Randomised controlled trial is considered the gold standard for evidence-based evaluation of the efficacy of a new drug. The control group may receive a placebo or standard therapy. The use of a placebo in clinical trials raises ethical concerns and debates, especially in disorders where proven effective treatments are available.
The physician would like to offer her patients the best-proven intervention as control, as she would like to know whether a new experimental therapy is better than the existing standard. However, this approach can lead to erroneous outcomes. For clinical trials in certain conditions, e.g., angina, headache, migraine, anxiety and depression where the efficacy assessment is based on symptoms, the response rate for placebos tends to be high. In such a situation, an active control trial demonstrating no difference between a new therapy and the available effective therapy is of little value.
Regulatory authorities require evidence of absolute efficacy of a new experimental therapy before giving marketing approval. Moreover, the difference in efficacy between an experimental and standard therapy is likely to be smaller than the difference between the experimental therapy and placebo. Hence, placebo-controlled trials require fewer subjects, saving time and cost. Also, placebo-controlled trials allow a more accurate assessment of whether the adverse events occurring during the trial are due to the pharmacologic properties of the new drug or due to symptomatic expression of the disorder. These scientific considerations are ethically important as placebo-controlled trials can provide rigorous initial evidence of efficacy without exposing large numbers of patients to potentially ineffective new treatments.
The conduct of placebo-controlled trials should comply with universal ethical requirements. Risks of using placebo controls in trials of mild conditions, e.g., allergic rhinitis and heartburn would be acceptable. However, placebo controls would be unethical if withholding an available therapy is likely to expose the research participants to death or irreversible morbidity, such as in cases of cancer and infections. The duration of the placebo administration should be restricted to the minimum time required for testing efficacy. Rigorous oversight and monitoring by the investigator are necessary to protect clinical trial participants. Placebo-controlled trials in severely ill patients should be conducted in inpatient settings with constant monitoring, where rescue drugs would be readily available. The investigator should make efforts to make the participants understand the rationale of placebo use and the probability of receiving a placebo. There should be additional safeguards for vulnerable populations.
The use of innovative add-on designs where both placebo and new drugs are added to standard effective therapy can reduce the risk of withholding effective treatment for subjects. Such studies are beneficial when the available therapy is effective in reducing mortality or irreversible morbidity. In a three-arm trial comparing a new drug, placebo and active control, making the new drug or active control group larger than the placebo group can reduce the chance of patients being randomized to placebo. In early escape rescue designs, the study participants, whose medical condition worsens or fails to improve to a predefined degree, are promptly withdrawn from the trial and are given appropriate standard therapy.
Placebo-controlled trials are scientifically indispensable but should be ethically justified and conducted.
Writer is a consultant on clinical research & development from Mumbai. firstname.lastname@example.org