The exclusion of biological products (approved under the Public Health Service Act) from Title I of the Hatch-Waxman Amendments is being revisited today in the light of philosophical shifts in regulatory review, cost containment, and scientific consistency. The definition of drug versus biologic—be it scientific, legal, or administrative—is evolving and these overlapping working definitions further blur the regulatory distinction between drugs versus biologics. This is most clearly seen with the emergence of specified biotechnology products and the precedent of Center for Drug Evaluation and Research (CDER)-approved recombinant deoxyribonucleic acid (rDNA)-derived products under Section 505 of the Food Drug & Cosmetic (FD&C) Act. Improvements in production methods, process controls, and analytical test methods have given the Food and Drug Administration (FDA) the impetus for greater harmonization in regulatory review such as the Biologics License Application (BLA), which replaced the Product License Application (PLA) and Establishment License Application (ELA). Industry and regulators collaborated to create fast-track approvals and the ‘specified biotech’ paradigm to shed the long-standing “product = process” dogma. In doing so, entire classes of biotech-derived products are being brought to market faster, and significant manufacturing changes are being supported without repeating extensive Phase III clinical studies, and as some postulate—closer to the realm of multisource (or interchangeable products) competition by noninnovator companies.
Though specified biotech and comparability protocols do not equal multisource biotech, there are many common conceptual elements, parallel tracks, and intersections that support cost savings and faster route to market for noninnovator manufacturers, especially with regards to demonstrating therapeutic equivalence. Though each situation is case-dependent, what are some common features that could allow the same manufacturing changes under specified biotech as those supported for noninnovator multisource biotech pharmaceuticals? Given the range of complexity of moieties under the biotech umbrella, no single approach of demonstrating therapeutic equivalence would suffice for all. It should be evaluated first on a product class basis (eg, monoclonal antibodies, interferon, fibrinolytics, etc.) and then on a case-by-case basis using a tiered approach of combined analytical characterization + pharmacokinetic/pharmacodynamic (PK/PD) assessments + surrogate endpoint equivalence, if required. Assessment of immunogenicity, development of neutralizing antibodies, or other hypersensitivity reactions may require additional clinical studies for both innovator and noninnovators alike.
To accomplish this goal, a sponsor may develop extensive structure-activity relationship (SAR) databases for major classes of compounds (eg, somatotropins, fibrinolytics, monoclonal antibodies, etc.) expanding upon principles outlined in current FDA and International Conference on Harmonization (ICH) chemistry, manufacturing, and controls (CMC) guidance documents. Throughout development a manufacturer (innovator or multi-source firm) may be able to support those physico-chemical differences that do not impact clinical safety or therapeutic equivalence. The expansion of these comparability protocols into SAR databases may eventually allow for class-specific guidance documents or monographs and facilitate a unified regulatory review model for drugs and certain specified biologics.
Currently, there are at least four potential regulatory filing strategies for multisource biotech pharmaceuticals: a 505(b)(2), a BLA, a Canadian New Drug Submission (NDS), or a European Marketing Authorization Application (MAA). There are other international filings available (eg, Japan, Latin America, etc.) as well. The 505(b)(2) allows a multi-source biotech approval route—with an AB rating—when compared against innovator products previously approved under Section 505 of the FD&C Act. Albeit the 505(b)(2) may be the most clearly defined route, it has limited utility in that the number of Section 505-approved biotech products available to multisource competition is small when compared to those specified biotech products approved under the PHS Act. The BLA is also a new application that will allow multisource biotech products to compare therapeutic equivalence to innovator products approved under the PHS Act. Demonstrating therapeutic equivalence to an innovator compound, however, does not result in an AB rating since there is no mechanism under the Hatch-Waxman Amendments or current FDA policy that would allow assignment. Hospital formularies, however, can support interchangeabil-ity with greater latitude based on efficacy data and physician input. The MAA must be filed via the Centralized Procedure but it is not clear that there would be consensus among the Member States as to an adequate level of testing. Thus, a scientifically sound and consistent approach is lacking due to variations in legal, administrative, and regulatory definitions. Despite these limitations, could a single standard be developed and applied to such a multitude of biologic product scenarios as is currently done for Abbreviated New Drug Applications (ANDAs)?
While the multisource biotech dossiers could not follow the exact same approach currently used for generic drug applications, there are many common elements. The physico-chemical characterization and PK/PD comparisons would be to a listed product or external reference standard. Where changes were observed, those aspects would be highly integrated into an existing SAR development database for their impact on safety and efficacy. Where those data did not exist, the applicant would be compelled to provide additional data/studies. Thus, a tiered approach of demonstrating therapeutic equivalence will be applied and become increasingly harder to show based on: 1. Product complexity and characterization issues, 2. Clinical indications, and 3. Demonstration of additional safety for observed changes. This process allows for the greatest linkages to established safety and efficacy data by first demonstrating physico-chemical comparability for both innovator and multisource competition alike. Where differences exist, those changes must be evaluated in a scientifically sound and consistent manner.
This article reviews technical considerations for analytical, pharmacokinetic, clinical, and regulatory aspects in demonstrating therapeutic equivalence (of various classes of biologics) in the light of current FDA policy and law. Patent law and manufacturing/ process development issues are not covered in this article but are detailed in several references.
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Zeid, R.L. Regulatory and Development Issues in the Demonstration of Therapeutic Equivalence for Multisource Biotech-Derived Pharmaceuticals. Ther Innov Regul Sci 34, 919–959 (2000). https://doi.org/10.1177/009286150003400328
- Generic biotech
- Multisource biotech
- Therapeutic equivalence
- Surrogate endpoints