Does the increasing placebo response impact outcomes of adult and pediatric ADHD clinical trials? Data from the US Food and Drug Administration 2000–2009

Abstract

In a study of recent antidepressant clinical trial data, it was found placebo response had grown significantly over time and that contrary to expectations, trial outcome measures and success rate were not impacted. The aim of this paper was to evaluate if this trend of increasing placebo response and stable outcome measures could be seen in clinical trial data for Attention-Deficit Hyperactivity Disorder, a different psychiatric condition with susceptibility to placebo response. For this reason, we evaluated efficacy data reported in the FDA Medical and Statistical reviews for 10 ADHD medication programs (4917 patients, 17 trials, 29 treatment arms). Placebo and medication response were measured as percent symptom reduction and effect sizes and drug-placebo differences were calculated for each treatment arm and analyzed in relation to year of approval. We also investigated the potential role of age and medication class on trends and outcomes. Results showed a similar pattern to antidepressants wherein the placebo response is rising significantly over time (r = 0.636, p = 0.006) and effect size (r < 0.0001, p = 1.0), drug-placebo difference (r = -0.238, p = 0.214), and success rate (28/29 97%) have remained unaffected, likely due to a parallel, although not statistically significant increase in medication response (r = 0.326, p = 0.085). Age and medication class did not alter these observed time trends but pediatric trials and stimulants were found to have more robust treatment effects than adult trials and non-stimulants. The results of this study suggest that like antidepressants, the relationship between placebo response and the outcomes of ADHD clinical trials is weak at best.

Magnitude and pattern of placebo response in clinical trials of antiepileptic medications: Data from the Food and Drug Administration 1996–2016

“…These source-verified and independently reviewed data confirm previous suggestions of a rising placebo response from analyses of published studies [2][3][4] and further support the findings from previous researchers that AED efficacy has not changed significantly over the years [8,9]. This constellation of effects appears to be a general phenomenon across clinical trials for disorders of various types, as this pattern of rising placebo and stable outcomes has been seen in psychiatric [10,11] and non-psychiatric conditions.…”

Magnitude and Pattern of Placebo Response in Clinical Trials of Oral Antihyperglycemic Agents: Data From the U.S. Food and Drug Administration, 1999–2015

“…In support of our hypothesis, both sets of analysis of treatment arms from the two common types of placebo-controlled trial design (exclusively placebo-controlled and augmented placebo-controlled) demonstrated that there is a nontrivial placebo response in clinical trials for type 2 diabetes. Similar to the apparent generalized phenomenon seen in trials of other psychiatric and physical conditions (5)(6)(7)(8), the magnitude of placebo response is rising significantly over time, whereas effect sizes and success rates have remained unaffected.…”

“…This pattern of a rising placebo response and stable outcome measures is similar to the pattern seen in other chronic illnesses, supporting the assumption that this pattern may represent a generalized phenomenon across placebocontrolled clinical trials. As in the case of antidepressants (5), attention-deficit hyperactivity disorder medications (6), antihypertensives, and antiepileptics (7,8), the significant growth in placebo response in both exclusive and augmented placebo-controlled trials of type 2 diabetes appears not to have had an effect on trial efficacy outcomes. Like other medication trials, this lack of effect on efficacy outcomes appears to be related to the apparent, although not statistically significant, proportional increase in drug response over time ( Figs.…”

“…If such a placebo response were to be present in clinical trials of diabetes, the assumption would be that the response pattern emerging over time would be similar to the pattern observed in trials of other conditionsdan increase in the magnitude of placebo response without significant change in the efficacy outcomes (effect size and success rate) of trials for oral antihyperglycemic agents. The reason we assume that this pattern will emerge in diabetes trials is because rising placebo response and stable outcome measures over time appear to be a general phenomenon across placebo-controlled trials of all types, as has been seen in depression (5), attention-deficit hyperactivity disorder (6), hypertension, and epilepsy trials (7,8). Enhanced expectation of improvement may be behind this rising placebo response but other variables may play a role as well.…”

Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016

“…Effect size, drug-placebo differences, and success rate have remained stable, due to a parallel increase in drug response. This pattern of rising placebo response and unaffected trial outcomes does not appear to be unique to antidepressant trials; we have also seen it in clinical trials for ADHD medications [ 5 ], antiepileptics [ 6 ], and antihyperglycemics [ 7 ].…”