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Biosimilar insulin is the term most widely used for generic insulin similar to an approved insulin product on the market.
Biosimilar insulins are produced by recombinant DNA (rDNA) technology but are manufactured and sold without the rigorous preclinical and clinical testing required of the human and analogue insulins currently available in the United States and Europe.
Janet B. McGill
Currently, generic drug manufacturers around the world have rDNA technology capability and many produce insulin for markets in Eastern Europe, Asia, South America and Africa. One or more of these insulin products may make their way to the United States in the foreseeable future. As prolific prescribers of biologic therapies, endocrinologists need to understand the changing landscape of generic biologic products.
Human insulin, the first peptide produced by rDNA technology, was approved for human use in 1980. Analogue insulins, which have provided greater flexibility and precision in the treatment of patients with type 1 and type 2 diabetes, followed in the 1990s. Lantus has the largest market share of all insulins in the United States and the world, with Novolog and Humalog close behind. However, patent protections for human insulins have expired, and the analogue patents are due to expire between 2013 and 2016, opening the door for generic entrants into the lucrative US market.
Third-party payers and pharmacy benefit managers are among those pushing for generic alternatives to expensive biologic therapies. In 2011, more than three-quarters of small molecule drugs prescribed were generic, but fewer than 5% of biologics have generic competition in the United States. The lack of generic biologics is due to patents on both the molecule and manufacturing processes, which in essence extend the product patent protection. Although the cost savings for small molecule generics is significant, the anticipated price reduction of biosimilars is expected to be only 25% less than the innovator drug. Nonetheless, due to the high price of most biologic medications and the chronic use required by many patients, the overall cost savings is expected to be substantial.
Blazing a path to approval
In response to concerns about the high price of many biologic therapies, Congress passed the Biologic Price Competition and Innovation Act (BPCI) in 2009 that requires the FDA to develop a pathway for the approval of generic biologic medications, referred to as follow-on biologics (FOBs) or biosimilars. The FDA recently released Guidance for Industry policy statements to clarify requirements for approval of biosimilar products. The challenges faced by the FDA include the determination of interchangeability and the need for clinical testing to demonstrate equivalent pharmacokinetics, pharmacodynamics, safety and efficacy. Thus far, the FDA has stated that these questions will be decided on a case-by-case basis, presumably depending on the analytic similarity of the biosimilar peptide product to the innovator compound and the risks of adverse reactions. The European Medicines Agency published policies for biosimilars in 2006, and subsequently reviewed one application for biosimilar insulin products in 2007. The application was rejected for a number of reasons.
In November 2010, various concerns were raised about the process of biosimilar development and extent of testing required at a 2-day FDA hearing. One of the concerns is immunogenicity, which can occur with insulin but is more likely to be problematic with larger molecules with differing glycosylation patterns and with monoclonal antibodies. Animal studies are not helpful, and human studies are generally not powered to detect differences in immunologic response. The aggregate number of patients enrolled in phase 1 and phase 2 studies is insufficient to detect allergies or other antibody-mediated adverse responses to biologic agents, so testing for neutralizing antibodies and cytokine responses (in some cases) is done as a surrogate during the abbreviated development of biologic products.
Other concerns raised at the hearing were related to potency of the biosimilar products compared with the parent compound, the purity and the dosing equivalence. These questions are critical for those who take insulin due to the very narrow therapeutic window. Stability over time and at variable temperatures should be established, but with what rigor? Although the FDA has indicated that testing in humans will be required for the approval of biosimilar insulin, the exact requirements in terms of types of clinical trials, number of participants and duration have not been clearly established. In the recently released Guidance for Industry documents, the FDA repeatedly states that it will rely on the totality of evidence in assessing biosimilars.
A very important question from the perspective of prescribers is whether biosimilar insulins will be interchangeable with brand-name products. Interestingly, despite the similarity in pharmacokinetics and pharmacodynamics of the rapid-acting analogues, shifting contractual preferences generally call for a new prescription. An unsettled issue is whether biosimilars in general and insulin in particular will be able to utilize the International Nomenclature Name (INN), otherwise known as the generic name, or whether a discrete brand name will be required in addition to the INN. Pharmacy benefit managers have generally been in favor of the application of INN identifiers to generic biologics and in favor of pharmacy substitution. This would make tracking and reporting problems more difficult for prescribers, who generally favor unique names for biologic products. For example, if a patient has a reaction to one biosimilar insulin product, it would be difficult to avoid future reactions if the INN is the only name used.
An additional problem receiving little attention is the issue of liability for adverse occurrences with biosimilar products. With small molecule drugs, the originating company remains responsible for product liability, even when the adverse event occurred with a generic. Who will assume the liability of adverse occurrences with biosimilars when the peptides are manufactured in other countries? Likewise, recent drug shortages suggest that reliance on imported medications could create unanticipated supply problems.
Will we see biosimilar insulins in the future? The answer is yes, but exactly when, how many and the level of market penetration is not known. Stay tuned …
Janet B. McGill, MD, is an Endocrine Today Editorial Board member, professor of medicine; Director, fellowship in Endocrinology, Diabetes and Metabolism; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri.
Disclosure: Dr. McGill did not provide any relevant financial disclosures by the press date.