Pain is among the most common symptoms leading patients to seek medical treatment. Still, most analgesic treatment options are characterized by poor efficiency, high adverse event rates, serious safety concerns, and potential abuse liability. Pain management remains in need of better, safer medication.
Underestimating the placebo effect is a serious risk
Development of novel pain medication has been frustrated by the robust placebo effect. Literature shows that the chances for success with low-abuse potential drugs are only 4.7%. This can be particularly costly with Phase 3 representing the most common period for attrition1.
Substantial evidence shows expectation, conditioning, and patients’ beliefs in treatment efficacy can all play a role in augmenting placebo response. Whilst conducive to clinical care, these factors can degrade signal detection in clinical trials.
The blinding and randomization paradigms used in clinical trials are not protection against high placebo response. In accordance with the ceteris parabus principle we might expect the outcome for an investigational product to follow an “additive” model in which the outcome for the IP is the placebo effect and the specific effect of the study drug, but that has not been consistent with results for actual studies.
In that ceteris parabus model, adding an extra 20% placebo response should raise response rates in both groups by 20%. Indeed, a 20% increase to an expected 30% produces a placebo group response of 50%. However, adding that extra 20% to a 50% IP response rate might only produce a 60% overall response rate. Such data suggesting a ceiling on total efficacy means an increase in the placebo effect usually reduces the drug-placebo difference2.
Indeed, the placebo effect remains a potent comparator, and most experienced drug developers know, if signal is to be detected, they will need to combat the threat of high placebo response. But how do they best cope with this worthy opponent?
Evidence-based strategies
Implementing evidence-based strategies to mitigate placebo response in pain trials is the best foundation in research for novel therapies.
A leading global biopharmaceutical company followed this approach in their Phase 3 trials and gained FDA approval for their non-opioid pain medication for post-surgical pain.
The company took advantage of Signant Health’s multifaceted approach to placebo response mitigation which includes several focused placebo mitigation strategies: Site staff/rater training, participant training and data analysis.
They collaborated with our scientific experts to carefully interact with participants while limiting placebo augmenting communication. Implementing the science of placebo response was operationalized through interactive trainings investigators.
Most clinical trials for pain rely on subjective outcome measures. To lessen the potential influence of warmly engaged site staff, workshops taught specific techniques designed to promote alliance with study participants appropriate to research rather than clinical care. Educating and empowering participants as partners in research, supports higher data reliability and validity.
Ultimately the proof is in the pudding, and the biopharmaceutical's investigational product showed a significant difference in reducing post-surgical pain compared to placebo.
Conclusion
Important public health needs make the stakes in development of safer and more effective pain treatments higher than ever. The success of the company's novel non-opioid analgesic represents a significant step forward in pain management for millions of people worldwide.
This success leveraged carefully designed, rigorous trial methodologies and the expert implementation of evidence-based solutions to common research problems.
About the authors
Martina Micaletto is a Clinical Scientist at Signant Health, with extensive experience in the pharmaceuticals industry. She specializes in computerized cognitive batteries, scale administration and scoring, rater training and certification, and endpoint assessments. Martina is skilled in statistics, research, negotiation, psychology, and customer care. She holds an MSc in Social and Cultural Psychology from The London School of Economics and Political Science (LSE) and an MSc in Development and Psychopathology from The University of Reading.
Gary Sachs, Therapeutic Area Leader in bipolar disease and mood disorders at Signant Health, is a recognized expert in clinical trial methodologies. He founded the Bipolar Clinic at Massachusetts General Hospital and is an Associate Professor of Psychiatry at Harvard Medical School. With over 200 publications, Dr. Sachs also serves on the Scientific Advisory Boards of the National Alliance on Mental Illness and the Depression and Bipolar Support Alliance.
References
- Maher DP, Wong CH, Siah KW, Lo AW. Estimates of Probabilities of Successful Development of Pain Medications: An Analysis of Pharmaceutical Clinical Development Programs from 2000 to 2020. Anesthesiology. 2022 Aug 1;137(2):243-251. doi: 10.1097/ALN.0000000000004265. PMID: 35504001.
- Boussageon, R., Howick, J., Baron, R., Naudet, F., Falissard, B., Harika‐Germaneau, G., ... & Blanchard, C. (2022). How do they add up? The interaction between the placebo and treatment effect: A systematic review. British Journal of Clinical Pharmacology, 88(8), 3638-3656.
- Kaptchuk TJ. Powerful placebo: the dark side of the randomized controlled trial. Lancet 1998;351:1722-5.
- Horan W, Sachs G, Velligan D, et al Current and Emerging Technologies to Address the Placebo Response Challenge in CNS Clinical Trials: Promise, Pitfalls, and Pathways Forward Innov Clin Neurosci. 2024.
