By Kevin E. Noonan –

It is fair to say (no matter what else can be said) that the current administration is outcome- rather than process-driven. This general inclination is true of the Department of Health and Human Services and the agencies contained thereinunder, and the Food and Drug Administration exhibited this tendency in a recent Draft Guidance regarding the requirements for a biosimilar-producing applicant to obtain approval for an abbreviated Biologic License Application (aBLA).

Here the outcome is lower drug prices, as expressly stated by Secretary Kennedy in a press release. Characterizing the change as an illustration of “bold action,” the press release attributes the lower number of approved biosimilar drugs (76) compared to conventional small molecule generic drugs (over 30,000) as the result of “a burdensome approval process” (ignoring the difference between the over forty years that have elapsed since passage of the Hatch-Waxman Act and fifteen years since the BPCIA was passed as part of the Affordable Care Act, as well as the recognized differences in technology and costs/efforts for bringing a biosimilar drug to market (see “No One Seems Happy with Follow-on Biologics According to the FTC” and “Emerging Health Care Issues: Follow-on Biologic Drug Competition“). FDA Commissioner Marty Makary M.D., M.P.H. echoes his boss’s theme, stating that “[b]y streamlining the biosimilar development process and helping advance interchangeability, we can achieve massive cost reductions for advanced treatments for cancer, autoimmune diseases, and rare disorders affecting millions of Americans” (Dr. Makary’s philosophy can be found in his book, Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health). Now-former Director, FDA Center for Drug Evaluation and Research, George Tidmarsh, M.D., Ph.D. in more measured tones characterized the changes as being due to the FDA’s commitment “to advancing common-sense policies that further promote efficient and effective biosimilar and interchangeable biosimilar development, without compromising safety and effectiveness,” a worthy aspiration but perhaps being less than expected or hoped-for. The economic and political impetus is also set forth in the press release, which notes that “[e]xpensive biologic medications make up only 5% of prescriptions in the U.S. but account for 51% of total drug spending as of 2024. FDA-approved biosimilars are as safe and effective as the branded drugs, yet their market share remains below 20%.” There is little to no recognition that perhaps the reason approved biosimilar drugs are “as safe and effective as the branded drugs” is because of the “burdensome approval process” (a blind spot shared by many; see “Interchangeable Biosimilars: In a Battle of Safety vs. Cost, Where Does Sen. Lee Stand?“).

The press release states simply the point of the new Guidance: based on “the agency’s accrued data and experience since the first biosimilar was approved in 2015” (the same evidence excoriated as being “unduly burdensome” earlier in the press release), “comparative efficacy studies generally have low sensitivity compared to many other analytical assessments,” and touts that the new Guidance “reduces this unnecessary resource-intensive requirement for developers to conduct comparative human clinical studies” in favor of such analytical studies. Also denigrated are testing requirements for interchangeability, which has been the subject of earlier Guidance changes.

The Guidance is remarkably brief in view of the purported sea change it is promised to produce in biosimilar approval requirements. The Guidance itself reiterates some of these policy-based (as opposed to science-based) rationales for the changes set forth therein. The Introduction section of the Guidance sets forth an earlier Guidance (Scientific Considerations in 37 Demonstrating Biosimilarity to a Reference Product) from 2015 providing information related to satisfaction of the statutory requirements under Section 351 of the PHS Act for biosimilarity and FDA’s interpretation thereof (including “comparative analytical studies, an assessment of toxicity, comparative human PK and PD studies (if there is a relevant PD measure(s)), and a clinical immunogenicity assessment.” The devil being in the details, the Guidance announces that the substantive changes are a consequence of the “significant experience in evaluating analytical differences between proposed biosimilar products and their reference products and understanding the impact of those analytical differences on clinical performance.” According to the Guidance, “currently available analytical technologies can structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity using in vitro biological and biochemical assays” and “comparative analytical assessment (CAA) is generally more sensitive than a [comparative efficacy study,] CES to detect differences between two products” relevant to biosimilarity.  Under circumstances where a CAA indicates biosimilarity as defined in the statute, “FDA recommends that sponsors consider a streamlined approach where a CES may not be necessary to support a demonstration of biosimilarity,” which may include “an appropriately designed human pharmacokinetic similarity study and an assessment of immunogenicity.” In a specific recommendation the Guidance provides that:

A streamlined approach should be considered when:

• The reference product and proposed biosimilar product are manufactured from clonal cell lines, are highly purified, and can be well-characterized analytically;

• The relationship between quality attributes and clinical efficacy is generally understood for the reference product, and these attributes can be evaluated by assays included in the CAA; and

• A human pharmacokinetic similarity study is feasible and clinically relevant.

The Guidance also recognizes “there may remain” instances and circumstances where a CES may be appropriate, and sponsors are “encouraged” to discuss such instances and circumstances with the Agency.

As with all draft Guidances, this one sets forth immediately before the Introduction the caveat that:

Whether the requirements in this Guidance improvidently expose the public to inadequately tested/screened/examined biosimilar drugs will depend on how the Guidance is implemented and (with even more uncertainly) the particular biologic drug for which the biosimilar is approved. And it remains questionable whether any such changes will significantly impact the number, time to market, or cost savings of new biosimilar drugs.