April 15, 2010 (Vol. 30, No. 8)

Case-by-Case Decision-Making Process May Be Best Approach for Safe and Efficacious Drugs

More than $10 billion worth of biologics are expected to be off-patent by 2010, creating enormous incentives for the development of generic alternatives to these drugs. As a result, it is anticipated that the market for biosimilars will grow significantly in the coming years.  

For companies with extensive experience in the generic pharmaceutical marketplace, establishing bioequivalence and producing safe and efficacious products has always been key. The lessons that have been learned in this sector, especially as they relate to the Hatch-Waxman approval process, should be used to help establish the framework for biosimilars.

Based on an article by Henry Grabowski in Health Affairs, according to the Hatch-Waxman Act, in reviewing abbreviated new drug applications (ANDAs), the FDA relies on a prior finding of safety and efficacy for a referenced pioneer drug, with a generic applicant having only to demonstrate bioequivalence between its product and the referenced drug.

Although Hatch-Waxman provides a clear path for generic drug market entry, it generally does not apply to biologics.  Biologics are generally regulated under the Public Health Service Act, which has no equivalent provision to the ANDA that allows for the expedited approval of generic versions of approved, on-market products. Some early biologics such as human growth hormone, insulin, and conjugated estrogens were approved as drugs under the Food, Drug and Cosmetic Act. ANDAs could be approved for these products, subject to FDA resolution of the scientific and other issues involved.

As of this writing, Congress is considering legislation that would include an approval pathway for biosimilars and seeks to address the complexity of these biologic-based drug candidates, as compared to the chemistry-based measures of bioequivalence of small molecule drugs covered under the 1984 Hatch-Waxman legislation.

The legislative proposal would allow the FDA to examine biosimilar products on a case-by-case basis and also make determinations about interchangeability. It will be incumbent on the FDA to gather needed clinical information and set forth a new standard for these complex products.

Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, has said that, “Unlike small molecule drugs whose chemical composition can easily be determined to be the same as an approved product, the very nature of protein products makes comparisons of one protein to another, including to establish safety and efficacy, more scientifically challenging.”

In a September 18, 2008, letter to Representative Frank Pallone Jr., chairman of the Subcommittee on Health, of the Committee on Energy and Commerce, Frank M. Torti, M.D., M.P.H., principal deputy commissioner and chief scientist of the FDA, echoed this concern. 

In response to Representative Pallone’s question about the FDA’s possible mandatory requirements for clinical trials for all follow-on biologics (FOBs), Dr. Torti wrote that “FDA believes that legislation should require that sponsors of follow-on products meet the same high standards for approval as reference biological products. 

“For instance, the extent of clinical information required depends on how much is known regarding the mechanism of action, the degree to which structural similarity could be assessed, comparative pharmacokinetic and pharmacodynamic data, and immunogenicity. Given the current level of understanding, at least some clinical information will be needed to assess the safety and efficacy of most FOBs. Legislation should require clinical trials, but FDA should be given the discretion to determine through a transparent and public process what clinical trials are needed to support the licensure of a FOB.”

Dr. Torti further wrote: “At this time, we have not approved a recombinant protein (as distinguished from a synthetic or naturally sourced protein) through the 505(b)(2) pathway without clinical trials (other than bioavailability or bioequivalence).” 

Complex Pharmaceuticals

Past experience with certain complex—albeit nonbiological—pharmaceuticals may be instructive. Pancreatic enzyme products are a good example. The FDA observed that the identities of those features of the drug that made “clinically meaningful contributions to the drug’s therapeutic effects” were at that time unknown.

As a result, the Agency held that no ANDA applicant’s product could be approved until those features of the product had been “sufficiently defined,” which would require the proposed generic applicant to provide information sufficient to identify and characterize those constituents of the product that are responsible for the drug’s therapeutic effects. 

In 2006, the FDA’s conclusion regarding these protein-like products noted that the complexity of these products in effect made them “unknowns” for which currently available chemical and bioanalytical tools likely are not able to demonstrate sameness. Specifically, according to FDA guidance issued at the time, “Because of the complexity of pancreatic extract products, it is unlikely that currently available physicochemical and biological analytical tools would be able to demonstrate that the active ingredients in pancreatic extract products from two different manufacturers are the same.”

And herein lies the challenge, and the opportunity, for the drug-development community.

MS Treatments

Among the first case studies of the implementation of managing generic or biosimilar products with immunogenicity concerns may be current treatments for multiple sclerosis (MS). Immunogenic response could range from an imperceptible, clinically insignificant level of antibodies to one that detracts from either safety or efficacy. 

A recent issue of Neurology noted that patents on leading drugs for the treatment of MS are beginning to expire. The majority of these MS treatments are biologics; however, one in particular, the glatiramoid, glatiramer acetate injection (GA, Copaxone®), is a complex drug with immunomodulatory activity.

GA is not a singular molecular entity  but a heterogeneous mixture of synthetic proteins and polypeptides with an incalculable number of active amino acid sequences in a defined range of molar ratios. As such, the FDA has long recognized that it is not a conventional drug, either in chemical composition or in its presumed mechanism of action. At a 2009 industry conference, Andrew Myers, Ph.D., chair, department of chemistry and chemical biology, Harvard University, referred to GA as a “biologic on steroids.”

As one might expect, drugs for MS that modify pathologic immune function also have the potential to modify healthy immune function. The long-term immunologic safety of most current MS complex and biologic therapies (GA, interferon beta-1b, and interferon beta 1-a) has been established over many years of use and depends on a consistent manufacturing process.

So although GA was not approved as a biologic because the multiepitopic sequences in GA are not completely characterized, no glatiramoid mixture prepared by a different manufacturer than the original manufacturer, even if using precisely the same process, can be demonstrated to be the same as GA. Due to the exquisite sensitivity of the immune system, a “new” GA with even slight differences in amino acid sequences may have a different immunogenic effect on patients.

Complex, protein-like drugs and biologics offer unique challenges to both drug-development professionals as well as regulatory decision makers. In fact, regulatory bodies around the world are struggling with the issues surrounding bioequivalence with these complex products.

Because of this complexity, I posit that drug-development strategies should be based on a case-by-case decision process predicated on the ability to: fully characterize the clinically significant portions of the molecule under development; establish  appropriate bioequivalence endpoints  such as pharmacokinetic parameters; develop clinically meaningful and validated pharmacodynamic surrogate markers; and undertake a clinical study with appropriate endpoints to assess safety and efficacy when compared to the reference listed drug. 

These strategies can only strengthen the industry and the ability and discretion of the FDA to evaluate, and approve, safe and efficacious product candidates.

Thomas B. Smith, M.D. ([email protected]), is vp of medical affairs at Teva North America Brand Pharmaceuticals.

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