The case for cross-over trials in phase III.

Abstract

There is a common belief that cross-over trials should not be used in phase III of drug development. This was reinforced by a statement in the draft CPMP Note for Guidance on biostatistical methodology in clinical trials which was circulated for review in March 1993: 'Hence crossover trials in patients should be avoided as far as possible'. We do not share this belief. Historically, many successful drug developments in indications such as hypertension and asthma have depended heavily on cross-over trials in their phase III programmes, leading to regulatory approval for a number of well established medicines. The evidence on which these developments were based appeared sound at the time, and has not been questioned by later experiences with these medicines. Furthermore, the general level of understanding of these medical indications is now even more well developed, and hence the circumstances under which cross-over trials may be used to advantage for new drugs in phase III are even more likely to be correctly identified. There are some well-known disadvantages of cross-over trials relative to parallel group trials. These are reviewed and the ways in which early indications of such problems might be detected in phases I and II or elsewhere will be discussed. However, there are also two key advantages, the well-known one of study size and a less well-known one arising in the context of treatment-by-patient interaction. In phases I and II these advantages lead routinely to the use of the cross-over design. Some methods of analysing cross-over trials have been criticized in a number of recent articles. We compare the properties of a number of alternative analysis strategies by means of simulation and conclude that these concerns about methods of analysis do not imply that cross-over trials should be avoided, especially if baseline measurements can be included in the design. Any small risks attached to their use should not normally concern the regulator as they will tend to diminish estimates of treatment effects rather than enhance them. In summary, cross-over trials remain a potentially valuable research tool in the development of new medicines at all stages including phase III. It is unnecessary and counterproductive to exclude them from use.