Facilitating Platform Clinical Trials During Global Public Health Emergencies
Introduction
The COVID-19 pandemic highlighted the need to generate reliable evidence rapidly and efficiently to support decision making by regulators, healthcare providers, and others. Although there are some remarkable success stories of clinical trials delivering actionable evidence, most of the clinical trials conducted during the pandemic were inadequate in terms of design to answer relevant research questions and failed to generate actionable results. Platform trials with their hallmark of evaluating multiple interventions within a shared framework, and the adaptability built into their design, could be an effective solution to address many of the challenges identified.
Regulatory authorities understood the public health need and the urgency triggered by the pandemic encouraging good clinical trial design and conduct to generate reliable evidence. Clinical trials that are inadequately designed or conducted may result in wasting of research resources and most importantly of participants effort at a critical time. The pandemic also highlighted global differences in regulatory approaches and capacity One of the key lessons from the pandemic is the need to expand regulatory capacity, and to enhance communication and harmonization on regulatory approaches.
In this paper, we discuss opportunities and challenges for planning and conducting global platform trials. We will also discuss various perceptions and considerations aimed at highlighting regulatory perspectives that facilitate efficient and reliable platform trials. Our focus will be on ensuring the safety of participants, as well as maintaining the reliability of the trial results.
This paper contains three main sections:
- Trial design and conduct considerations. This will include a discussion of key trial characteristics, such as developing protocol elements that need to be considered when conducting a platform trial during a pandemic, including specific design elements;
- Regulatory considerations including addressing certain perceived barriers and enablers;
- A brief discussion of certain lessons learnt from the COVID-19 pandemic.
The audience for this paper includes national and international regulatory agencies facing public health emergencies, as well as other stakeholders involved in planning and conducting clinical trials. We hope this paper will also encourage the rapid establishment and efficient conduct of platform clinical trials during public health emergencies to provide robust evidence for public health decision making.
General trial design considerations
Platform trials possess a number of clinical trial design characteristics that allow for the investigation of multiple investigational medicinal products (IMPs) in a continuous manner, possibly in different diseases/conditions, with different IMPs 'entering' and 'leaving' the platform at different times based on a pre-specified plan.
During a public health emergency, a platform trial can be used as an efficient framework adapting to the evolution of the emergency situation to investigate in a coordinated and robust fashion multiple questions relevant to public health, in addition to the collection of safety and efficacy data for regulatory submissions towards (initial or subsequent) marketing authorization / licensing. For example, investigation of treatments against different strains or emerging variants of pathogens triggering a public health emergency can be addressed in different ways in a platform trial and such designs may be preferred over an investigation of treatments in separate arms or trials.
Interventions to be investigated may encompass both single investigational medicinal products and combinations, and the specific design of their comparison (as laid out in the core protocol or a sub-protocol) may allow to generate data and isolate treatment effects to the extent and level (e.g., pharmacokinetics, pharmacodynamics, clinical endpoints both early and late during the disease course) needed for the assessment of benefits and risks.
In a public health emergency situation, an additional benefit of platform trials in establishing the safety and efficacy of preventive or therapeutic medicines may be their ability to efficiently embed these options in clinical care.
Clinical trials should continue to meet Good Clinical Practice standards established by the International Council for Harmonisation for Technical Requirements for Pharmaceuticals for Human Use, in order to uphold the health and safety of trial participants and the validity of trial data, as well as any relevant international and national context specific guidance. Further learnings are discussed in the ICMRA document “ Reflections on the regulatory experience of remote approaches to GCP and GMP regulatory oversight during the COVID-19 Pandemic”.
Specific trial design considerations
Choice of interventions
It is recommended to pre-specify a clear and transparent mechanism and criteria for the selection and/or prioritization of investigational medicinal products for potential investigation in the platform trial. Such criteria could be based for example on their therapeutic potential, as determined by emerging data, scientific plausibility, or unmet medical needs. If there are multiple candidate investigational medicinal products with sufficient data to support their inclusion, prioritization among candidates can take into account practical aspects such as the potential for wide availability and access should the data eventually support a marketing authorisation. Flexibility to incorporate new candidate medicines into the platform based on evolving knowledge may be key to the success of platform trials.
