Guest commentary: American pathway to generic biologics approval remains undefined

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.

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As we stand at the forefront of major changes across thehealthcare industry, a pathway for the approval of generic biologics will beone of the major initiatives in the government's efforts to achieve reducedcosts. Worldwide, biologic drugs—now a common treatment option for people withconditions such as multiple sclerosis, diabetes, cancer and rheumatoidarthritis—account for about one of every eight prescriptions. By 2015, anestimated $20 billion worth of biologic drugs are expected to come off patent,providing a lucrative incentive for companies to develop and manufacturegeneric biologics. The American pathway to generic biologics approval, however,remains undefined.   

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

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

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

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

The second bill, introduced by Reps. Anna Eshoo (D-CA), JoeBarton (R-TX), et al., "The Pathway forBiosimilars Act," includes a complex process unlike current drug and biologicapprovals. The bill has a specific requirement for clinical trials of genericbiologic candidates to prove acceptable therapeutic equivalence andinterchangeability, but gives the FDA the power to waive any trials other thanthose designed to assess immunogenicity. However, under this bill, the FDAcould waive the requirement of immunogenicity trials, but only after the Agencyundergoes an extensive notice and comment period resulting in a publishedguidance advising that such a waiver is scientifically feasible and explainingthe data surrounding the decision.  

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

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

There is also a diverse range of drugs that do not fitcomfortably in the "biologic or non-biologic" paradigm for generic drugapproval. While some biologics are relatively well characterized and can beverified as bioequivalent to each other, some synthesized, non-biologic,complex drugs derived from nonliving sources share some of the same attributesas 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 ofchallenges to regulatory agencies evaluating follow-on versions of these agents.In accordance with the Waxman-Hatch Act, chemical and physical characterizationof a generic drug must be performed to appropriate levels. Thus, requirementsfor safety and efficacy testing and determination of the appropriate approvalpathway for follow-on complex and biogeneric drugs will likely depend on theextent to which a drug can be characterized in order to ensure comparabilitybetween the generic and the reference listed product (RLP). 

It is important the final legislation recognizes and supportsFDA authority and discretion to make generic drug approvals on a case-by-casebasis, considering drug complexity and drug efficacy and safety inpatients.   

For example, low-molecular-weight heparin (LMWH) enoxaparinis a complex heterogeneous mixture of polysaccharides obtained by fractionationor 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 havenot only been described by the manufacturer, but can be replicated and testedin PD studies. Immunogenicity testing, too, shows generic enoxaparin hascomparable immunogenic effects to those of the RLP, Lovenox (within the marginof error). For these reasons, generic preparation of enoxaparin is appropriatefor approval via the ANDA process. 

However, many other complex drugs cannot be fullycharacterized using state-of-the-art multidimensional analyses. Even smalldifferences in the composition of complex drugs and substances can lead tosignificant differences in safety, such as immunogenicity, and efficacy. Insome cases, the materiality of the differences is not well understood, and eventhe differences themselves cannot necessarily be recognized or characterized.

Take, for example, glatiramer acetate (GA), a treatment forrelapsing-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 theglatiramoid class. Called a "biologic on steroids" by Dr. Andrew Myers,chairman of the Department of Chemistry and Chemical Biology at HarvardUniversity, the scientific community has yet to identify the pharmacologicallyactive sequences in GA; therefore it is difficult, if not impossible, to showthat two glatiramoids, made by different manufacturers, have the same activeingredients. 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, organdamage and eosinophilia—signs never observed in similar pre-clinical studiesinvolving GA. This experience demonstrated that very minor differences amongglatiramoids can have very serious implications for drug safety andefficacy.  Obviously, clinicaltrials 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 topredict how potentially unobservable differences in follow-on products will betranslated into unwanted immunogenicity, and what will be the resultingefficacy and safety ramifications. As such, it is very important to devise anappropriate testing strategy, including a range of complementary assays for thedetection and characterization of antibodies induced against follow-on complexdrugs and biologics. Moreover, correlation studies should be planned to assessthe relationship between immunogenicity and efficacy and safety results overtime, 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. Theappropriate regulatory pathway must be examined on a case-by-case basis, asshould the requirement for clinical trials, in order to maintain and ensurepatient safety.  

With billions of dollars at stake and multiple major issuesup 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 StrategicRegulatory Affairs and Post-Marketing Labeling/Compliance for TevaNeuroscience, where he is responsible for all post-marketing aspects ofregulatory affairs. Nicholas received his PhD in pharmacology from theUniversity of Tennessee Center for Health Sciences in 1982. After postdoctoralwork at the University of Mississippi, he joined Mylan Pharmaceuticals inMorgantown, W.Va., as director of Scientific Affairs. He has also heldpositions at Marion Laboratories, Marion Merrell Dow and Hoechst MarionRoussel, where he was involved with all aspects of regulatory matters,including product development and approval. Prior to his current position, hewas vice president of U.S. Regulatory Affairs and Compliance, Marketed Productsfor Aventis Pharmaceuticals and was responsible for regulatory matters forapproved products.



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