As I mentioned in my last post in this space (July 27, 2010), a new European Medicines Agency (EMA) Guideline on the Investigation of Bioequivalence went into effect August 1st and includes a section on biowaivers based on the Biopharmaceutics Classification System (BCS). The BCS is a regulatory framework through which immediate-release solid formulations of drugs (new formulations, generics, etc.) are eligible for waivers of clinical bioequivalence studies if they are well-absorbed (or, as a surrogate, more permeable in a validated in vitro test system than a high permeability internal standard) and highly soluble. The EMA criteria for BCS-based biowaivers are slightly less stringent than those of the US FDA. For example, an API is eligible for a biowaiver in Europe with ≥ 85% absorption in humans (vs. ≥ 90% in the US) and high solubility across the range of pH values from 1 to 6.8 (vs. pH 1 to 7.5 in the US). In the EMA guideline, solubility is more important than permeability and in vitro permeability data is accepted only in support of clinical data. In the US, at least, BCS-based biowaivers are a popular regulatory pathway, particularly among generic drug developers.
The new guideline was the centerpiece of the IQPC Conference on Bioavailability and Bioequivalence in Munich October 25-27. European drug regulators shared their perspectives and experience, as did representatives of several drug and biologics companies as well as one preclinical contract research organization, Absorption Systems, which has considerable experience with in vitro studies in support of BCS-based biowaivers.
Speaking of generics, a surprising statistic was reported in August on PharmTech.com, based on figures released by the EMA: through July, the number of generic drug applications submitted to the agency was down considerably compared with 2009 and 2008. Through July, a total of only 9 generic drug applications had been started and 12 finalized, compared with 38 and 51, respectively, for all of 2009. In 2008, the numbers were 30 started and 4 finalized. The figures were published without comment, pending analysis and interpretation in the EMA’s annual reports.
How to account for only 9 applications started in the first seven months of 2010? Patent expirations, healthcare costs, and World Health Organization advocacy to get cheaper drugs to patients in the developing world are all issues that have been in the news this year. Yet generic drug submissions to the EMA are down substantially. I am not aware of corresponding data for US FDA generic drug submissions, but I wonder if a similar trend is seen there.
Perhaps generic drug companies were waiting for the new EMA bioequivalence guideline to go into effect, in which case we should expect a burst of activity in the second half of the year. Or maybe it’s because the new guideline explicitly states that it “does not cover aspects related to generic substitution as this is subject to national regulation.” I was hoping to have a comment from the European Generics Medicine Association or the EMA but have not received a response to my inquiries. If you have an explanation, please enlighten me!