Planning for the Next Pandemic: Ethics and Innovation Today for Improved Clinical Trials Tomorrow

Abstract

The coronavirus pandemic has brought public attention to the steps required to produce valid scientific clinical research in drug development. Traditional ethical principles that guide clinical research remain the guiding compass for physicians, patients, public health officials, investigators, drug developers and the public. Accelerating the process of delivering safe and effective treatments and vaccines against COVID-19 is a moral imperative. The apparent clash between the regulated system of phased randomized clinical trials and urgent public health need requires leveraging innovation with ethical scientific rigor. We reflect on the Belmont principles of autonomy, beneficence and justice as the pandemic unfolds, and illustrate the role of innovative clinical trial designs in alleviating pandemic challenges. Our discussion highlights selected types of innovative trial design and correlates them with ethical parameters and public health benefits. Details are provided for platform trials and other innovative designs such as basket and umbrella trials, designs leveraging external data sources, multi-stage seamless trials, preplanned control arm data sharing between larger trials, and higher order systems of linked trials coordinated more broadly between individual trials and phases of development, recently introduced conceptually as "PIPELINEs. " ARTICLE HISTORY

Challenges and solutions in clinical research during the COVID‐19 pandemic: A narrative review

“… Human ethics in study enrollment 5,11,41 fear of infection among participants 7,41,50 High risk participants (Elderly people, pregnant women) 41,45 Obtaining informed consent form 7,24,49 …”

Vaccine Innovation Meta-Model for Pandemic Contexts

“… PricewaterhouseCoopers [ 43 ] 2020 R 14 COVID-19 vaccine challenges: What have we learned so far and what remains to be done? Forman et al [ 18 ] 2021 R 15 Urgent lessons from COVID-19: why the world needs a standing, coordinated system and sustainable financing for global research and development Lurie, Keusch, and Dzau [ 44 ] 2021 R 16 Promoting versatile vaccine development for emerging pandemics Monrad, Sandbrink, and Cherian [ 17 ] 2021 R 17 Planning for the next pandemic: Ethics and innovation today for improved clinical trials tomorrow McMillan et al [ 45 ] 2021 R 18 Novel vaccine adjuvants as key tools for improving pandemic preparedness Pogostin and McHugh [ 1 ] 2021 R 19 Rapid growth in the COVID-19 era Lee et al [ 46 ] 2021 R 20 Vaccines for a healthy future: 21st DCVMN annual general meeting 2020 report Pagliusi, Hayman, and Jarrett [ 7 ] 2021 R 21 Can the covid‐19 pandemic disrupt the current drug development practices? Won and Lee [ 12 ] 2021 R 22 Increasing efficiency in vaccine Production: A primer for change Aars, Clark, and Schwalbe [ 47 ] 2021 R 23 Improving pandemic preparedness through be...…”

“…Lower R&D lead times were not only related to technological innovations (I 7 and I 8 ), but also to process innovations, such as the adaptive and decentralized clinical trial design (I 6 ) [ 45 ]. Enabled by flexible regulatory pathways (F 4 ) [ 41 ], conditioned by high levels of community transmission (F 2 ) [ 2 ], and supported by the possibility of changing trial protocol parameters according to observations, adaptive clinical trials allowed parallelism among clinical trial phases (M 6 ) and, in some cases, enabled the merge between them (e.g., Phases I/II and II/III) [ 44 ].…”

“…Likewise, in cases where there are no safety profiles already demonstrated, the adoption of in-silico clinical trials based on digital technologies (G 3 ) might reduce, refine, or partially replace preclinical and clinical trials (S 4 -D 4 :S 9 -D 9 ) [48]. From a process perspective, standardizing clinical trial procedures (G 11 ) might enable the test of multiple vaccine candidates against a single control arm [18], facilitate data sharing and comparison of results across studies [50], and eliminate redundant activities [45], among other benefits. Finally, the technological and process guidelines are accompanied by other infrastructure guidelines, such as (i) the establishment of a global genetic sequence repository (G 13 ) to share the genetic sequencing of potential pandemic pathogens [2]; (ii) the sharing of continent-based virus sharing networks (G 14 ) to receive, verify, store, and share virus isolates locally [44]; (iii) the building of a containment laboratories network (G 15 ) to validate animal models [44]; (iv) the development of continent-based clinical and biological sample networks (G 16 ) to locally collect, store, and share clinical and biological samples [43]; and (v) the establishment of country-based clinical supercenters (G 17 ) to recruit patients, manage trials, and collate trial data [45].…”

A rapid review of community engagement and informed consent processes for adaptive platform trials and alternative design trials for public health emergencies

“…APTs are guided by a single master protocol which enables the comparison of several treatments/vaccines against a single control aimed at standardizing study procedures across participating sites and contexts in order to minimize the duplication of efforts, streamline ethical review and achieve adequate, and diverse participation when time is of the essence 9 . A prominent feature in APTs is the ability to drop arms for futility or harm as trial data emerges, and also to introduce new treatment arms as new products become available for evaluation 8 , 13 , 14 . Examples of this type of trial include the PRINCIPLE primary care trial 15 , TOGETHER 16 , REMAP-CAP 17 , RECOVERY 18 treatment trials, and SOLIDARITY which used an adaptive platform to evaluate new COVID-19 therapeutics or vaccines in multiple sites and often in multiple countries around the world 19 .…”