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.
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.