The present survey confirms the findings of others, that few clinical trials were able to avoid disruption during the pandemic, and yet although many faced temporary pauses or suspensions, all but a few were cancelled [16–18]. Estimates suggested that during the pandemic National Institute of Health (NIH) funded research suffered losses of more than $10 billion due to COVID-19, with over 85% of research projects being affected by either directly or indirectly . In this report we have described some of the adaptations CROs explored in their pragmatic approach to the challenges posed by the pandemic. Not only were many of these adaptations successful but they have significant implications for the future conduct of trials.
It wasn’t surprising that CROs indicated that Phase II and Phase III studies were the most heavily affected by the pandemic. Limitations on travel during the pandemic saw the decentralised approach come to the fore [20, 21]. Some trials have used primary care sites, such as general practice clinics and pharmacies, to deliver interventions and/or conduct sample collection rather than hospitals or CRO sites. Home visits have been used to reduce the number of people study subjects need to come into contact with – which is likely to be a key retention factor when study conditions associated with weakened immune systems. Overall, the decentralised approach, which can also encompass online assessment, delivery of interventions and self-assessment has been considered as a means of widening recruitment options and boosting retention, two major concerns for all clinical trials [15, 20, 21]. It seems reasonable to conclude that efforts to adopt more decentralised strategies will continue post-pandemic; however, consideration needs to be given to concerns over data quality oversight, increased complexity to management and costs.
Methods of gaining consent remotely or electronically were viewed favourable by our respondents. Remote consenting certainly reduces the reliance on paper forms, which the pandemic has highlighted can be problematic. The validity of the electronic signature has been repeated and reconfirmed by comments and publications from the US FDA and the EMA [13, 22]. There are concerns about the quality, regulatory compliance and especially the recognition of electronic signatures as the new standard. However, it is recognised that there are inefficacies inherent in many of the methods currently employed to record consent. This has created an impetus to identify new ways to address the situation and has shown clearly that the clinical research world is extremely innovative and ready to change and incorporate new approaches quickly. However, it has also been suggested that this increased flexibility might, once again, aid participant recruitment.
Both the FDA and EMA were aligned in that the primary concern remains patient safety and that all parties must maintain their efforts to avoid any unnecessary infection in populations that may already be at high risk. Both opened the door to the pragmatic use of electronic media and electronic signatures during the pandemic [22, 23] and even recommended remote monitoring visits (if applicable) via electronic channels. It was clear that this will change the way authorities judge trial format and will enable them in the future to oversee sites, investigators and eventually patients while trials are still in progress. Total transparency, digital procedures and remote control while maintaining the highest level of quality and accomplishment of the regulatory requirements are the milestones to achieve and maintain. There is still some way to go but the future is clear to see.
The necessary introduction of remote practices also created increased opportunity for team communication and collaboration. To minimise risk it was considered essential to conduct regular meetings between the whole trial team and investigators around protocol amendments and exploring mechanisms to facilitative the introduction of remote practices. Various conclusions were made from the answers provided by the survey participants which were that good communication allowed most respondents to address the issues of trial management quickly as issues arose. The use of remote meetings and video conferences has been a key part of a technology transformation revolution. Due to the pandemic, this transformation is expected to remain and will influence existing industry processes going forward . However, concerns were voiced over the ability to maintain engagement across teams by virtual communications alone, particularly if communication is driven by emails. It is clear that there remains a role for face-to-face interactions, it could be argued that participants may feel more comfortable communicating in person or that certain social signals or nuances may be missed in video interactions. The adoption of new tools could influence the future internal need for qualified staff and specific training for these tools. This will improve and accelerate the speed of research assuming all parties agree and are involved, which in the long run will be highly cost effective.
For decades, the landscape and model for clinical trials necessitated on-site, in-person monitoring and auditing. Information on study participants and events were recorded on paper case report forms. Medical records were documented on paper. The only way that representatives of study sponsors, CROs and regulatory authorities could review such data was by traveling to study sites and manually combing through these records. Recent years have seen a remarkable technological shift and many clinical trial case report forms are now electronic. The COVID-19 pandemic appears to have provided the impetus to revisit the feasibility and utility of remote monitoring. Travel restrictions, quarantines, and safety concerns have prevented on-site monitoring activities at most sites. Along with other adjustments such as remote consent, telehealth visits, off-site diagnostic studies, and shipping of oral study therapy directly to patients' homes, the FDA, the National Institutes of Health Central Institutional Review Board, and the National Cancer Institute have also encouraged remote monitoring [6, 13]. COVID-19–related changes have shown us that remote or virtual methods can allow completion of some study visits in a manner that is quicker, cheaper, and less burdensome, without sacrificing quality.
A major proportion of our respondents found it necessary to make adaptations to their trial procedures as has been reported elsewhere [2– 6]. Amending trial protocols is time consuming and places a significant burden on study budgets [24, 25]. It is clear that the timelines for approval of amendments is currently unpragmatic and can result in subjects needing to stop receiving treatment and loss of primary study data. It may also result in sponsor procrastination because they anticipate that approval by regulatory and ethical bodies will be protracted. Considering the move to more adaptive approaches to trial protocols it seems reasonable to predict that future trial protocols may involve more pragmatic language and increased flexibility to reduce the number of amendments. However, it is essential that any modifications in trial delivery are introduced robustly across the board to avoid protocol deviations.
A major area of change was that of supply management; having to make the ‘extra mile’ in the real meaning of the word to bring the drug supplies to some patients enrolled in trials . The changes and loss of the planned study delivery pathway forced many managers to consider how to make drugs and test equipment and other necessary tools and materials available to patients while maintaining Good Clinical Practice compliance and abiding by the ethical and confidentiality guidelines. This situation also underlined the importance of external service providers dedicated to help accomplish this goal. A very small proportion our participants (4%) indicated that only 4% of studies could not deliver the essential requirement of drug delivery to sites/patients, whereas nearly half adapted new strategies for the supply distribution chain to patient.
Sponsors appeared to have adopted a pragmatic approach to the burden placed on budgets and resources imposed by the pandemic. Even when studies were paused or cancelled there were few calls for budget adjustments. In general, sponsors and service providers maintained close communications which appeared to be positive in most cases noting just a few exceptions (only four negative remarks). Sponsors were amenable to increased requirements that CROs faced in attempting to keep studies running. Good communication appeared the key factor in the successful introduction and adoption of alternate methods and novel tools to ensure study delivery. Where Sponsors attempted to evaluate novel methods of trial delivery a common theme to arise was whether an approach shifted a burden or challenge from one aspect of a trial to another. CROs were sensitive to the potential that seemingly beneficial approaches may displace costs and create potentially unseen burden elsewhere.
Consideration of our survey data leads to the conclusion that those involved in clinical trials during the pandemic advanced a flexible approach to addressing the challenges posed by COVID-19, with all parties working closely together to find solutions. A range of innovative and pragmatic practices for managing and running clinical trials were introduced. It has been proposed that the pandemic has been the axis point for the industry and that many of our adaptations will become part of future working practices. The pandemic has also highlighted areas where ‘structural’ barriers to the way we conduct studies make it difficult to adopt innovation. It will be important in the upcoming months and years to evaluate/audit and validate the methods we have employed before new regulations and guidance can be provided.