Generic medicines invariably cost less (up to 85% less) than brand-name innovator medicines—also known as Reference Product/RMP/RLD—because they do not have to go through the same rigorous clinical studies to demonstrate safety and effectiveness.

Any generic medicine however must perform the same in the body as the RMP/RLD meaning that dosage, form and route of administration, safety, effectiveness, strength and labeling must be consistent. It must also meet equivalent standards of quality and manufacturing as the reference product. In some cases where reference products are older and the characterization techniques used at the time are outmoded, a higher standard must be met.

For generic products then, bioequivalence is crucial. The guidance to achieve bioequivalence between the reference and generic products depends upon the route, type and complexity of the former. A demonstration of only pharmaceutical equivalence may be required in some cases, but in others there is a need for detailed therapeutic equivalence with a clinical endpoint.

Notable efforts from regulators to make the development and approval of generic products as simple and as inexpensive as possible are being made. However, regulatory guidance for the development of topical generics highlights some of the issues that have arisen when trying to demonstrate bioequivalence.

Previously, the approval of generic topical products required the demonstration of therapeutic equivalence to the reference product through a clinical endpoint study. Due to the complex physiological mechanisms involved in dermal absorption and the sometimes-limited therapeutic action of these products, large numbers of patients were required for these clinical studies. This means that studies were cumbersome and expensive.

As a result, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and, the European Medicines Agency (EMA), advised on and subsequently approved at least two topical generic medicines based on (extended) pharmaceutical equivalence and in vitro bioequivalence to the reference product using a combination of in vitro release testing (IVRT), in vitro skin permeation testing (IVPT) models.

Bioequivalence was also supported by data from in vitro disease activity models using human nails and skin. In 2015, the EMA published a concept paper asking for feedback on their proposed requirements to obtain topical generic product approval without any clinical testing. The EMA subsequently published draft guidelines in 2018 which remain to be finalized.

The FDA produced a draft guidance on acyclovir cream in 2017 that offered an in vitro only option to demonstrate bioequivalence. The FDA subsequently published other product specific guidance which frequently reference the acyclovir guidance.

In all cases, the guidance focuses on IVRT and IVPT as the key in vitro methods for demonstrating bioequivalence. As such the use of such methods could be seen as an attractive alternative to clinical studies. However, significant differences and inconsistencies within the guidance provided remain.

Generally, the EMA and FDA agree with regards to the requirements of pharmaceutical equivalence from a qualitative and quantitative perspective with allowances for small variations and replacement of non-functional excipients when needed. However, there is increasing focus on matching the physical structure/microstructure (Q3) of the reference product which involves extensive rheological characterization and potentially an assessment of drug in solution and suspension over shelf life. In addition, comparison of the metamorphosis or transformation of the products upon application is also becoming mandatory.

The agencies are learning with each generic application they receive. Many of the demands made on the generics were not made on the reference products where excipient loss and permeation changes in drug thermodynamic activity and drug crystallization were not even considered. Although it is likely that any material differences would be seen in IVRT and potentially IVPT studies, it is currently unlikely these differences could be statistically interpreted using such methods or even clinically when the product transforms after application. As such, further work and guidance is required.

The FDA is accepting pre-ANDA meetings and the EMA continues to use scientific advice meetings to provide product specific guidance on the suitability of methodologies and protocols. The key areas in which advice is given concern the demonstration of sameness/equivalence between a topical reference product and generic product: specifically, (extended) pharmaceutical equivalence and bioequivalence.

Nevertheless, the basic principles of all relevant guidance are that a topical generic product is considered complex and should be qualitatively, quantitatively, physically/structurally and bioequivalently the same as the reference product.