Article | February 1, 2018

Addressing Placebo Response, Therapeutic Misconceptions And Expectations

By Mark Opler, Ph.D., MPH and Gianna Capodilupo, MA

Addressing Placebo Response, Therapeutic Misconceptions And Expectations

Double-blind, randomized placebo-controlled clinical trials are highly challenging and resource-intensive. Drug-development costs have risen dramatically over time, yet success rates have not improved1. In parallel, rates of placebo response across multiple therapeutic areas are at historic highs and progressively increasing2. Multiple reviews in different therapeutic areas, including pain3, epilepsy4, Crohn’s disease5, schizophrenia6, and others suggest a worsening trend - year over year, the rates of placebo response are going up.

It has been widely reported and accepted that patient expectations can influence placebo response/effect.7 Expectations can be influenced by statements and actions from clinical trial site staff- or from caregivers and family members- which may significantly contribute to a patient’s level of therapeutic expectation, or the level of improvement the patient anticipates in response to any treatment. Professionals with good intentions while recruiting patients (e.g., “We have high hopes for this medication” etc.) and/or hopeful comments from caregivers supporting patients in their deliberations about participation in trials (e.g., “I read something about this drug online—it might work for you”), may pave the way for increased therapeutic expectation. Placebo response mitigation strategies must incorporate investigator training, site training, and patient/caregiver training in order to be effective, ensuring that patients have realistic expectations about participation in the study.

A related, but distinct, issue that methodologists must tackle beyond therapeutic expectation is that of therapeutic misconception. Therapeutic misconception is best characterized as “a research subject fail(ing) to appreciate the distinction between the imperatives of clinical research and those of ordinary treatment.”8

In brief, a research subject who cannot differentiate between participation in a clinical trial and receiving clinical care is experiencing therapeutic misconception. This is not necessarily due to a failure on the part of the investigator, the subject, or the informed consent process; rather, it is the natural tendency of people to make decisions based on individual beliefs and experiences. This can have an effect on self-reporting symptoms, and undermine the integrity of the subject’s responses and data in the study. Identifying patient perceptions and attitudes that may interfere with unbiased participation, as well as a clear description of the purpose of the trial, highlighting the difference between participation in research and routine medical care will help reduce or eliminate patient misconceptions about the study drug/treatment. This will also give the site confidence that a patient is making cognitively informed decisions about the role of placebo in the trial.

There are several steps that can be taken at the patient level to ensure valid, reliable data collection, and to improve the likelihood of trial success. Investigators should work to ensure that all potential study subjects consistently meet standards which contribute to the study’s success. These standards include those stated above, as well as accurately reporting on symptoms as experienced during and between study visits. It is also important to ensure each patient has the ability to be a good informant, which encompasses adequate capacity and mental status, appropriate motivations to participate, and insight into their compliance history. If these are not present, concerns regarding compliance with the study drug/placebo medication arise. One final step that can be taken is to ensure that the patient has a sufficient understanding of the construct under investigation. This in turn will provide a valid assessment of frequency and severity of treatment-related experiences, with a focus on relevant phenomena.

Most sites and investigators likely implement a form of patient education into their routine process of recruitment- standardized or otherwise. Given the frequency of therapeutic misconception that may occur (in one sample, as high as 31% of subjects expressed unrealistic beliefs about a trial in which they were participating9), all trial team members and their studies are likely to benefit from a more rigorous approach to this issue.

Improving outcomes in clinical trials and reducing the trend toward high placebo response across different therapeutic areas requires the involvement of multiple stakeholders. Randomized, placebo-controlled clinical trials are pivotal events in drug discovery; they often represent the culmination of lengthy preclinical investigation, immense investment of labor, intellectual capital, and considerable financial resources. Protection of that investment through placebo response mitigation techniques must become a routine aspect of our trial methodologies.

Other critical aspects that must not be neglected are the ethical and moral imperatives tied to ensuring that all participants are fully informed—not simply procedurally, but emotionally, intellectually, and cognitively. Reducing placebo response may serve multiple critical ends, fulfilling not only the scientific and economic promise of drug development, but also enhancing our humanitarian mission.


  1. Di Massi J, et al. 2010. Clin Pharmacol Ther 87(3):272–7.
  2. Enck, et al. 2011. Philos Trans R Soc Lond B Biol Sci 366(1572):1889–1895.
  3. Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweinhardt P, Bennett GJ, Mogil JS. 2015. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain 156(12):2616–26.
  4. Rheims S, Perucca E, Cucherat M, Ryvlin P. 2011. Factors determining response to antiepileptic drugs in randomized controlled trials: a systematic review and meta-analysis. Epilepsia 52(2):219–33.
  5. Gallahan WC, Case D, Bloomfeld RS. 2010. An analysis of the placebo effect in Crohn's disease over time. Aliment Pharmacol Ther 31(1):102–7.
  6. Dold M, Kasper S. 2015. Increasing placebo response in antipsychotic trials: a clinical perspective. Evid Based Ment Health 18(3):77–9.
  7. Finniss, D. G., Kaptchuk, T. J., Miller, F., & Benedetti, F. (2010). Biological, clinical, and ethical advances of placebo effects. The Lancet, 375(9715), 686-695.
  8. Lidz CW, Appelbaum PS. 2002. The therapeutic misconception: problems and solutions. Med Care 40(9 Suppl):V55–63.
  9. Appelbaum PS, Lidz CW, Grisso T. 2004. Therapeutic misconception in clinical research: frequency and risk factors. IRB 26(2):1–8.

Mark Opler, PhD, MPH, ( is founder and chief scientific officer of ProPhase, LLC and an assistant professor with both the NYU School of Medicine and Columbia University Medical Center.