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Ethical principles and placebo-controlled trials - interpretation and implementation of the Declaration of Helsinki's placebo paragraph in medical research.

ABSTRACT: BACKGROUND:In October 2013, the Declaration of Helsinki was revised a seventh time in its 50 year history. While it is the most widely accepted set of ethical principles for the protection of patients participating in medical research, the Declaration of Helsinki has also been subject of constant controversy. In particular, its paragraph on the use of placebo controls in clinical trials divides the research community into active-control and placebo orthodox proponents, both continuously demanding revisions of the Declaration of Helsinki in favour of their position. The goal of the present project is to compare the mainly theoretical controversy with regulatory implementation. METHODS:We distributed a questionnaire to national drug regulatory authorities from different countries to collect information on the authorities' respective approaches to interpretation and implementation of the Declarations' placebo paragraph in the conduct of medical research. RESULTS:Our findings suggest that the majority of drug regulatory authorities have established a practice of a middle ground, allowing placebo controls in some instances. Various interpretations of "serious harm" and "methodological reasons" are proposed as well as safeguards to avoid abuse of the option to use placebo-controls. CONCLUSION:Leaving the placebo paragraph open to various interpretation is a result of the Declaration of Helsinki's character as a guidance document. With the current version controversy will continue. The Declaration should be continued to be strengthened to enforce the appreciation of conducting medical research with the highest ethical standard.

SUBMITTER: Skierka AS

PROVIDER: S-EPMC5856313 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Ethical principles and placebo-controlled trials - interpretation and implementation of the Declaration of Helsinki's placebo paragraph in medical research.

Skierka Antonia-Sophie AS Michels Karin B KB

BMC medical ethics 20180315 1

<h4>Background</h4>In October 2013, the Declaration of Helsinki was revised a seventh time in its 50 year history. While it is the most widely accepted set of ethical principles for the protection of patients participating in medical research, the Declaration of Helsinki has also been subject of constant controversy. In particular, its paragraph on the use of placebo controls in clinical trials divides the research community into active-control and placebo orthodox proponents, both continuously ...[more]

PMID: 29544543

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Project description:Conventional randomized placebo-controlled study design assumes the absence of drug*placebo interaction. We hypothesized the presence of such an interaction and that conventionally estimated drug effect might be biased. The objectives of the study were to determine the drug*placebo interaction effect (main) and compare conventionally estimated and interaction model-estimated drug effects (secondary).We used a hybrid of balanced placebo and randomized placebo-controlled designs. Four hundred eighty healthy volunteers were randomized to three groups. The first received hydroxyzine (25 mg) described as hydroxyzine or placebo, the second received placebo described as hydroxyzine or placebo, and the third received hydroxyzine and placebo described as unknown; each in a randomized crossover design. Seven participants failed to crossover. Group assignment was concealed from participants and study coordinators. Coordinators were blinded to group and intervention assignment. Participants and coordinators were deceived as to study objectives. Main outcomes were mean area-under-the-curve of drowsiness (therapeutic outcome) and mouth-dryness (adverse outcome), self-reported on 100 mm visual analog scale over 7 h. Drug, placebo, placebo?+?interaction, and total effects were estimated using analysis of covariance by comparing received hydroxyzine/told placebo to received placebo/told placebo, received placebo/told hydroxyzine to received placebo/told placebo, received hydroxyzine/told hydroxyzine to received hydroxyzine/told placebo, and received hydroxyzine/told hydroxyzine to received placebo/told placebo, respectively. Drug effect was also conventionally estimated in the third group.Mean (SD) age was 31.4 (6.6) years, 65% were males. There was significant difference between placebo?+?interaction effect and placebo effect for both drowsiness and mouth-dryness with a mean difference (95% confidence interval) of 35.1 (5.6 to 64.6) and 23.8 (2.4 to 45.2) mm*hr, respectively. Total effect was larger than the sum of drug and placebo effects for drowsiness (139.7 (109.8 to 169.6) vs. 99.1 (68.2 to 130.0) mm*hr) and mouth-dryness (63.6 (41.1 to 86.1) vs. 34.7 (11.1 to 58.4) mm*hr). Conventionally estimated drug effect was larger than interaction model-estimated drug effect for drowsiness (69.2 (45.5 to 92.8) vs. (58.3 (31.6 to 85.0) mm*hr) and mouth-dryness (19.9 (5.3 to 34.5) vs. 9.5 (-9.2 to 28.1) mm*hr).There is significant and important drug*placebo interaction effect that may bias conventionally estimated drug effect.ClinicalTrial.gov identifier: NCT01501591 (registered December 25, 2011).

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Ethical principles and placebo-controlled trials - interpretation and implementation of the Declaration of Helsinki's placebo paragraph in medical research.

Publications

Ethical principles and placebo-controlled trials - interpretation and implementation of the Declaration of Helsinki's placebo paragraph in medical research.

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