Without a viable path for interchangeability, many companies have been hesitant to pursue biosimilars. The Biologics Price Competition and Innovation Act, therefore, hasn't lived up to its promise of lowering the cost of biological drugs. The U.S. Food and Drug Administration's newly issued guidance on demonstrating interchangeability for biosimilars essentially parrots the requirements the FDA laid out in its 2017 draft guidance.
Even with this new guidance, applicants are still facing uncertainty in demonstrating interchangeability. In order to achieve the promise of the BPCIA and increase biosimilar uptake, it is time for Congress to create an interim step to interchangeability.
When the BPCIA was created, interchangeability was the holy grail at the end of a company's biosimilar development. Interchangeability was supposed to be the great equalizer: like mandatory substitution in the small molecule space, interchangeability was supposed to keep biosimilar prices low by obviating the need to incur the cost of marketing and detailing a biosimilar product.
But uncertainty regarding what the FDA would require to demonstrate interchangeability — as well as the costs required to try and make such a demonstration — caused many companies to shun interchangeability, and in some cases the entire biosimilar pathway. The result: a relatively low number of applications with little diversity in the therapeutic agents, higher-than-expected prices for approved biosimilars and low market penetration.
In 2017, the FDA issued a draft guidance for demonstrating interchangeability for biosimilar products — a guidance that was eagerly awaited but did little to substantively assuage concerns. The FDA's newly issued interchangeability guidance changes little from 2017. The FDA is still taking a "totality of the evidence approach" and warns that its standards for demonstrating interchangeability "may vary depending on the nature of the proposed interchangeable product.”
While there has been some streamlining in its approach, the FDA is proposing roughly the same types of data and information as in 2017: (1) identification and analysis of critical quality attributes (like identity, safety, purity and potency); (2) analysis of mechanisms of action; (3) analysis of expected pharmacokinetic differences in different populations; (4) analysis of expected differences in immunogenicity risk in different populations; (5) differences in expected toxicities; and (6) information on other factors that affect safety or efficacy.
Because the complexity of a product could influence the amount of clinical data required, the FDA continues to encourage meetings with the agency early and often. A good practice in any event.
The FDA is also continuing to "encourage" the use of switching studies for demonstrating interchangeability. As in its previous draft guidance, FDA proposes what it calls a "flexible approach," the rigidity of which this author suggests an applicant adhere to closely. In the FDA's approach, the focus is on the impact of switching on pharmacokinetic and pharmacodynamic endpoints as opposed to clinical efficacy endpoints.
For products dosed more than once, the FDA recommends a two-arm study (a switching arm and a nonswitching arm) that provides at least two separate exposure periods to the two products and having a final switch from the reference product to the proposed biosimilar. The FDA continues to express its preference for data generated using a U.S. reference product.
However, the FDA is allowing submission of data using a non-U.S. comparator if the applicant provides a bridging study to "justify the relevance of the data obtained using the non-U.S.-licensed comparator.”
Finally, the FDA's guidance acknowledges that an applicant may seek licensure for fewer than all approved indications, but recommends "a sponsor seek licensure for all the reference product's licensed conditions of use when possible." The FDA does, however, provide for extrapolation of data across indications if the sponsor provides scientific justification for extrapolation in the interchangeability context.
While the FDA's guidance provides a framework, an applicant is still faced with uncertainty as to whether the FDA will accept its interchangeability showing as well as the high costs associated with making such a showing. In addition, medical professionals and payers are concerned with taking patients off of therapies that are working and moving the patient to a biosimilar; even one proven to be "highly similar with no clinically meaningful differences."
But what if we created an interim step to interchangeability that would encourage market entry and penetration of the biosimilar product, allow the applicant to still make an interchangeability showing and protect innovation?
Consider this proposal: Congress should amend the BPCIA so that an approved biosimilar is considered “interchangeable” to the reference product for treatment-naïve patients. Specifically, BPCIA could mandate that treatment-naïve patients receive the approved biosimilar product or the lowest-cost available version of the product. In either case, the reference sponsor would be able to maintain prescriptions for all patients currently on therapy, but patients new to the therapy would receive the cost benefits of an approved and “highly similar” biosimilar product. Companies would be encouraged to pursue biosimilars because they would have meaningful access to the market, and would not have to incur the costs of marketing or detailing the product. The biosimilar applicant would also have an incentive to develop data to support interchangeability while having a product on the market.
The promise of interchangeability has too long been an unreachable brass ring. A biosimilar product is one that is “highly similar with no clinically meaningful difference” as compared to a reference product, and should be available to patients brand new to the therapy in question. An interim step that requires that treatment-naïve patients receive an approved biosimilar while keeping existing patients on therapy will encourage biosimilar applications, increase biosimilar market penetration and lower drug costs.
Originally published on Law360 (Subscription required)
 Food and Drug Administration (May 2019) Guidance for Industry: Considerations in Demonstrating Interchangeability With A Reference Product. (“Guidance”) at 4.
 Id. at 5, 9.
 Id. at 5, 9-14.
 Id. at 10.
 Id. at 11-12.
 Id. at 16.
 Id. at 5.
 Id. at 14-15.
 As an aside, because the indication for which a drug is being prescribed is not written on the prescription, one wonders if seeking approval for all the indications of a reference product — or undertaking the cost of demonstrating extrapolation of data across indications — is worth the investment.
 See 42 U.S.C. § 262(i)(2).
 Either proposal could include an option where the doctor could specify the prescription should be “dispensed as written.” However, the concern is that this would increase marketing spend on getting doctors to write “DAW” versus funneling those costs towards development of new therapies.
 This system could be further improved by offering tax breaks or similar incentives to biosimilar sponsors to perform the switching and bridging studies required to demonstrate interchangeability. Again, defraying these costs to the applicant will lead to an increased number of biosimilar products and the attendant decrease in cost of biologic products.
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