key: cord-1043145-b5cz5rnx
authors: Branch-Elliman, Westyn; Lehmann, Lisa Soleymani; Boden, William E.; Ferguson, Ryan; Monach, Paul
title: Pragmatic, adaptive clinical trials: Is 2020 the dawning of a new age?
date: 2020-07-17
journal: Contemp Clin Trials Commun
DOI: 10.1016/j.conctc.2020.100614
sha: 8749b89a480d57dde690cd481211f28368579c98
doc_id: 1043145
cord_uid: b5cz5rnx

Given the high case fatality rate of SARS-CoV-2, for which there is no cure and no vaccine, clinicians are forced to make decisions about how best to manage patients with limited high-quality evidence to guide treatment. Traditional randomized controlled trials provide strong experimental evidence, however, tend to be slow, inflexible, and have limited generalizability. Adaptive and pragmatic designs are an attractive alternative, which meet our ethical obligation during the SARS-CoV-2 pandemic to balance speed, agility, and generalizability with both prospective study and scientific rigor.

Given the high case fatality rate of SARS-CoV-2, for which there is no cure and no 25 vaccine, clinicians are forced to make decisions about how best to manage patients with limited 26 high-quality evidence to guide treatment. Traditional randomized controlled trials provide strong 27 experimental evidence, however, tend to be slow, inflexible, and have limited generalizability. 28

Adaptive and pragmatic designs are an attractive alternative, which meet our ethical obligation 29 during the SARS-CoV-2 pandemic to balance speed, agility, and generalizability with both 30 prospective study and scientific rigor. 31

As of April 2020, the SARS-CoV-2 infected more than 2 million people and caused more 33 than 130,000 deaths world-wide, with no end in sight.

[1] Given the high case fatality rate of 34 SARS-CoV-2, for which there is no cure and no vaccine, the imperative to save lives in the 35 present compels clinicians to embrace any potentially effective treatment, including those that 36 are empirical or unproven. On the time-honored pyramid of medical evidence-increasing in 37 validity from expert opinion, preliminary data derived from basic pre-clinical laboratory studies, 38 case reports, and observational studies to the pinnacle of rigorous scientific investigation, the 39 randomized controlled trial-clinicians on the frontlines find themselves stuck at the bottom. 40

Since the mid-20 th century, the gold standard of quality scientific evidence is derived 41 from double-blind, placebo-controlled, multi-center, randomized controlled trials (RCTs), 42 however, generating data from these studies is as cumbersome as their name suggests. 43

Designing, executing, and analyzing outcomes from such RCTs takes years and consumes vast 44 sums of funds and manpower. The conduct of traditional RCTs is challenging, they require large 45 numbers of patients with restrictive eligibility criteria, and are often limited in terms of their 46 generalizability to "real world" patients. Such RCTs-particularly those conducted in the U.S.-47 often proceed at a glacial speed and are associated with recruitment delays and cost overruns. 48

By their nature, traditional RCTs are inflexible and besieged by long gaps between study 49 completion, publication, dissemination, and implementation. Clearly, none of these attributes are 50 desirable during a global pandemic that requires answers that can be achieved and actualized 51 quickly. SARS-CoV-2 is a modern apocalypse that mandates a different, more nimble and 52 agile, investigational approach. 53

While traditional RCTs address the question, "Exactly how effective is a given treatment 54 in a pre-specified and well-defined population?", during a pandemic, there is an urgent need to 55 answer a different question, "Is this treatment effective at all?" We are witnessing, in 2020, a 56 crisis within the clinical research community and the need to pivot away from our usual comfort 57 zone-rigid, conventional clinical trials targeted to a limited population--toward more agile study 58 designs, which can generate sound experimental evidence in a timeframe that matches the 59 virus's swift spread. There is an ethical imperative to obtain scientifically sound data quickly and 60 with as few subjects and resources as possible. Clinicians and investigators share the goal of 61 delivering the most effective and safest treatments, and the speed and magnitude of the SARS-62

