Abstract
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) produce guidelines for the design of pivotal psychiatric drug trials used in new drug applications. It is unknown who are involved in the guideline development and what specific trial design recommendations they give. Cross-sectional study of EMA Clinical Efficacy and Safety Guidelines and FDA Guidance Documents. Study outcomes: (1) guideline committee members and declared conflicts of interest; (2) guideline development and organisation of commenting phases; (3) categorisation of stakeholders who comment on draft and final guidelines according to conflicts of interest ('industry', 'not-industry but with industry-related conflicts', 'independent', 'unclear'); and (4) trial design recommendations (trial duration, psychiatric comorbidity, 'enriched design', efficacy outcomes, comparator choice). Protocol registration https://doi.org/10.1101/2020.01.22.20018499 (27 January 2020). We included 13 EMA and five FDA guidelines covering 15 psychiatric indications. Eleven months after submission, the EMA had not processed our request regarding committee member disclosures. FDA offices draft the Guidance Documents, but the Agency is not in possession of employee conflicts of interest declarations because FDA employees generally may not hold financial interests (although some employees may hold interests up to $15,000). The EMA and FDA guideline development phases are similar; drafts and final versions are publicly announced and everybody can submit comments. Seventy stakeholders commented on ten guidelines: 38 (54%) 'industry', 18 (26%) 'not-industry but with industry-related conflicts', six (9%) 'independent' and eight (11%) 'unclear'. They submitted 1014 comments: 640 (68%) 'industry', 243 (26%) 'not-industry but with industry-related conflicts', 44 (5%) 'independent' and 20 (2%) 'unclear' (67 could not be assigned to a specific stakeholder). The recommended designs were generally for trials of short duration; with restricted trial populations; allowing previous exposure to the drug; and often recommending rating scale efficacy outcomes. EMA mainly recommended three arm designs (both placebo and active comparators), whereas FDA mainly recommended placebo-controlled designs. There were also other important differences and FDA's recommendations regarding the exclusion of psychiatric comorbidity seemed less restrictive. The EMA and FDA clinical research guidelines for psychiatric pivotal trials recommend designs that tend to have limited generalisability. Independent and non-conflicted stakeholders are underrepresented in the guideline development. It seems warranted with more active involvement of scientists and independent organisations without conflicts of interest in the guideline development process.
Highlights
Reports have found that newly authorised medicines often have questionable or no added patient-relevant benefits compared to older treatments (Motola et al, 2006; van Luijn et al, 2010; Prescrire, 2019; Wieseler et al, 2019; Erhel et al, 2020)
We applied the following inclusion criteria: (1) the guideline should be published by the European Medicines Agency (EMA) or Food and Drug Administration (FDA) on how to design pivotal trials for drug approval; (2) the guideline should cover all aspects of pivotal trial design and not address specific trial aspects only, e.g. inclusion criteria or specific outcome measures; and (3) the guideline should cover psychiatric diagnoses as defined in current or previous versions of the Diagnostics and Statistics Manual of Mental Disorders (DSM) or the International Classification of Diseases (ICD)
We filed Freedom of Information Act requests to the EMA and FDA to access the committee member lists and their declared conflicts of interest
Summary
Reports have found that newly authorised medicines often have questionable or no added patient-relevant benefits compared to older treatments (Motola et al, 2006; van Luijn et al, 2010; Prescrire, 2019; Wieseler et al, 2019; Erhel et al, 2020). In a cohort of drugs approved by the German drug regulatory agency between 2011 and 2016, the Institute for Quality and Efficiency in Health Care (IQWiG) judged that 10% had substantial benefits compared to already available treatments, while 58% had no proof of added benefits (Wieseler et al, 2019). Out of 18 newly approved drugs in the combined field of psychiatry/neurology, only one was judged to have substantial added benefits compared to already available treatments (Wieseler et al, 2019). Systematic reviews of commonly used psychiatric drugs, of antidepressants for depression (Jakobsen et al, 2017; Munkholm et al, 2019) and of central stimulants for Downloaded from https://www.cambridge.org/core.
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