Regulatory advice and drug development--a case study in negotiating with regulators.

Regulatory guidance on the development of drugs has existed for well over half a century in some territories. As drug development grew to become global so was born the need for harmonization. Beginning in the 1990 s, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) developed guidelines which were adopted by the Food and Drug Administration (FDA) in the U.S.A., the European Medicines Agency (EMA) in the European Union and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. These guidelines are generally not disease specific. A visit to the web sites of any of the aforementioned Agencies or, for that matter other regulatory agencies outside of these, will witness a plethora of additional/separate guidances, some of which are disease specific. In addition to such written guidances, more specific advice (for example, on a drug development program at the end of Phase II) may be requested from the Regulator. Despite the harmonization efforts expressed through ICH, the actual advice given by different regulatory authorities in practical situations, however, may be inconsistent. This paper will describe a case of seeking advice on a Phase III programme from the FDA and the EMA, obtaining different opinions and developing an innovative solution to satisfy both Authorities without necessarily extending development time significantly. The case is chronic kidney disease; the issues concern study design (non-inferiority, margin, etc.); the solution required a non-traditional design and associated sample size considerations. We conclude with some general advice on 'talking to the regulator'. This work was originally presented as a Poster at the Statistical Methods in Biopharmacy, 6th International Meeting, Paris, 21-22 September 2009.