CoV-2 pandemic highlight the need to pursue this goal as rapidly as possible. 63

Conventional RCTs have for decades been the "top" of the evidence pyramid. However, 64

beyond traditional designs, such as conventional RCTs and observational evidence, exists a 65 worthy modern alternative: adaptive and pragmatic clinical trials. These designs strike a delicate 66 balance between the conflicting needs of clinicians--who need to make bedside decisions and 67

to save lives now--and the needs of the broader medical and scientific community, which needs 68 to collect evidence of sufficient quality and scientific rigor to ensure that progressively better 69 clinical decisions are made as the SARS-CoV-2 pandemic evolves. Pragmatic and adaptive 70 trials produce true "experimental evidence-" unlike case reports and observational studies-71 and thus results generated from these designs provide a sound basis for medical and policy 72 decision making. Despite many attractive aspects of pragmatic and adaptive trials, their 73 adoption has been limited for various reasons, including difficulty interpreting messy "real-world" 74 data and challenges with implementing complex randomization schemes. However, data 75 interpretation can be improved by using validated quality checklists, such as the CONSORT 76 extension for adaptive trials,[2 3] and methodologic advancements over the past decade 77 created an opening for more widespread adoption and acceptance of the validity of these 78

Adaptive and pragmatic designs, as the name implies, have two essential features: participants receiving the intervention that appears to be the most effective and may minimize 105 the number of participants required to achieve an answer. For example, in a study testing IL-6 106 inhibition for treating COVID-19, if there is evidence from early participants that suggests 107 efficacy, then future participants will be more likely to be randomized to the treatment arm. This 108 design satisfies the ethical need for equipoise and allows investigators to balance collecting 109 strong evidence to help future patients while optimizing outcomes for the individual patients in 110 the study, who have dedicated their health, well-being, and time knowing that their efforts may 111 only benefit others. Play-the-winner designs maintain randomization, which is the key element 112 of clinical trials that reduces the chance that confounding factors will explain the relationship 113 between the exposure and the outcome. 114

In 1984, the highly efficient ECMO study required only 12 neonates to reach the 115 conclusion that ECMO was effective for reducing mortality: 11 in the treatment arm (10 116 survived) and 1 in the control arm, who died. However, in 1984, this study was highly 117 controversial, suggesting a magnitude of benefit too good to be true, and was not accepted as 118 high-quality evidence. A subsequent ECMO study with a different adaptive design randomized 119 neonates 1:1 until there were 4 deaths in one group, with the prespecified plan to treat 120 additional patients with the more effective approach until 4 deaths occurred in that group or 121 statistical significance was achieved.

[15] The first 4 deaths all occurred quickly and all in the 122 standard-of-care group, and the final results of the study, published in 1989, were 6/10 surviving 123 with standard-of-care and 28/29 with ECMO. This adaptive design was also rejected as 124 insufficiently robust, and a conventional RCT was undertaken from 1993-1995. [ In 2020, with SARS-CoV-2 threatening millions of lives, can we afford the luxury of 131 conventional RCTs where the tradeoff of time spent in rigorous trial execution is incremental 132 loss of life? Can we as a clinical research community adapt to meet the challenges of our time? 133

We live in the information age, and effective evidence-based interventions must be allowed to 134 spread as quickly as SARS-CoV-2 itself. Adaptive and pragmatic designs meet our ethical 135 obligation during the SARS-CoV-2 pandemic to balance the rapidly changing standards of care 136 with speed, agility, and scientific rigor as we seek the best treatments for our patients. The age 137 of the pragmatic, adaptive clinical trial has come. 138 139

All authors have no conflicts of interest to report. 141 Funding: 142 WBE is supported by NHLBI

Development process of a consensus-driven 149 CONSORT extension for randomised trials using an adaptive design

The adaptive designs CONSORT extension (ACE) 152 statement: a checklist with explanation and elaboration guideline for reporting 153 randomised trials that use an adaptive design

Pragmatic Trials

Series: Pragmatic trials and real world 158 evidence: Paper 1. Introduction

Hydroxychloroquine and azithromycin as a treatment of 160 COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine or chloroquine with or 163 without a macrolide for treatment of COVID-19: a multinational registry analysis

Hydroxychloroquine or chloroquine 166 with or without a macrolide for treatment of COVID-19: a multinational registry analysis

The Lancet

A randomized trial of hydroxychloroquine as 169 postexposure prophylaxis for Covid-19

Adaptive designs in clinical trials: why 173 use them, and how to run and report them

Extracorporeal Circulation in Neonatal Respiratory Failure: A Prospective Randomized 177 Study

Adaptive randomized study of idarubicin and 179 cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in 180 untreated patients 50 years or older with adverse karyotype acute myeloid leukemia

A randomized study of clofarabine versus clofarabine 184 plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with 185 acute myeloid leukemia and high-risk myelodysplastic syndrome

Extracorporeal membrane oxygenation and 189 conventional medical therapy in neonates with persistent pulmonary hypertension of the 190 newborn: a prospective randomized study

UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation