Drug regulatory authorities have guidelines in place making it possible to register alternative formulations of the same molecule with minimal development. This permits generic manufacturers to obtain licenses for their products once the innovator patent has expired. A common approach is to use so-called bioequivalence studies in which healthy volunteers take innovator and generic drug on separate occasions and the concentration time profile of the medicines is compared[1]. This works quite well in many cases. However, there are some instances where this approach does not work. For example, many treatments for asthma are given in inhaled form. This being so, the concentration in the blood is an inadequate indication of potency. Parallel assay trials are then sometimes proposed to show equipotency of the new formulations with the old[2, 3]. The need for such studies became acute in recent years because of the banning of chlorofluorocarbon (CFC) formulations due to their environmental impact. Manufacturers have moved to replace CFC formulations by hydrofluoroalkane (HFA) formulations. Indeed, officially CFC formulations have now been phased out. However HFA formulations have not been successfully introduced in all cases to replace them. In fact, parallel assay studies suffer from a number of problems. First, they require much bigger numbers of subjects than conventional bioequivalence studies. Second, they can never be as convincing as regular bioequivalence studies since, for an oral formulation, equivalence in the blood plausibly implies equivalence of concentration at all effect sites. However, for a parallel assay, whatever outcome measures are used, one could always plausibly imagine that there are some effects or side-effects that might reveal a difference.
It may be that a dual assay approach is required using separate efficacy and tolerability assays with the emphasis in the former in showing that potency is as great as for the standard and the emphasis in the latter in showing that it is no greater.
1. Senn, SJ. Statistical issues in bioequivalence, Statistics in Medicine 2001; 20: 2785-2799.
2. Senn, SJ, Lillienthal, J, Patalano, F, Till, MD, An incomplete blocks cross-over in asthma: a case study in collaboration, in Cross-over Clinical Trials, Vollmar, J., and Hothorn, L. A., Eds., Fischer, Stuttgart;1997 pp. 3-26.
3. Miller, CJ, Senn, S, Mezzanotte, WS. Bronchodilation of formoterol administered with budesonide: Device and formulation effects, Contemp Clin Trials 2008; 29: 114-124.