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Guest commentary: American pathway to generic biologics approval remains undefined
August 2009
by J. Michael Nicholas  |  Email the author
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As we stand at the forefront of major changes across the healthcare industry, a pathway for the approval of generic biologics will be one of the major initiatives in the government's efforts to achieve reduced costs. Worldwide, biologic drugs—now a common treatment option for people with conditions such as multiple sclerosis, diabetes, cancer and rheumatoid arthritis—account for about one of every eight prescriptions. By 2015, an estimated $20 billion worth of biologic drugs are expected to come off patent, providing a lucrative incentive for companies to develop and manufacture generic biologics. The American pathway to generic biologics approval, however, remains undefined.   

In 1984, the United States passed the Waxman-Hatch Act, a hard-fought piece of legislation allowing companies five years of exclusivity for new drugs and three additional years for new-generation products. Under the act, an applicant must demonstrate its generic drug product is "bioequivalent," or show safety and efficacy equivalence, to the branded drug product. The influential act, in its efforts to balance interests of the brand name pharmaceutical and generic drug industries, substantially reduced prescription drug prices and expenditures, provided increased patient access to therapeutics drugs and accelerated the pace of drug innovation.

Fast-forward 25 years: Biogenerics have been approved and used in the European Union, India and several other countries over the last few years. In fact, since 2004, the European Medicines Agency (EMEA) has approved the sale of six biosimilar drugs, with several more pending regulatory review. Meanwhile, the U.S. is still formulating a comprehensive biogeneric approval process.  

Congress has now entered the debate, and two competing bills are guiding discussions on what will likely detail the final regulatory framework for approval of generic biologics in the U.S.

The bill proposed by Rep. Henry A. Waxman (D-CA), "Promoting Innovation and Access to Life-saving Medicine's Act," would allow the determination of acceptable therapeutic equivalence and interchangeability of a generic biologic to be determined by the U.S. Food and Drug Administration (FDA), as it currently does for brand biologics. The agency would have full discretion in determining whether additional data are necessary to prove similarity, interchangeability, efficacy and/or safety and would also be authorized to require post-marketing studies.

The second bill, introduced by Reps. Anna Eshoo (D-CA), Joe Barton (R-TX), et al., "The Pathway for Biosimilars Act," includes a complex process unlike current drug and biologic approvals. The bill has a specific requirement for clinical trials of generic biologic candidates to prove acceptable therapeutic equivalence and interchangeability, but gives the FDA the power to waive any trials other than those designed to assess immunogenicity. However, under this bill, the FDA could waive the requirement of immunogenicity trials, but only after the Agency undergoes an extensive notice and comment period resulting in a published guidance advising that such a waiver is scientifically feasible and explaining the data surrounding the decision.  

What remains to be seen is how the differences between small-molecule and complex, or biologic, drugs will affect efforts to develop a straightforward approval process for generic biologics.  

As exact copies of branded drugs, generic small molecule products are identical to the innovator drug in terms of dosage, safety, strength, administration, quality, performance and intended use. A biologic drug, however, is made of a protein made by a living organism and is difficult or impossible to precisely replicate.

There is also a diverse range of drugs that do not fit comfortably in the "biologic or non-biologic" paradigm for generic drug approval. While some biologics are relatively well characterized and can be verified as bioequivalent to each other, some synthesized, non-biologic, complex drugs derived from nonliving sources share some of the same attributes as biologics, specifically:

  • cannot be characterized;
  • are not amenable to pharmacodynamics (PD) or pharmacokinetics (PK) bioequivalence studies; and
  • pose significant immunogenicity risks if manufactured even slightly differently from the innovator's process. 

These complex products are already posing a number of challenges to regulatory agencies evaluating follow-on versions of these agents. In accordance with the Waxman-Hatch Act, chemical and physical characterization of a generic drug must be performed to appropriate levels. Thus, requirements for safety and efficacy testing and determination of the appropriate approval pathway for follow-on complex and biogeneric drugs will likely depend on the extent to which a drug can be characterized in order to ensure comparability between the generic and the reference listed product (RLP). 

