Placebos by Kathryn T Hall

Author:Kathryn T Hall [Hall, Kathryn]
Language: eng
Format: epub
Tags: Placebo; nocebo; expectations; nostrums; clinical trials; precision medicine; neuroscience, placebo surger;
Publisher: MIT Press
Published: 2022-09-14T00:00:00+00:00

Minimizing Placebo Responses in Trials

Despite the consistent significant but small benefit of antidepressants over a placebo, the road to approval is still littered with near misses and failures, and some FDA decisions are still hanging in the balance. The failure to beat a placebo has been attributed to a myriad of factors: lax inclusion and exclusion criteria, the trial duration being too short or too long, a lack of adherence to the study drug, the wrong dose or formulation, the wrong study population, too small or too large trial sizes with too many sites, or the drug just doesn’t work.

As many reasons as there are for failure, there are strategies in place to remove their influence. We can group these into three buckets: patient variables, clinical trial designs, and outcome measures. Ironically, with marginal differences between a drug and placebo, clinical trialists need to boost the statistical power by enrolling more patients into the trials. This need for more subjects has contributed to the globalization of clinical trials, which in turn has led to increased heterogeneity due to differences in access to clinical care (in some countries, enrolling in a trial is a way to get treatment), risk factors, and beliefs about health care that can influence expectations.15 Trialists yielding to financial and temporal pressures might relax inclusion criteria, further increasing heterogeneity in the target population. Another problem is the growing cohort of professional patients who game the system by simulating patient effects to get enrolled in trials for money.

Adherence is also a critical factor in response to treatment. While medication adherence is likely a proxy for healthy behaviors, several studies have found that both drug and placebo adherence are associated with better health outcomes.16 Still, poor adherence can in many cases be blamed for drugs failing to beat the placebo response. To address this problem, smart pill bottles are being deployed in clinical trials to monitor when patients take their study meds.17

Perhaps the biggest variable driving patient heterogeneity is the patient. In the case of depression, there is tremendous heterogeneity in the presentation and origin of symptoms. Some patients exhibit every symptom, and others only exhibit one or two. Some patients display depressive symptoms later in life after major events, and others show symptoms from a young age with no obvious “event.” Because of these differences, it can be difficult to identify the mechanistic treatment needs of each individual patient based on the responses of the group. Add in gender, education, and social, psychological, and financial stressors, and you can see how the appropriate treatment could vary within just one individual at different stages in life, let alone for millions on a nationwide scale over time.

The elements of clinical trial design including the size, duration, number of treatment arms, and follow-up frequency are just a few of the variables that can influence outcomes in both the drug treatment and placebo arm of a trial. After more than seventy years of using placebo controls in clinical trials, we are only

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