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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Public Health Service Act (42 U.S.C. 262).
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355).
Drug Price Competition Act and Patent Term Restoration Act of 1984.
Food and Drug Administration Modernization Act (FDAMA) of 1997.
CBER. Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology. Rockville, MD: U.S. Food and Drug Administration; April 1985.
CBER. Supplement to the Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology: Nucleic Acid Characterization and Genetic Stability. Rockville, MD: U.S. Food and Drug Administration; April 1992.
CBER. Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals. Rockville, MD: U.S. Food and Drug Administration; May 1993.
CBER. Guidance on Alternatives to Lot Release for Licensed Biological Products. Rockville, MD: U.S. Food and Drug Administration; July 1993.
CBER. Elimination of Establishment License Application and Product License—Final Rule. U.S. Food and Drug Administration. Federal Register (Vol 64; 202; 56441–56454), October 20, 1999.
CBER. Guidance for the Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products. Rockville, MD. U.S. Food and Drug Administration: April 1996.
CBER. Guidance for Industry: The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use. Rockville, MD: U.S. Food and Drug Administration; October 1997.
CBER. Guidance for Industry: Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and New Variant Creutzfeldt-Jakob Disease (nvCJD) by Blood and Blood Products. Rockville, MD: U.S. Food and Drug Administration; August 1999.
CBER. Guidance for Industry: Possible Dioxin/PCB Contamination of Drug and Biological Products. Rockville, MD: U.S. Food and Drug Administration; August 1999.
International Conference on Harmonization (ICH). Final Guideline on Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of rDNA-Derived Protein Products. Geneva, Switzerland: ICH Secretariat; February 1996.
International Conference on Harmonization (ICH). Draft Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. Geneva, Switzerland: ICH Secretariat; August 1998.
International Conference on Harmonization (ICH). Guidance on Quality of Biotechnological/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products. Geneva, Switzerland: ICH Secretariat; September 1998.
International Conference on Harmonization (ICH). Guidance on Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin. Geneva, Switzerland: ICH Secretariat; September 1998.
International Conference on Harmonization (ICH). Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. Geneva, Switzerland: ICH Secretariat; August 1999.
CBER. Final Rule: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products and Biological Products. U.S. Food and Drug Administration. Federal Register. (Vol 62; 39889–39903), July 24, 1997.
CBER. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product. Rockville, MD: U.S. Food and Drug Administration; January 1999.
CBER. Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Plasma-Derived Biological Products, Animal Plasma or Serum-Derived Products. Rockville, MD: U.S. Food and Drug Administration; February 1999.
CBER. Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for a Biological In Vitro Diagnostic Product. Rockville, MD: U.S. Food and Drug Administration; March 1999.
CBER. Guidance for Industry On the Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Information for an Allergenic Extract or Allergen Patch Test. Rockville, MD: U.S. Food and Drug Administration; April 1999.
CBER. Guidance for Industry For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Blood and Blood Components Intended for Transfusion or for Further Manufacture and For the Completion of the Form FDA 356h “Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use.” Rockville, MD: U.S. Food and Drug Administration; May 1999.
CBER. Draft Guidance for Industry: Current Good Manufacturing Practice for Blood and Blood Components: (1) Quarantine and Disposition of Prior Collections from Donors with Repeatedly Reactive Screening Tests for Hepatitis C Virus (HCV); (2) Supplemental Testing, and the Notification of Consignees and Transfusion Recipients of donor Test Results for Antibody to HCV (Anti-HCV). Rockville, MD: U.S. Food and Drug Administration; June 1999.
CBER. Guidance For the Submission of Chemistry, Manufacturing and Controls Information and Establishment Description for Autologous Somatic Cell Therapy Products. Rockville, MD: U.S. Food and Drug Administration; January 1997.
CBER. Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances. Rockville, MD: U.S. Food and Drug Administration; November 1994.
CBER. Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic rDNA-derived Product of a Monoclonal Antibody Product for In Vivo Use. Rockville, MD: U.S. Food and Drug Administration; August 1996.
CBER. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use. Rockville, MD: U.S. Food and Drug Administration; February 1997.
CBER. Guidance for Industry: Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations. Rockville, MD: U.S. Food and Drug Administration; July 1999.
FDA. Guidance for Industry: Fast Track Drug Development Programs—Designation, Development, and Application Review. Rockville, MD: U.S. Food and Drug Administration; November 1998.
Zeid RL. Generic biologics: Notes from the path less traveled. BioPharm. 1999;12(3):24–32.
Zeid RL. Generic biologics: Glimpses through the mist. RAPS. February 1999.
Zeid RL. Generic biologies: Could the impossible become reality? RAPS. March 1999.
Zeid RL. Demonstrating Therapeutic Equivalence for Biotech-derived Products. Presentation at International Business Communications (IBC) USA Conference: Rx & Biotech Generics, Georgetown University, Washington, D.C.; September 21–23, 1999.
Statement of Policy for Biotechnology Products. Federal Register. (51) 23309, June 26, 1996.
Approved Drug Products with Therapeutic Equivalence Evaluations. (‘Orange Book’), XVI ed., 1996, CCH (Chicago).
CDER. Draft Guidance for Industry—Applications Covered by Section 505(b)(2). Rockville, MD: U.S. Food and Drug Administration; October 1999.
BIO (Biotechnology Industry Organization) Presentation by Dr. Alan Goldhammer during Generic Recombinant Drugs/Biologics Session. 1998 Annual RAPS Meeting.
Stein KE. Preclinical and Clinical Development of Biological Therapeutics: Focus on Pharmacokinetics and Pharmacodynamics. Annapolis, MD; October 18, 1999.
FDA. Biological Response Modifiers Advisory Committee Meeting Minutes: Bethesda, MD, July 15, 1999.
Chapter 25: Acceptance Sampling in Juran ‘s Quality Handbook, 5th ed., Joseph M. Juran & A. Blanton Godfrey, eds. New York: McGraw Hill; March 1999.
Zabrecky JR, Brown, EK, Compton, BJ, Kretschmer MW, Fowler E, and Bemardy JD. Combining ELISA, RP-HPLC, and SDS-PAGE to Define the Potency of a Complex Biologic. BioPharm. 1998; 11(10), 34–44.
Kittle JD, Pimentel BJ. Testing the Genetic Stability of Recombinant DNA Cell Banks. BioPharm. 1997;10(10) 48–51.
About this article
Cite this article
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