By Sid Bhoopathy
Complex drug products (CDPs) comprise a growing pharmaceutical sector, due to the safety, efficacy, and compliance benefits they provide. CDPs include those with complex active ingredients (e.g., peptides, natural source products), complex formulations (e.g., liposomes, iron colloids), complex routes of delivery (e.g., locally acting drugs), and drug-device combinations (e.g., inhalers, nasal sprays, auto injectors, and transdermal systems). As reflected in recent regulatory science initiatives by the Food and Drug Administration (FDA), there is a rising interest in making generic versions available for all CDP categories by applying a rational, science-driven approach that conceptually relies on quality by design.
According to FDA, generic drug products must meet the same standards of quality, efficacy, and safety as their reference listed drug (RLD) counterparts. Therefore, procedures are established to demonstrate that generic products are therapeutically equivalent and interchangeable with such. Therapeutic equivalence is generally achieved by assuring pharmaceutical equivalence and bioequivalence (BE) of the generic to the RLD products.
For solid oral drug products intended for systemic delivery, human pharmacokinetic (PK) studies supported by in vitro dissolution are largely successful in establishing BE. For locally acting drug products, such as topical dermal and ophthalmic formulations, establishing equivalence often proves to be more challenging. In such cases, plasma concentrations may not be an accurate measure of drug availability as these are downstream to the site of action. Direct measurement of the active ingredient locally can also be unreliable due to variations in application area and/or duration of exposure. Physiology of the skin and eye, including numerous pathways for drug absorption and changes in the diseased state, also contribute to overall variability.
Consequently, and with few exceptions, BE methods for such products are restricted to clinical endpoint studies because all drugs have a clinical endpoint that was used to support their initial approval. This approach, which FDA states to be the “least accurate, sensitive, and reproducible of the general approaches for measuring bioavailability or demonstrating equivalence” (21CFR320.24), typically consists of a three-arm comparative efficacy trial in which the RLD and generic are each tested vs. placebo in a relevant patient population for the approved indication.
The high variability and low sensitivity of clinical endpoint trials introduce substantial technical difficulties and necessitate large studies at high cost. These hurdles have produced a major barrier to the development and registration of dermal and ophthalmic locally acting generic products. The burden also affects the drug innovators, who must demonstrate equivalence between batches for scale-up and postapproval changes. There is a clear need to expand the use of alternative methodologies for equivalence assessment outside these few product- or mechanism-specific examples.
The cover article in the February issue of the AAPS Newsmagazine discusses an integrated and dynamic methodology, centered on nonclinical techniques, for optimizing formulations and accelerating equivalence assurance of locally acting drug products, a subset of CDPs. Read Strategies for the Equivalence Assessment of Locally Acting Complex Drug Products: Focus on Alternative Methodologies, from the RS section, and then participate in the discussion point below.
What can be done to facilitate adaptation of alternative methodologies for equivalence evaluation of complex drug products?