How should IBD clinical research evolve in the COVID era?
Laurent Beaugerie, ClinCom Member
An interview with Gionata Fiorino
During this period when we are so tormented by the SARS-CoV-2 pandemic, Gionata Fiorino, from Humanitas Research Hospital in Milan, agreed to give us his views on the challenges of adapting IBD clinical research.
Gionata, I am sure you will agree with us that the COVID crisis is having a major impact on how we are managing patients with IBD, and how we are designing/conducting clinical and translational research in the field of IBD. As an expert in clinical research at a big European centre, you will certainly have personal experience of all the changes that are taking shape after more than six months of crisis. You may have some ideas that you wish to share with us on how to optimise the feasibility and quality of IBD research during these challenging times and looking to the future.
First of all, have you observed any changes in participation rates in randomised controlled trials (RCTs) related to existing or new drugs? If yes, what aspects underlie a reluctance to participate, and what measures are the key to limiting this trend?
Yes, we faced two main challenges at the beginning of the pandemic in Italy. First, the local and national lockdown had a severe impact on the possibility of attending the investigating centre in order to comply with all the procedures. Second, the lack of safety data on existing and investigational drugs related to the risk of infection and complications of SARS-CoV-2 has limited the enrolment in RCTs from both the investigators’ and the patients’ side. However, we have applied some effective strategies to deal with these challenges. We stopped the enrolment of new patients in RCTs unless no valid therapeutic alternatives were available. For those patients already enrolled in RCTs, we adopted certain strategies, such as telemedicine for some study visits, home delivery of experimental drugs, when and where possible, and agreements with local labs to perform the tests required by the protocols. These strategies were discussed and agreed with the companies sponsoring the studies and with our local Trial Office and Ethical Committee. This strategy allowed us to keep treating our patients with experimental drugs without any significant problem in terms of compliance with protocols. Since the end of the national lockdown in our country, we have been able to return to the normal approach, recruiting new patients and continuing to treat patients without any problems.
And what about any changes in the participation of patients in observational cohorts or questionnaire studies, whether related or unrelated to the COVID crisis?
We have been able to conduct observational or questionnaire studies quite easily. We experienced some delays only in those studies where certain examinations, such as colonoscopy, MRI or bowel ultrasound, were required, since the access to these procedures was very difficult during the lockdown phase.
Regarding ongoing therapeutic trials, many designs include repeated blood samples, colonoscopies and face-to-face consultations. Depending on the local context and COVID prevalence, it may be impossible or difficult to adhere strictly to the protocol. Have you experienced this and what solutions have you developed with sponsors or funders to adapt/modify the research protocols?
As previously mentioned, we adopted some strategies to increase flexibility in regard to research protocols without impacting on the quality of data. Telemedicine for non-key visits (where the patient was just assessed by evaluating electronic diaries), the use of local labs to perform routine blood and faecal tests and home delivery of study drugs proved very effective in allowing us to continue our research activities. Collaboration and flexibility on the part of sponsors/funders, the contract research organisations and Ethical Committees are key in these cases, but, more importantly, proactive collaboration from patients is crucial to the success of these strategies.
Unfortunately, the modification of research protocols and the subsequent approval require much time, and this can prove very difficult, especially when rapid adaptation to new situations (such as the spread of the pandemic or new restrictions) is required.
Regarding trials that are about to start, do you interact with sponsors and funders when adapting protocols to make them ‘COVID secure’ in response to the practical difficulties arising from the COVID crisis? Do you have any examples of electronic consenting and other regulatory aspects?
We have implemented some strategies to use telemedicine also for clinical research. However, there are many legal and privacy issues that should be solved before using these strategies routinely in clinical research. In multinational studies, these strategies also need to be adapted according to local regulations. We discussed mainly with the Steering Committees the design of studies requiring the fewest possible study visits and procedures, with an increased role for telemonitoring of study participants.
In France, FMT trials have been stopped because we need to develop and validate techniques to rule out the presence of SARS-CoV-2 in donor stools. What are your thoughts on this from a global perspective and more specifically the viewpoint of Italy?
We experienced the same situation in Italy. This decision makes sense, since safety comes first, especially for patients enrolled in clinical trials. However, research should continue to identify valid techniques that can exclude the presence of SARS-CoV-2 and also other pathogens in stools to overcome this problem and to allow progress in the FMT field. If research stops completely, many patients will have to renounce a potentially good alternative, especially for refractory disease.
The number of years needed to develop and approve a new drug seems to have exploded (or rather imploded!) in the field of SARS-CoV-2 vaccination. Can we expect that this agility and flexibility, without compromising safety, could one day apply in the field of IBD when it comes to trials on new therapies in IBD?
Honestly, I do believe that bureaucracy has increased too much in the context of clinical research in the recent past, since we spend more time on paperwork than on research itself. I think that the current situation may serve as a stimulus to find flexible and agile strategies to prove the efficacy and safety of new drugs without any significant loss of quality, and that this impact may continue even after the pandemic has come to an end.
Completion of efficacy/safety studies using observational cohorts and medico-administrative databases is less affected by the COVID crisis than the completion of classic RCTs. In addition, new efficacy/safety assessment methods are emerging, such as emulation of target trials. In this context, do you think that the COVID crisis could have a positive impact on the development of innovative methodological tools in the field of IBD research on therapeutics?
The pandemic has raised some important issues about drugs: In this period, we have come to understand the importance of drugs which have a flexible administration schedule, can be administered at home, have a good safety profile, are effective as a monotherapy (without any concomitant corticosteroid or thiopurine) and show rapid clearance in case of any side effect. I think all these aspects should be taken into account in the future development of new drugs.
The peer review of scientific manuscripts is dependent on the availability of physicians. The pandemic impacts highly on this. This might lead to changes in review time and acceptance rate. In contrast, COVID-19-related papers require a fast turn-around time to make new data available to the community as soon as possible. What is your experience with this?
I had direct experience with this issue. As an Associate Editor of the Journal of Crohn’s and Colitis (JCC), finding available reviewers for any submitted manuscript was quite hard and led to delays in the revision process. On the other hand, rapid publication of experience, points of view and data on COVID-19, especially during the first weeks of the pandemic, helped a lot. I find that the fast turn-around time for COVID papers may also have a potential weakness, since some papers have been published in important journals despite being of a generally poor quality, with a high level of bias. However, I agree that this is probably a necessary compromise to provide the scientific and medical community with important data in this difficult context.
By Laurent Beaugerie, ClinCom Member