Response to White House review – Emergency Clinical Trials
The Good Clinical Trials Collaborative responded to a recent call for input from the White House Office for Science & Technology Policy on how the U.S. and the world can mount a better clinical trials response to future health emergencies. Our response makes five recommendations on priority actions that the U.S. Government and others can take to be better prepared.
We argue that trial design is the cornerstone of an effective response and that efforts by funders, regulators and research organisations must prioritise, support, reward and enable well-designed studies and actively discourage poor design. Unless the design challenge is addressed, all other measures to improve the infrastructure and wider ecosystem are doomed to failure.
Read our response here:
Written response toWhite House Office for Science and Technology Policy:
Clinical Research Infrastructure and Emergency Clinical Trials
Martin Landray, Stefan Gold and Nicholas Medhurst
1. Prioritize good trial design: Key systemic actors (e.g. funders, regulators, commercial and non-commercial sponsors, and academia) should prioritise, support, reward and enable well-designed trials (and actively disincentivize studies with poor design).
2. Adopt and implement principles-based clinical trial guidance: The FDA, NIH and other government / government-funded organizations should adopt and apply the Guidance on Good Randomized Controlled Trials (RCTs) co-developed by diverse stakeholders as part of the Good Clinical Trials Collaborative. This guidance is based on the fundamental scientific and ethical principles of good RCTs, fosters innovation in trial design and delivery, and provides flexibility to meet the (unpredictable) needs of changing circumstances such as those seen in the context of a pandemic.
3. Fit-for-purpose infrastructure: U.S. Government should undertake process optimization research to identify barriers to, and necessary infrastructural features of, large-scale RCTs that are common across health issues. This should consider the people, skills, processes, partnerships, data & technology required to establish and operate high quality RCTs at speed and at scale (including diversity in populations, geography, health setting, and disease features). The findings of such process optimization research should be implemented as soon as possible in order to ensure improvements are in place well in advance of the next public health emergency. It is as important (and cheaper) to stop wasteful or ineffective practices as to institute new ones.
4. Preparation through useful practice: Between public health emergencies, ‘warm base’ RCT infrastructure (people, processes, partnerships, data & technology) should be employed to generate high-quality evidence through an ongoing diverse portfolio of good trials across common health issues in non-communicable diseases, mental health, and infections.
5. Public-private finance and partnership: U.S. Government should invest public funds to generate the necessary infrastructure to support high quality RCTs. Industry, academia and health service providers should be encouraged to make use of that infrastructure for trials of novel products, re-purposed treatments, and to address uncertainties in the use of existing therapies. Attractive features of this approach would be the opportunities for greater speed, scale, and inclusivity. However, to give confidence in this approach it will be necessary for FDA and other regulators to demonstrate and communicate the acceptability of results generated by it.
The design crisis
A high quality randomized clinical trial is one that provides a useful (reliable, informative, actionable) answer to an important question. Without such trials, clinical practice and the response to a public health emergency is vulnerable to hope, hype and uninformed practice – effective interventions remain unrecognized or under-used whilst ineffective or harmful practices persist. Such an approach is bad for individual patients, bad for public health, and bad for public trust in the healthcare response.
Good design is critical to success. That design must encompass scientific and ethical principles and ensure that the trial is practical and efficient for those who take part in it (patients, clinicians, healthcare organizations).
The COVID-19 pandemic illustrated the design crisis: Around 19 out of every 20 clinical trials launched in response to the COVID-19 pandemic were not fit for purpose, suffering from poor design – foreseeable inadequacies in scientific quality (not randomized, insufficient size), practicality, and coordination . Among the 1 in 20 that did aim for robust design and sufficient scale, many were slow to enrol or did not complete. As articulated by Zarin et al before the pandemic “From the perspective of researchers, this is a form of research inefficiency. But from the perspective of participants, preventable uninformativeness is a serious breach of trust and a violation of research ethics.” 
The system must prioritise, support, reward and enable well-designed studies (and actively disincentivize poor design) in order to improve knowledge-generation capacity both for emergency situations and in pursuit of better public health in general.
A practical example is found in work done by the Gates Foundation’s Design, Analyze, and Communicate (DAC) program , which helps the major global health research funder to consult with grantees to improve the ‘informativeness’ (practice-guiding impact) of clinical trials that they fund. This is a proactive investment in optimizing research plans that can deliver substantial efficiencies while enhancing research quality.
