Off-labeled Drugs
The use of off-labeled drugs for wound healing is not an uncommon practice. Medications that are approved for a specific use by the US Food and Drug Administration may also be used for off-label treatment if warranted by the physician's clinical judgment-with the proviso that there is a documented rationale for such use in the patient record. The practitioner prescribing any drug, device, or therapeutic agent must carefully consider the safety/efficacy/cost/benefits ratio of the prescription for the patient. Moreover, given the heterogeneity of patients we see in the clinic, often with multiple comorbidities, clinicians should also consider taking a moment to think about the mnemonic "ADD": age-drug, drug-drug, and drug-disease interactions when prescribing all drugs.
Oxandrolone
I have been a proponent of using off-label medicine sparingly in wound care, in particular, the use of oxandrolone (anabolic steroids). My clinical outcomes with a small number of patients were promising, and I was convinced of the efficacy of the drug for use in patients with spinal cord injury (SCI), those in a chronic catabolic state, or those with chronic nonhealing wounds.1,21,2
In 2000, I was invited to chair a research planning committee at the Veterans Affairs (VA), Health Services Research and Development Program, involving the use of oxandrolone in the treatment of pressure ulcers (PrUs) in patients with SCI. The principal investigator for this multicenter research project was William A. Bauman, MD, National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York. The research design was a parallel-group, placebo-controlled, randomized trial conducted from August 1, 2005, to November 30, 2008.3 The patients, healthcare providers, study personnel, and statisticians were blinded to treatment assignment. The study included 16 inpatients of SCI services at VA medical centers. In total, there were 1900 patients prescreened, 779 screened, and 212 randomly assigned inpatients with SCI and a Stage III or IV PrU. The pharmacological intervention was oxandrolone, 20 mg/d (n = 108), or placebo (n = 104) until the PrU healed or 24 weeks had elapsed.3
The primary outcome was healed PrUs. The secondary outcome was the percentage of PrUs that remained healed at 8-week follow-up. A limitation of the study indicated that the selection of severe wounds may have reduced treatment response. Approximately one-third of patients did not complete the study in the treatment and placebo groups. There were no significant adverse effects of the drug. The study was terminated after a "futility analysis showed" (interim analysis for futility: to see if the new treatment is unlikely to beat the control, then stop the trial for futility-this is called "futility analysis")4 a low probability of detecting a significant difference between the groups. The authors3 concluded that oxandrolone showed no benefit over placebo for improving healing or the percentage of PrUs that remained closed after 8 weeks of treatment. Essentially, the study showed that oxandrolone was no better than placebo-a negative outcome for the candidate treatment.3
Negative Outcomes
Most research investigators conduct an investigation to demonstrate the safety and efficacy of the drug; however, as in the case mentioned, it is possible to show the opposite is true and that the drug has no effect. A simplified way of explaining the importance of the negative effect phenomenon is to refer to it as the "null hypothesis." Disclosing negative research findings to the public is transparency in its purest form. However, many patients are never apprised on the findings of research studies, and most of the information they receive is from very conscientious practitioners, and advertisements through the Internet and television. It is not uncommon for pharmaceutical companies and some journals that are reliant on advertisement revenue to report only positive results.5
Where do we find journals that publish negative results? Some argue that an open-access database of negative results should be available. Several journals publish negative results that should be highly valued, for example, the Journal of Negative Results in Biomedicine, the Journal of Negative Results-Ecology and Evolutionary Biology, and the Journal of Articles in Support of the Null Hypothesis.5 Negative findings matter to those analyzing the safety and efficacy of pharmacotherapeutics and, most important, to our patients.
References