The purpose of a clinical trial is to evaluate an intervention for a clinical condition with the longer-range goal of improving human health and clinical practice. Positive (or negative) data can lead to a recommendation to use (or not to use) the treatment. NCCAM's goal is to provide definitive clinical trial data leading to recommendations for complementary and alternative medicine interventions. The better the quality of the studies, the greater the likelihood that they will yield compelling answers. By contrast, weaker studies might risk premature dismissal or acceptance of a modality.

Clinical practice recommendations are generally derived from "Phase III" clinical trials, in which large numbers of patients are administered the optimum dose of the treatment. The optimum dose is approximated by preceding Phase I /II dose-ranging studies, which provide preliminary data on safety and efficacy.

Phase I trials focus on safety, whereas Phase II studies focus on efficacy. The concepts of safety and efficacy are often at odds with each other. Lowering the dose can improve safety but at a cost to efficacy. Raising the dose will generally increase toxicity as well as efficacy. Estimating the optimum dose (i.e., a dose that is likely to be both safe and effective) can be difficult.

Note that use of a suboptimal dose that is safe but ineffective does not serve the larger goals of NCCAM or the complementary and alternative medicine community. Although the trial indicates only that the tested dose of the intervention was ineffective, the community may conclude that all doses of the intervention are ineffective, and patients will be denied possible benefit from the intervention. The inappropriate rejection of an intervention, because Phase I/II studies did not precede a "Phase III" trial and a suboptimal dose was used in the Phase III trial, is common for CAM modalities and is a primary reason for this discussion.

We note that the need for dose-ranging studies prior to Phase III trials applies not only to botanical and other biologically based CAM therapies, but also to other CAM interventions (e.g., mind-body approaches such as behavioral interventions and therapies such as massage, reiki, and acupuncture). Before moving into Phase III trials of these interventions, the investigator needs to know the optimum number, frequency, and length of sessions needed to achieve efficacy while minimizing negative consequences, such as poor recruitment rates or patient noncompliance with the treatment regimen.

For some CAM interventions and clinical conditions, substantial previous research may exist that has determined the optimum dose for a treatment. For others, dose-ranging studies will need to be performed prior to beginning more expensive Phase III studies. Therefore, if the scientific literature does not contain scientifically valid dose-ranging data, the investigator should consider collecting these data.

The goals of dose-ranging studies are to quickly and efficiently determine the dose that is both safe and effective. Many statistically based dose-escalation schemes exist, and they generally fall into two categories:

• Traditional (non-Bayesian)
• Bayesian.

NCCAM does not give priority to any one dose-ranging scheme. The choice of a study design should be made based on the clinical condition being treated, availability of current data in the literature, likelihood of efficacy, likelihood and seriousness of toxicity or other negative consequences, per subject cost, and anticipated time to response. Clinical investigators are urged to consult with biostatisticians for examples of dose-ranging schemes and to decide which scheme best fits the needs of the particular clinical problem.

December 2003

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