Combination Therapy: Should We See It More In Podiatric Clinical Trials?

   Given the ongoing emphasis toward incorporating more evidence-based medicine (EBM) in podiatry, there has been a noticeable increase of published clinical trials in the peer-reviewed podiatry literature. For example, in the November/December 2005 issue of the Journal of the American Podiatric Medical Association (JAPMA), six out of the eight original articles are clinical trials.    While these developments are certainly encouraging, there does seem to be a lack of published clinical trials involving combination therapy — the combination of one or more agents or treatment modalities—as either the main thrust of the study or as one of the treatment arms.    Kathleen Satterfield, DPM, raises these issues in her guest column for the “Diabetes Watch” column (see page 22). Whether podiatrists are treating plantar fasciitis or lower extremity complications in patients with diabetes, they commonly utilize a combination of treatments to help achieve the best results.    It stands to reason that published clinical trials focusing on or involving combination therapy for a given condition would be particularly useful for podiatrists.    However, there are significant obstacles to conducting clinical trials with combination therapy. A few podiatrists who have experience with clinical trials note the folks who run these trials “like them to be as simple as possible, answering a clear question and focusing on specific aims.” When assessing the efficacy of combination therapy in a study, there will be inevitable questions about which component of the combination therapy is more efficacious.    Statistical issues, increased costs and quality control concerns also come into play as one adds more variables to a clinical trial. As one DPM points out, each variable in a clinical trial generally requires 10 participants or subjects. Accordingly, a trial with three treatment arms would require 30 participants for the study. Then you would add in risk factor variables of interest (age, sex, body mass index (BMI) and comorbidities for example). This increases the number of required participants to 70. When you add in more variables, the number of required participants to facilitate statistical relevance increases and the statistical analysis accordingly becomes more complicated, time-consuming and costly.    Obviously, the majority of clinical trials will be funded by industry and the common perception is companies simply want to show the efficacy of their product by comparing it to a placebo treatment. As a podiatrist points out, this does satisfy the FDA in terms of a “starting point” in identifying whether a particular agent is efficacious and safe.    However, it would nice to see an increased emergence of clinical trials that compare a particular combination therapy to a standard monotherapy. Podiatrists who are familiar with clinical trials say this would not be difficult from the standpoint of trial design.    There are also some instances in which industry might be served by a clinical trial focusing on combination therapy. For example, say there is a topical for a given podiatric condition that is not as effective as an oral medication. Perhaps the manufacturer of the topical would be served by a study that compares the combination of the topical with another agent versus the oral medication.    If researchers show the combination of the topical with another agent has similar or close to similar efficacy to using the oral medication alone, the manufacturer of the topical could market the combination as a logical alternative treatment in patients who cannot take the oral medication due to contraindications or possible side effects.    Granted, there are legitimate hurdles for using combination therapy in clinical trials. However, given the prevalent use of combination therapy for common podiatric conditions, it merits serious consideration in future research endeavors.