Unless the design challenge is addressed, all other measures to improve the infrastructure and wider ecosystem are doomed to failure.
The need for principles-based guidance
It is not possible to confidently predict what the defining features of the next healthcare emergency will be (e.g. speed of outbreak, mortality) or what demands it will place on various components of the care pathway (e.g. diagnosis, community settings, hospital care). However, we do know that we will want and need robust evidence to guide policy decisions at the earliest opportunity, and guiding principles enable application of reliable methods even to entirely novel challenges.
Guidance that places undue emphases on adhering to current processes and current capabilities risks being unfit for future emergencies. Instead what is needed is a principles-based approach that accommodates and remains relevant to innovation in technologies and methods but also accommodates and remains relevant for application in as-yet-unknown emergency situations.
This need was summarised as a key action in the “100 Days Mission to Respond to Future Pandemic Threats” report from the G7:
We should refocus regulatory guidelines on the fundamental scientific and ethical principles that underpin randomised trials, whilst embracing flexibility and innovation across a range of health threats and technologies. We should build on models established by the US Food and Drug Administration Clinical Trial Transformation Initiative and the Good Clinical Trials Collaborative (supported by the Bill & Melinda Gates Foundation, Wellcome Trust, and African Academy of Science). The Good Clinical Practice for clinical trials guidance should be revised to focus on what matters for the generation of actionable information about effects of an intervention, rather than what is easy to check but less relevant, placing an emphasis on principles and purpose rather than process. 
Building on the work of the Good Clinical Trials Collaborative
The work to develop such guidance has already been done. The Good Clinical Trials Collaborative (GCTC), a non-profit programme worked with a diverse, global multidisciplinary group of individuals and organizations to co-create guidance that was
Based on key scientific and ethical principles and focused on issues that materially matter to the well-being of trial participants and the reliability of RCT results;
Clear, concise, consistent and proportionate to the context and setting in which RCTs are conducted, recognizing that there are risks associated with both usual clinical practice and a lack of reliable evidence on the effects of an intervention;
Forward looking, fostering innovation in health interventions and trial methods, including the appropriate use of routine healthcare data, technologies, and designs; and
Flexible, widely applicable, utilizable and durable across disease areas, intervention types, development phases, trial designs, geographies and time.
(Among the many contributors to the development of this guidance were senior and experienced figures from NIH, FDA, industry, academia, professional and patient organizations.)
Five key principles for Good Randomized Clinical Trials
1. Good trials are designed to produce scientifically sound answers to relevant questions.
Randomized clinical trials should help resolve important uncertainties about effects of health interventions. Depending on the context, the results may be needed to determine whether to proceed with development or further evaluation of the intervention or to inform regulatory licensing, clinical guidelines, and/or health policy. In each case, any uncertainties applying to the specific question(s) that remain at the end of the RCT should be sufficiently small to allow meaningful decisions to be made. This requires the combination of: randomization, adequate sample size, unbiased assessment of outcomes, and intention-to-treat analyses. 
2. Good trials respect the rights and well-being of participants
Randomized clinical trials should combine scientific validity with appropriate protection and respect for those who participate in them. These features are only possible to achieve with an emphasis on good communication and information sharing, consent, and management of the safety of those taking part.
3. Good trials are collaborative and transparent
Potential participants and/or members of the relevant community provide valuable contributions to the design, execution and interpretation of RCTS. Working collaboratively across organizations and sectors (e.g. government, industry, academia, healthcare) provides diversity of thinking and supports a delivery approach that is appropriate to the context, efficient and resilient. Transparency – trial registration, publication of protocols, and prompt reporting of results for scientific and lay audiences – aids the development of trustworthiness.
4. Good trials are designed to be feasible for their context
Randomized clinical trials should be tailored to be practicable given the available infrastructure in relevant settings. This includes making optimal use of pre-existing resources and facilities, including utilizing any expertise, skills, professional standards, and quality oversight mechanisms associated with routine healthcare practice. RCTs should not be wasteful of staff and participants’ time, use of interventional or other medical supplies, energy, or environmental resources. Where there are strengths and safeguards in routine systems, these should not be duplicated or altered without justification. The closer trial processes are to routine practice for participants and staff, the more efficiently and effectively they are likely to be delivered and the fewer mistakes are likely to be made, resulting in improved trial quality.
