Clinical trials to prevent/treat childhood asthma: methodologic issues

Abstract

There is currently much excitement about clinical trials for the primary and secondary prevention of childhood asthma [1–3]. For the first time in over 40 years there are real novel therapeutic possibilities that deserve testing. In thinking about the design of these trials, it is critical to consider four issues: the traditional validity threats to clinical trials, how fetal lung development influences clinical trial design, how asthma natural history and asthma subphenotypes influence trial design and finally, drug dosing for these studies. As might be suspected, fetal lung development has its greatest impact on primary prevention trials and asthma sub phenotypes have its greatest effect on secondary prevention trials. Although people often focus on the randomized controlled nature of clinical trials, the methodological issues of blinding and randomization address internal validity, and not the source population from which trial subjects are drawn. The greatest validity threat to any clinical trial is the external validity generalizability of results, can the trial results be extrapolated to the population at large and what will be the population impact of the new treatment or preventative. Concrete examples of these generalizability issues can be seen in the source population for two of the new primary prevention trials in childhood asthma: the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the recent trial of vitamin C to prevent asthma in smoking pregnant women [1,2]. In the former case, VDAART is focused on women with a prior personal, or family, history of asthma, or allergies and giving them vitamin D to prevent asthma in their offspring. If successful, it will be a generalizability leap to all pregnant women, even those with a low genetic risk of asthma in their children, to extrapolate the trial results. In the latter case of vitamin C, the source, or target population, is the 12% of pregnant women who smoke and, as yet, there is no evidence that vitamin C will prevent asthma in nonsmoking pregnant women. This issue of generalizability is important in targeting public health interventions particularly in the area of primary prevention.