Endpoints
For trials in public health emergencies, clinical outcome endpoints should be defined or chosen to permit assessment of a patient-relevant aspect(s). These should be sufficiently accurate, precise and measurable to ensure that true effects can be likely identified and the trial events, if defined, can be well solicited. The trial should consider to additionally record core outcome sets (COS) such as defined by the WHO or international initiatives, as available. Depending on the nature of the public health emergency, there may be a need to define new endpoints for the clinical trial that have not been used before e.g. using a newly developed scale. Even if the endpoint is not novel, e.g. time to recovery through day 28, there may be a need to carefully choose the time window for such a primary endpoint to ensure both clinical relevance as well as statistical power. Different endpoints may be used depending on the mechanism of action and target patient population, for example based on severity of the disease or condition being targeted by a specific therapeutic option. A common choice that would depend on this is between time to recovery and (time to) mortality endpoints. Across the platform there is a need for consistency but also flexibility to allow medicinal products the opportunity to demonstrate their benefits.
Population
A clear definition of the trial population should be provided in the clinical trial protocol. The more inclusion / exclusion criteria that have to be met, the more selective the trial population and is and the less generalizable the trial results are to the wider population. Internal control is necessary to allow inference about the relative treatment effect.
Adaptations
The adaptations typically employed within a platform trial design to address a public health emergency include the starting and stopping of arms, pre-determined modifications of randomization rules, interim analysis-based decisions, updating of the control and standard of care and potential changes in inclusion / exclusion criteria based on evolving knowledge.
Adaptations of endpoints and sample size re-estimation may also occur and should take into account existing, generally applicable guidance. For example, in the very early stages of a public health emergency, the most optimal primary endpoint may not be clearly defined, and investigation of multiple endpoints may be initiated to focus on the optimal one at later stages of development.
Operationalizing the design
When possible, networks of expertise and capacity should be established at the national but also at the international / regional level. These networks can be of investigators, sites and experts (e.g., methodology, ethics) for clinical trials to address public health emergencies in advance. Such networks are useful for conducting site and staff identification and training and potentially conducting simulation / crisis preparedness exercises for priority emergencies. Wherever possible it should be considered to set up such networks in advance of any public health emergency.
Potential sites are recommended to be identified as early as possible and prepared in advance of opening. Such preparations include through trainings and health professional exchanges including by telemedicine. Pre-identification and training of investigators, sub-investigators and critical trial staff will enhance site quality.
Careful planning to adequately recruit and retain participants is of paramount importance. Considering that the health delivery ecosystem must quickly adjust and change to accommodate the need during public health emergencies, the trial should focus on those activities and data elements that are essential to the reliability and meaningfulness of the study outcomes. Wherever appropriate, the use of endpoints that are routinely collected as part of clinical practice should be considered. This will improve study feasibility and efficiency.
Measurement tools
Digital health tools (DHT) provide an important opportunity to make trials even more efficient while lowering the burden on participants and trial staff. Identifying suitable DHTs in advance of future public health emergencies should be considered to allow these to be reliably deployed and used for data collection. The parameters of the DHT that should be specified to ensure that the DHT is fit for use include app programming, architecture, and validation criteria.
Regulatory Considerations
Reinforced collaborations are needed from regulatory authorities to ensure that major scientific findings are translated rapidly into approved interventions and practices to address public health challenges. Agility in regulatory functions can ensure both rapid development of medicinal products and maintenance of scientific standards for review and oversight. For example locally relevant guidance on patient and community engagement in emergencies should be followed.
A crucial additional regulatory consideration is international alignment on regulatory requirements for authorisation in terms of the data to be generated and providing timely input on this to the developers/sponsor. This is to ensure that there is alignment, as far as possible, that the generated data is actionable.
A public health emergency can bring specific challenges in view of the various public health measures in place, which may interfere with the traditional conduct of clinical trials. Some regulatory agilities can therefore be extremely helpful in times of emergency. These have demonstrated their usefulness in reducing administrative burden on sponsors and investigators by allowing access to treatments without compromising participant safety. Having a regulatory framework in place to allow sufficient agility to address issues arising from a global emergency is clearly essential. Agile regulations are increasingly important to ensure a timely response to the emergencies. It is important to distinguish between flexibilities of existing local legislation, where such flexibilities can be applied within the existing local legal framework, and others that cannot be implemented without changing existing legislation or issuing new emergency legislation. The former offers the opportunity for ‘quick wins’ which may be important when operating in a time-constrained environment.
