The regulatory landscape governing the approval of generic topical products is changing on both sides of the Atlantic. Governments and payers have recognised that historically there have been significant barriers to the introduction of new generics, which have dissuaded companies from wanting to invest in their development.
The major barrier has been the high cost of producing the clinical data to demonstrate therapeutic bioequivalence with the reference product, compared to the relatively small financial returns to be expected from the majority of topical products. As a consequence, many topical products have historically continued on the market with no generic challenge. The U.S. Government Accountability Office report in August 2016 noted that from 2010 to 2015, 57 percent of topical drug products “experienced an extraordinary price increase due to lack of competition,” with an on average increase of 276 percent.
So, what actions have the regulators taken? The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom, along with the European Medicines Agency (EMA), made the first move. Together, they approved at least two topical applications, one for nail and one for skin, where generic products whose content and physicochemical properties were exactly matched to the originator product and the bioequivalence was demonstrated using only in-vitro release testing (IVRT) and in-vitro permeation testing (IVPT) models.
The bioequivalence was also supported by data from in-vitro disease activity models using human nails and skin. In one, the submission also included an in-vivo skin blanching/vasoconstrictor assay study in healthy volunteers because one active ingredient was a steroid. IVRT measures the drug release from the formulation and is akin to the dissolution testing of tablets. IVPT measures the penetration into and permeation across human skin. Disease activity models measure the activity of drug on a disease-related pathway or an induced infection, typically simultaneously with penetration and permeation.
In 2017, the FDA produced its draft guidance on acyclovir cream, which for the first time offers an in-vitro-only option for demonstrating bioequivalence. The U.S. Food and Drug Administration (FDA) has since followed up with guidances for other products, which in the most part reference the acyclovir guidelines. In all cases the guidances focus on IVRT and IVPT as the key in-vitro methods for demonstrating bioequivalence.
At the end of 2018, after receiving comments on a concept paper published in 2015, the EMA published draft guidelines on generic topical development to cover all products, in contrast to the FDA’s product by product approach. Similar to the FDA, the EMA has focused on the IVRT and IVPT models to demonstrate bioequivalence. The EMA is currently seeking feedback on its draft guidance before June 2019.
Whilst on the face of it these models may seem to be straightforward laboratory experiments, they are in fact relatively complex, with many different variables that can impact results. Back in 2006, Chilcott et al. showed that between laboratories using exactly the same protocol you could get 30 percent variation on simple IVRT experiments.
It is now becoming clear that to use these methods for bioequivalence, regulatory authorities are requiring high levels of validation carried under rigorous levels of quality assurance oversight and are expecting levels of variability that can challenge the limits of the methodology. Early indications are that some laboratories new to the discipline have tried to develop suitable IVRT and IVPT methods and have been unable to reach the guidance’s thresholds.
From a development perspective, the experimental rigor needed means that only a few experienced laboratories are able to generate acceptable data packages. Furthermore, the time needed to demonstrate an acceptable level of validation, quality standards and variation means that the costs involved are not insignificant, but crucially remain less than clinical trials.
IVPT is a particular challenge: laboratories have to understand how to minimize the inherent variation that can be attributed to within and between different skin donors. Procedures must be meticulous and avoid any operator variation wherever possible. For many larger and more lipophilic drugs, the levels of drug permeating through the skin approach the analytical detection limits and are often at sub-nanogram concentrations. To add to this challenge, the guidances require these analytical methods be fully validated, which is no easy task.
Where the expertise exists to manage these challenges, the in-vitro methods are a lower-cost route to demonstrating bioequivalence compared to clinical trials. What is also now appreciated by regulators and developers is that any subtle difference between a new topical generic formulation and the originator product are far more likely to be apparent from IVRT data and, to a lesser extent, from IVPT data, because of the highly variable nature of trying to measure clinical outcomes. The industry is learning that the development of topical generic formulations is more complex than most solid oral dosage forms and typically require specific expertise. The significant investment required is still smaller than trying to demonstrate bioequivalence in the clinic.
As a result of the historical lack of generic submissions, the regulators in the United States and Europe have demonstrated openness in helping developers define the exact parameters expected. The FDA is now 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 first approval for acyclovir based on the FDA guidance has now been achieved. The Europeans in the new draft guidance have opened the approach to topical indications for the eye, nail and nose and other sites of local delivery, as well as the skin. The FDA has also announced research grants to look at different epithelial tissues beside the skin. We can expect more new generic topical products to appear on the market in the coming years, reversing the trend of previous years.
Jeremy Drummond is senior vice president of business development for MedPharm Ltd., a global provider of contract topical and transdermal product design and formulation development services.