5. Good trials manage quality effectively and efficiently
Planning for success requires focus on issues that matter – avoiding errors that would have a material impact on the well-being of the participants in the trial or the reliability of the results (which influence, directly or indirectly, the care of future patients outside the trial). Good quality should be prospectively built into the design and delivery rather than relying on retrospectively trying to detect issues after they occurred (when often they cannot be rectified). Monitoring, regulatory, auditing or inspection requirements should be proportionate and sensitive to the scientific and ethical qualities and objectives of a RCT. They should recognise the opportunity-cost of, and avoid, setting irrelevant or disproportionate requirements that might discourage the conduct or participation in good RCTs that are designed to address important questions.
Just as good trials should manage quality effectively and efficiently, so too should those who fund, deliver, oversee or regulate those trials.
Streamlining and quality are not opposed
Senior leaders at FDA have made clear:
Streamlining and quality are not opposed; rather, by applying quality-by-design principles, reliable evidence can be developed with planned, measurable quality when researchers focus on ensuring both the quality of data that address important research questions and trial conduct that protects patient safety. Providing incentives for such approaches could accelerate development of information on drug effectiveness and safety, giving US clinicians and patients earlier access to critical knowledge and advancing public health. 
To achieve appropriate scale, speed and efficiency, care must be taken to remove unnecessary barriers to broad participation of patients/members of the public, clinical staff, and healthcare organizations.  Prioritising development and maintenance of systems that enable broad efficiencies (e.g multi-centre ethics reviews and accessible IT and data systems) is another key driver of feasibility and efficiency. Investing in such systems as a common public good can help deliver a ‘warm base’ environment that serves all trials and public health.
Avoiding pandemic amnesia and emergency exceptionalism
It is easy to dismiss the failures of the COVID-19 pandemic (the multiple designed-to-fail studies and widespread adoption of hope- rather than evidence-based medicine) as aberrations in an otherwise functioning system. Likewise it is easy to assume that the successes (e.g. RECOVERY, REMAP-CAP, ACTIV, SOLIDARITY trials) can be readily repeated without the need for system transformation. In many ways, the only two things that are ‘special’ about the public health emergency setting are the clarity of focus (COVID-19 was the only item on the agenda in early 2020) and the pressing need for speed.
However, most of the challenges experienced in conducting clinical trials in public health emergencies are not unique to emergency situations, and the greatest value and efficiency can be achieved by understanding and overcoming common barriers to delivering good trials.
Two critical questions can help focus the lens of this White House OSTP initiative: (1) What is special or different (from routine care) about running a clinical trial? And (2) what is special or different (from trials between pandemics) about a clinical trial that is part of an emergency response?
It is important to identify and address policies, processes and incentives that inappropriately or disproportionately hamper the generation of sound evidence from RCTs whilst allowing evidence-free practice to run free.
Avoiding emergency exceptionalism also means that a ‘warm base’ infrastructure is built through ongoing delivery of active research projects that include non-communicable diseases and infectious diseases.
The US (like other health systems worldwide) is faced with the twin challenges of growing burden of common disease and escalating cost of the impact that has on individuals, their families, health systems, the economy and wider society. There is a pressing need for more a more efficient evidence-generation approach through the application of large-scale randomized controlled trials to evaluate ways to prevent and treat common health conditions, such as cardiovascular disease, diabetes, mental health, dementia and drug-resistant infection.
Success comes from good design, ongoing practice, and application of lessons learned supported by infrastructure (skilled people, efficient processes, effective partnerships, and accessible data & technology) all focused on the issues that have a material influence on the generation of useful (reliable, informative, actionable) answers to relevant questions.
At the heart of this approach sits the need for all those who fund, support, conduct and regulate clinical trials to focus on the fundamental principles of good randomized clinical trials.
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 Zarin DA, Goodman SN, Kimmelman J. Harms From Uninformative Clinical Trials. JAMA. 2019;322(9):813–814.doi:10.1001/jama.2019.9892
 Collins R, Bowman L, Landray M, Peto R. The Magic of Randomization versus the Myth of Real-World Evidence. N Engl J Med. 2020 Feb 13;382(7):674-678. doi: 10.1056/NEJMsb1901642. PMID: 32053307.
 Califf RM, Cavazzoni P, Woodcock J. Benefits of Streamlined Point-of-Care Trial Designs: Lessons Learned From the UK RECOVERY Study. JAMA Intern Med.2022;182(12):1243–1244. doi:10.1001/jamainternmed.2022.4810
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