Example of these regulatory agilities to consider may include:
Facilitated process for submission of clinical trial applications and post-trial authorization submissions
Additional flexibilities should be considered in the way information is submitted to regulators. Where this is not current practice, electronic submission of applications and other information (notifications, adverse drug reaction reports, etc.) should be considered, to facilitate working in a fully virtual environment. This could include accepting electronic signatures on these documents. Alternatively, allowing submission of hard copy documents can be helpful in the event of electronic disruption. It is recommended that regulators work towards a rapid transition to electronic submission in non-emergency settings as well.
Ideally a clinical trial protocol should be written such that protocol breaches and deviations are avoided and the protocol itself allows the necessary flexibility, without compromising participant safety. The reporting of serious breaches of the protocol that put participants at risk remains essential. Where regulatory authorities require other deviations to be submitted, they could consider accepting the submission of a cumulative list of deviations at regular intervals or allowing them to be kept in the trial master file without submission, rather than having them submitted individually.
Expedited regulatory review of clinical trial applications
Regulatory authorities recognize the importance of expediting the review of trial applications directed at countering an immediate threat. When feasible, having a dedicated team to handle those applications is helpful, allowing reviewers to focus on a specific condition for which knowledge of its natural history is evolving.
Consideration should also be given to expediting access to regulatory pre-submission advice for trials aiming to address the public health emergency. Given the multiple parties involved in multicenter clinical trials authorizations, actions should be taken to reduce duplication while ensuring rigorous and prompt authorization processes. For instance, systems of parallel submission to regulators and research ethics review, and adoption of flexible risk-proportionate processes could ensure efficient coordination between relevant parties.
Prioritization of differing clinical trial design
Well designed, appropriately planned, large national or international trials that are powered to provide reliable results, while allowing for the addition or removal of investigational products as data become available, should be prioritized as they are the more likely to provide timely and clinically actionable answers. Additional support from public health or other governmental authorities could be sought to promote trials that have the potential to provide relevant information to address the public health emergency.
While COVID-19 trials were well supported, as mentioned earlier many trials did not generate the actionable data required to make medicine authorization or public health policy decisions. One lesson here may be the use of coordinated prioritization schemes for trials, for example some countries produced a designation scheme to support ‘important’ trials. This was used to fast-track the identification, funding, and delivery of COVID-19 studies, including a prioritization process to ensure valuable, and limited, resources were directed towards those clinical research studies that were deemed of highest priority in the fight against COVID-19. Such schemes can include both expedited regulatory and ethics review of the study.
Consent
In an emergency situation, the principle of informed consent prior to participation applies. Based on flexibilities communicated and implemented by some regulatory authorities an alternative form of obtaining consent to traditional methods may be appropriate, for example e-consent or verbally given consent with a witness documenting it. The consent and circumstances are to be documented, and the use of technologies available to inform the participant and document the consent may help to avoid delays in participation in a trial. Importantly, informed consent should foresee sharing results including raw data with regulators, as well as with third parties e.g., for meta-analysis within the limitations of existing regulatory frameworks.
Informed consent remains a continual process, for which visits and interventions present opportunities for an exchange about maintenance of consent and voluntary trial participation. This is important for platform trials in a public health emergency where there may be many protocol changes within the trial. Provisions for rapid re-consent should be made even though the need for re-consenting should be minimized.
Lessons Learnt
One of the key lessons from the response to the COVID-19 pandemic was the benefit of rapid, proactive communication, collaboration, co-operation, and co-ordination between regulators, researchers, funders, triallists and associate third parties and governments for an end-to-end approach to support drug development, availability and access. Indeed, all organizations involved in designing, approving, managing and delivering research to provide access to safe and efficacious medicines worked together in ways often desired, but never achieved before.
Regulators acted as enablers to research and rapid availability of therapeutic options, whilst safeguarding patient safety and data trustworthiness. Regulators from across the globe were quick to publish guidance on regulatory flexibilities to allow trials to be run effectively in the context of a lockdown and other infection control measures.
