The use of placebo control in clinical trials has long been a topic of spirited debate. Proponents maintain that placebo control is necessary for proving the safety and efficacy of investigational products. Critics argue that use of placebo sacrifices patient welfare and is unethical if a proven therapy is available. In analgesia studies, the question of whether or not to use placebo control is further complicated by the placebo response, which can make it difficult to detect efficacy signals. In this blog, Premier Research’s industry-leading analgesia experts take a fresh look at the key considerations surrounding the use of placebo control in chronic pain studies.
Argument for placebo control in analgesia clinical trials
There are several reasons for using a placebo control group in chronic pain studies:1
- Gold standard – Placebo-controlled, double-blind randomized controlled trials remain the gold standard for evaluating efficacy and safety
- Risk/benefit – Placebo is useful as an add-on to standard of care in studies evaluating the risk or benefit of adding an investigational treatment to standard of care
- Establishing effectiveness – Placebo control may be justified if there is a robust placebo response or if the standard of care is only partially effective, which is common in analgesia
- Endpoints – Placebo control is essential for the selection of clinical trial endpoints when subjective pain measures are used due to variability in the perception and reporting of pain
Factors to consider when determining whether a placebo control group is appropriate include pain intensity, availability of standard therapies, ability to justify the study design from a regulatory standpoint, and ethical considerations.
Regulatory perspective on placebo control in pain studies
In the U.S., the FDA has not issued specific guidance on the use of placebo control in analgesia clinical trials. In the EU, the official stance of the EMA is that placebo-controlled trials are necessary, as long as ethical use is clearly understood and implemented.2 The EMA Guideline on the Clinical Development of Medicinal Products Intended for the Treatment of Pain provides recommendations on the use of placebo control in confirmatory efficacy studies. According to the guideline, placebo-controlled trials—often with the inclusion of an active comparator of known effectiveness—are required for monotherapies. For add-on or combination treatments, the EMA advises a standard study design involving randomization to either active test treatment or placebo plus open-label, dose-optimized standard of care.3
Potential modifications to placebo control
One of the main concerns in placebo-controlled chronic pain trials is subjecting study participants to undue suffering. Using placebo control is not synonymous with leaving patients untreated. The use of rescue medication is an important mechanism for preventing undue suffering. Study designs can also be modified to address potential ethical concerns and enhance retention. Three-arm studies that include investigational treatment, active control, and placebo are common. Other potential modifications include:4
- Add-on designs where all patients are given a standard therapy in addition to either study drug or placebo
- Early-escape designs that allow for the use of rescue medications if clinical status worsens or fails to improve
- Limited-placebo designs in which a placebo control group is used for a limited time at the beginning of an active control to establish assay sensitivity
- Randomized-withdrawal designs where all patients are given the study drug for a specified time before randomization to continued treatment with either the study drug or placebo
Regulatory, ethical, and practical issues around the use of a placebo should be addressed early on in an analgesic development program. Requesting scientific advice and protocol review from the appropriate regulatory agency can help clarify the pathway to marketing approval. Partnering with a research organization with analgesia experience or reviewing the protocols of recently approved drugs in a similar therapeutic area may also be useful for gleaning insight into successful study designs.
Despite progress in our understanding of the mechanistic and molecular basis of pain, breakthroughs in novel analgesic drug development remain rare. To make advances, sponsors need to understand placebo considerations in chronic pain trials and implement innovative strategies for reducing response bias and variability.
To learn more about placebo control and the placebo response, download our new white paper, Placebo Considerations in Chronic Pain Studies.
Premier Research has performed more than 870 trials across nearly every type of pain and major class of analgesics, including every NSAID analgesic on the market today. Contact us to schedule a conversation with one of our experts and leverage our experience as you tackle the most innovative areas of analgesia research.
1 Castro M. Placebo versus best-available-therapy control group in clinical trials for pharmacologic therapies. Proc AmThorac Soc 2007;4:570-73.
2 European Medicines Agency. EMEA/CPMP position statement on the use of placebo in clinical trials with regard to the revised declaration of Helsinki. EMEA/17424/01. London, 28 June 2001.
3 European Medicines Agency. Guideline on the clinical development of medicinal products intended for the treatment of pain. EMA/CHMP/970057/2011. 15 December 2016.
4 U.S. Food and Drug Administration. Guidance for Industry: E10 Choice of Control Group and Related Issues in Clinical Trials, May 2001. Available at https://www.fda.gov/media/71349/download.