It is important the final legislation recognizes and supports FDA authority and discretion to make generic drug approvals on a case-by-case basis, considering drug complexity and drug efficacy and safety in patients.   

For example, low-molecular-weight heparin (LMWH) enoxaparin is a complex heterogeneous mixture of polysaccharides obtained by fractionation or depolymerization of polymeric heparin derived from natural sources (e.g., porcine intestine). The intrinsic order of saccharides in LMWHs is, and can be, identified. Moreover, pharmacologically active sequences within enoxaparin have not only been described by the manufacturer, but can be replicated and tested in PD studies. Immunogenicity testing, too, shows generic enoxaparin has comparable immunogenic effects to those of the RLP, Lovenox (within the margin of error). For these reasons, generic preparation of enoxaparin is appropriate for approval via the ANDA process. 

However, many other complex drugs cannot be fully characterized using state-of-the-art multidimensional analyses. Even small differences in the composition of complex drugs and substances can lead to significant differences in safety, such as immunogenicity, and efficacy. In some cases, the materiality of the differences is not well understood, and even the differences themselves cannot necessarily be recognized or characterized.

Take, for example, glatiramer acetate (GA), a treatment for relapsing-remitting multiple sclerosis, a chronic and degenerative disease. This drug, comprising a complex mixture of polypeptides containing a huge, perhaps incalculable, number of active amino acid sequences, is part of the glatiramoid class. Called a "biologic on steroids" by Dr. Andrew Myers, chairman of the Department of Chemistry and Chemical Biology at Harvard University, the scientific community has yet to identify the pharmacologically active sequences in GA; therefore it is difficult, if not impossible, to show that two glatiramoids, made by different manufacturers, have the same active ingredients. Furthermore, research by Teva, who discovered and manufactures GA, showed long-term treatment in animals with another glatiramoid, TV-5010 (protiramer), led to systemic toxicity and caused extensive fibrosis, organ damage and eosinophilia—signs never observed in similar pre-clinical studies involving GA. This experience demonstrated that very minor differences among glatiramoids can have very serious implications for drug safety and efficacy.  Obviously, clinical trials will be needed to obtain approval of drugs in the glatiramoid class, including follow-on GA products. 

With complex products like GA, it is currently impossible to predict how potentially unobservable differences in follow-on products will be translated into unwanted immunogenicity, and what will be the resulting efficacy and safety ramifications. As such, it is very important to devise an appropriate testing strategy, including a range of complementary assays for the detection and characterization of antibodies induced against follow-on complex drugs and biologics. Moreover, correlation studies should be planned to assess the relationship between immunogenicity and efficacy and safety results over time, using different methodologies. 

For complex drugs like GA and for many generic biologics, which present similar issues in terms of the inability to prove immunogenicity, science should dictate the requirements for approval of generic versions. The appropriate regulatory pathway must be examined on a case-by-case basis, as should the requirement for clinical trials, in order to maintain and ensure patient safety.  

With billions of dollars at stake and multiple major issues up for debate in the pursuit of a viable generic biologic approval pathway, access to safe and effective medicines is key.

Dr. J. Michael Nicholas is senior director of Strategic Regulatory Affairs and Post-Marketing Labeling/Compliance for Teva Neuroscience, where he is responsible for all post-marketing aspects of regulatory affairs. Nicholas received his PhD in pharmacology from the University of Tennessee Center for Health Sciences in 1982. After postdoctoral work at the University of Mississippi, he joined Mylan Pharmaceuticals in Morgantown, W.Va., as director of Scientific Affairs. He has also held positions at Marion Laboratories, Marion Merrell Dow and Hoechst Marion Roussel, where he was involved with all aspects of regulatory matters, including product development and approval. Prior to his current position, he was vice president of U.S. Regulatory Affairs and Compliance, Marketed Products for Aventis Pharmaceuticals and was responsible for regulatory matters for approved products.


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