Whilst this rapid guidance was welcomed and was very effective for setting up and running single country trials, the available flexibilities were not globally aligned, meaning that sponsors of multi country trials had to navigate different frameworks in different countries, including within the same region. A lesson here is that more globally harmonized ‘core’ regulatory flexibilities would have been useful to reduce potential hurdles to the conduct of multi country trials. In addition, a gap analysis of flexibilities can be conducted so that regulators can critically appraise their national legislation to determine if changes could be made for better preparedness.
Great efforts were made to speed up decision making: information sharing between regulators and developers, increased interactions, additional flexibility in the timing of data requirements and the timing of reviews that were faster and more flexible than standard procedures. The immediate and ongoing collaboration between developers and regulators was instrumental in improving timelines for both trial approval and subsequent clinical use. This has been discussed in the ICMRA “Report on the review of regulatory flexibilities/agilities as implemented by National Regulatory Authorities during Covid-19 pandemic.” However, this required significant commitments from both sides and rapid, efficient interactions which may not be translatable to a normal situation. Nevertheless, a lesson here may be to encourage ‘rolling’ review-like regulatory processes applied to non-pandemic situations, for a limited number of high priority medicinal products that address an unmet need, acknowledging a much more resource intensive process than ‘standard’ review. is especially relevant for platform trials, where many aspects of assessment are the same for different products in the same platform. The rolling review process is especially efficient for platform trials, as the learnings about the trial in general from one product, can carry over into assessments of subsequent products in the platform.
Results from COVID-19 trials were shared and rapidly made available, which helped to support rapid, (conditional) regulatory approvals, clinical guidance and adoption into practice. This was particularly efficient in large platform trials, where recruitment was efficient, and sufficient robust data could be generated quickly to support regulatory and policy decision making. One lesson that could be learnt is that all medicines regulatory agencies should have emergency use or adapted authorization processes in place for public health emergencies to react to emerging positive data, in preparation for future emergencies and that developers should project manage the timing and oversight of communications to facilitate review.
One lesson learnt with respect to the designation schemes for priority trials is that international networks could be created in the pre-pandemic phase to develop a rapid determination of multinational studies with such a designation in the pandemic context. Another important point is that despite potential public perception otherwise, regulatory assessment timelines have been met. Indeed, some regulators prioritized COVID-19 trial assessment work and reduced their assessment timelines to approve protocols platform trials by half (to 14 calendar days) during the pandemic. The latter was published on regulators’ websites to communicate this flexible, pragmatic way of working and to manage expectations. It was also learnt that substantial amendments to platform trials are quicker to assess and approve than a brand-new protocol for a new trial, building resilience into the trial design from the start.
During the COVID-19 pandemic it was apparent that the public may perceive assessment as slow due to the intense media focus on trials as never before, even if this did not reflect the reality on the ground. This runs the risk that news cycles get ahead of the science, raising expectations and the public perception of slowness. The importance of deploying tools that can help sponsors engage with regulators to seek advice early during protocol development such as regulatory or scientific advice meetings is key.
It is important to highlight that although regulatory flexibility during the pandemic is essential to conduct efficient clinical trials, these flexibilities have not led to reduced quality/ safety/ efficacy. Regulatory processes were revised so that COVID-19 trials were prioritized and assessed by dedicated teams more efficient and effective. Regulatory oversight of trials ensured that the same high standards for assessing quality, safety and efficacy could be applied to the assessment.
Conclusions
The COVID-19 pandemic brought new trial designs in the form of platform trials to the fore. The way the regulatory system adapted happened in real time, with timelines much shorter than previously used and under unprecedented media scrutiny.
It is essential that the learnings from this public health emergency are not forgotten, nor remain solely the unshared experience of the regions where such trials were set up and run. For the next public health emergency, wherever it may be in the world, regulators need to be ready and prepared – with processes, communication channels, and a strong framework of how to approve such trials so they can start as quickly as possible. This document describes the clinical trial design elements that can be used and regulatory solutions to potential perceived barriers.
This experience points to a future where in case the next pandemic arrives, sponsors, regulators, triallists and participants are ready, willing, and prepared to plan, design and conduct fast, efficient, and appropriate trials bringing safe and effective medicines into use as quickly as possible. This document summarizes some of the learning and discusses how this might be possible from a regulatory viewpoint, but also highlights the commitment on the part of global regulators for better and more efficient trials.