key: cord-0049129-jd70l54t
authors: Butcher, Nancy J.; Mew, Emma J.; Monsour, Andrea; Szatmari, Peter; Monga, Suneeta; Offringa, Martin
title: Response to “Trials for depressive disorder in adolescents: the emperor’s new clothes,” a letter to the editor by Alain Braillon, MD, PhD.
date: 2020-08-27
journal: J Clin Epidemiol
DOI: 10.1016/j.jclinepi.2020.08.010
sha: 80238f8f472d271c2be57695b97c32c5e695d694
doc_id: 49129
cord_uid: jd70l54t

nan

Dr. Braillon raises a number of important points in response to our review of outcomes measured in adolescent major depressive disorder (aMDD) clinical trials. [1] These points are not only relevant to the field of psychiatry but bear on the design and analysis of all trial outcomes and on systematic reviews and meta-analyses of small trials. Ultimately, this discussion raises the question: what is the use of a trial if the measured outcomes are not meaningful to patients and if the results cannot be incorporated in evidence syntheses?

To Dr. Braillon's first point, we agree that well-defined and clinically relevant trial outcomes are essential to overcome deficiencies of past research. We recently discussed key issues to consider when selecting, measuring, and reporting outcomes when designing or reviewing pediatric mental health trials. [2] Our call for a standard to enable trial reproducibility, comparison, and synthesis (i.e., the development of a core outcome set; COS) for aMDD [1] and other areas of mental health research [3] is related to the need to establish which outcomes are essential and important to measure. [2, 4] Recent efforts in adult MDD have identified outcomes important to patients, families, and healthcare professionals -many of which have been rarely measured. [5] Outcome selection driven by end-users of trial results is an important avenue to reduce research waste. [6, 7] In the development of an upcoming aMDD COS, endusers' voices will be front and center. [4] Second, Dr. Braillon highlights the importance of defining and achieving clinically important differences. A statistically significant difference does not necessarily translate to improved health or lead to changed practice or policy decisions. While defining and justifying the minimal clinically important difference or change is commonly recommended for clinical trial protocols and reports, [8] this remains a rarity, [9, 10] including for aMDD trials. [11] Reporting such information, however, is key to research transparency and interpretation of trial results. There is a new dawn: the DELTA 2 guidelines offer strong guidance that can address this gap. [12] Third, we agree that large, high-quality aMDD trials measuring meaningful outcomes are possible and should be performed. The development and implementation of a COS for aMDD will help ensure that results from such large seminal trials are measuring the "right" outcomes in the "right" way, assuring their validity and relevance. The reality remains that locally conducted trials will still occur, and meta-analyses will remain an important driver of clinical decision-making. Prospective meta-analyses could be used to harmonize such trials to leverage data across trials to answer clinically relevant questions in a timely fashion, [13] as recently purported for the pooling of patient data across COVID-19 trials. [14] This approach has been successful in other areas of pediatric research. [15, 16] Pragmatic trials that implement mental health COS also promise to deliver large, usable datasets.

Finally, the noted lack of guidance from regulators on which outcomes should be measured is well known. But who should decide what should be measured? Although regulators and funders undoubtedly play an important role, we believe that it should be patients and their care-providers that drive the standards for relevant, valid, and feasible outcomes to measure in trials. 

Systematic scoping review identifies heterogeneity in outcomes measured in adolescent depression clinical trials

From research to practice: The importance of appropriate outcome selection, measurement, and reporting in pediatric mental health research

Counting what counts: The case for harmonized outcomes in child and youth mental health research

Core outcome set development for adolescent major depressive disorder clinical trials: A registered report

Identifying outcomes for depression that matter to patients, informal caregivers, and health-care professionals: qualitative content analysis of a large international online survey

Biomedical research: increasing value, reducing waste

The COMET Handbook: Version 1.0

Outcome reporting recommendations for clinical trial protocols and reports: a scoping review

How well is the clinical importance of study results reported? An assessment of randomized controlled trials

Clinical significance in pediatric oncology randomized controlled treatment trials: a systematic review

Primary outcome reporting in adolescent depression clinical trials needs standardization

DELTA(2) guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial

A guide to prospective meta-analysis

Pooling data from individual clinical trials in the COVID-19 era

Interventions commenced by early infancy to prevent childhood obesity-The EPOCH Collaboration: An individual participant data prospective meta-analysis of four randomized controlled trials

Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration