Last year, we interviewed Dr. Niazi on a range of topics relevant to biosimilar development. We followed-up with him recently to get his thoughts on some recent developments in the field. Dr. Niazi is Adjunct Professor of Pharmaceutical Sciences at the University of Illinois and the University of Houston, founded the first US biosimilar company, Therapeutic Proteins (later Adello and Kashiv), and is the founder of Novel351k, as well as a biosimilar advisory company PharmSci.
Biosimilars Review & Report: Streamlining the biosimilar approval process has been a topic of some urgency for the US biosimilar community for the last few years. Specifically, the focus has been on eliminating the requirement for comparative clinical trials. Have regulatory agencies in other regions removed this requirement? Can you provide examples of when the new rules were implemented?
Sarfaraz K. Niazi, PhD: Indeed, this is the Achilles heel of the regulatory system. Scientific publications, including those from the FDA, have shown that biosimilars can never fail efficacy testing for simple statistical modeling reasons. After decades of evaluation, the Medicines and Healthcare Products Regulatory Agency has declared that efficacy testing is not necessary. The European Medicines Agency is developing a paper titled “Concept paper for the development of a Reflection Paper on a tailored clinical approach in biosimilar development” with a comments submission deadline of April 2024 (https://www.centerforbiosimilars.com/view/biorationality-ema-announces-readiness-to-waive-comparative-efficacy-studies-of-biosimilars). I anticipate that the EMA will follow the stance taken by the MHRA. The FDA has taken neutral position while encouraging developers to use its guideline; this should allow waiver of efficacy testing, but the burden of claiming this waiver lies with developers.
Surprisingly, the developers are eager to conduct such studies to demonstrate the efficacy of their biosimilars to prescribers—this is because almost all US developers are larger companies. Many publications, including ones from the FDA, have suggested that biosimilars with pharmacodynamics biomarkers are not required to conduct efficacy testing. The major event will come when the FDA allows the licensing of a monoclonal antibody without efficacy testing. Once that happens, the biosimilar landscape will shift towards smaller companies, and I believe several large companies will get out of the biosimilar business. Smaller companies will soon be able to develop biosimilars at a fraction of current cost and with substantially less capital expenditure to depreciate. The trend will be the same as occurred with generic drugs: prices will drop and soon it will not be feasible for the large pharma to compete.
BR&R: To what extent should the streamlining of clinical trials for biosimilar agents be based on commercial considerations (i.e., lowering the barrier to entry for smaller companies) and/or scientific rationale (i.e., the insensitivity of phase 3 noninferiority trials and the experience gained in the approval of biosimilar agents in the US and EU)?
Dr. Niazi: Ihave always maintained that these decisions should never be based on commercial considerations and only on scientific rationale. Are we abusing humans in conducting these trials and violating the US code? The FDA has conducted clinical efficacy testing for interchangeability and concluded that the switching and alternating studies are irrelevant.
The Evidence Regarding Biosimilar Immunogenicity
BR&R: What have we learned from the results of immunogenicity testing in biosimilars vs. reference products to date? Are there any new biologic candidates or categories for biosimilar development that might pose a reasonable risk for immunogenicity differences?
Dr. Niazi: This is one of the most misunderstood attributes. First, all biological products are immunogenic; it is their inherent property. However, if immunogenicity does not result in an anti-drug antibody, then it is not relevant. The FDA has already issued a guideline for insulin, which is highly immunogenic. Second, if the primary structure of the biosimilar is the same as it is for the reference product (and it is), there can be no difference in the T-cell immune response. Unless a biosimilar product uses a novel excipient that might have an immunogenic response, there are no issues of immunogenicity of biosimilars, and to date, no product has been held back by any regulatory agency because of this issue. Yet, this issue has a strong appeal for originator product manufacturers, and it is frequently accepted, mainly by prescribers, because of a lack of knowledge and understanding. The FDA has elaborated on this topic extensively, and this should be the key learning point for all stakeholders. If there are any impurity issues, they are readily identified and resolved in clinical pharmacology testing.
Can the FDA Decide to Ditch Interchangeability?
BR&R: The FDA’s testing requirements for biosimilar or interchangeable approval have varied over time. How much authority does the FDA have to waive existing BPCIA rules when considering the approval of a particular biosimilar?
Dr. Niazi: This is a very interesting discussion. Obtaining changes through legislative action is a long, drawn-out exercise, complicated by political concerns, but the FDA has discretion to vary the information required to establish biosimilarity.
The interchangeability issue is controversial, of course. Trade groups representing biosimilar makers have asked to retain interchangeability status, or at least the mention of it on a biosimilar label. The FDA has issued a new guideline prohibiting identifying a product as interchangeable in its label to ensure that this status is not used to promote the product.
However, the FDA cannot remove the interchangeable classification. It can instead award this classification without additional efficacy testing, as it has already done; the FDA can waive efficacy testing requirements that are also listed in the BPCIA and also remove the need for bridging studies when the reference product is not a US-licensed biologic. The FDA cannot alter the patent dance issue, even though it has extended the Purple Book. Eventually, patent considerations will follow the same path as those available for generic drugs.
