guidance document designed to assist therapeutic protein product makers, and, by implication, manufacturers of their biosimilar counterparts, in identifying and reducing safety risks from the use of their products. The final guidance focuses on patient-specific and product-specific factors affecting immunogenicity, which is defined by the agency as “the propensity of the therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events.” Exploring ways in which biologics sponsors can reduce the likelihood that their products will generate an immune response from patients, FDA suggests specific risk mitigation strategies to avoid anaphylactic and other adverse events that have resulted in sponsors terminating the development of potentially useful and necessary medicines. Developers of biosimilars will need to review the entire guidance with care to determine how to best incorporate its recommendations into their product development plans.

Conclusion

Even though two companies have now broken the drought in the filing of biosimilar applications at FDA, many issues remain. FDA still has not provided guidance on how a biosimilar applicant can satisfy interchangeability, especially the statutory language that dictates that interchangeability be proven for “any given patient,” which could be read to require studies in all the approved indications for a brand name biologic (e.g., Remicade® has eight different indications). Meanwhile, even though an interchangeable biosimilar is probably years away, efforts persist in certain American states to impose restrictions on how any such interchangeable biosimilar can be substituted for its reference product. Meanwhile, the agency’s draft guidance on clinical pharmacology, issued in May 2014, was lambasted in comments filed by BIO, PhRMA, and various innovator companies, showing that the biosimilar battles will continue to be played out on every possible front.

Michael Swit & Alan Klein
August 2014

MASwit@duanemorris.com
AKlein@duanemorris.com