Protecting Clinical Trials in Cystic Fibrosis; COVID-19 Mitigation Measures Crowd Sourced from the European Cystic Fibrosis Society Clinical Trials Network

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent and home delivery of study drug. We discuss the practicalities of remote source data verication, protocol amendments, changing trial site location, and staff absences and home working. We outline how to protect trial outcomes, including home assessments, safety reporting, protocol deviations and recruitment challenges. Finally, we discuss the importance of continued access to study drug via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia and consortia with future protocol design and risk mitigation plans.


Background
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has disrupted clinical trial conduct and setup worldwide, largely due to mitigation efforts including self-isolation and reorganization of hospitals and staff to handle escalating admissions of infectious patients. Clinical trial teams, hospitals, sponsors as well as competent authorities have scrambled to adapt to the challenges posed by the pandemic. The overriding concern is protection of clinical trial participants and healthcare professionals involved in trial conduct. The FDA issued regulatory guidance for sponsors in mid-March 2020 (1), closely followed by EMA guidance a few days later (2). Guidance for ongoing trials includes switching to telephone/remote visits when possible, extending trial duration, home delivery of study drug, and remote monitoring. These documents also provide guidance on protocol amendments, updating informed consent, documenting protocol deviations, and handling missing data after trial completion. Sponsors are advised to assess the feasibility of starting new trials and enrolling new patients into ongoing trials.
Since 2009, the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has been working to improve the quality and conduct of clinical trials in the rare disease cystic brosis (CF), with the aim of accelerating the availability of new therapies. We currently federate 58 trial sites across 17 countries in Europe. Our work includes review of study protocols and investigator brochures, development and standardization of clinical trial measures and outcomes, training of investigators and research coordinators and quality assurance of trial sites (3).
As SARS-CoV-2 spread across Europe in early 2020, it became clear that the crisis would impact the conduct of clinical trials in CF. We started regularly surveying our member sites to understand the impact on CF trials across Europe. The results of each survey were promptly returned to sites and partner patient organizations. We described the methodology and survey results previously (4).
Over the summer we took advantage of the lull in SARS-CoV-2 infections to review the survey results and extract information about the mitigation measures that sites had implemented to ensure continuity of clinical research. We then combined the information into a structured document and circulated it to all network sites for comment.
Our collaborative approach allowed us to source the best mitigation practices from all over Europe, thereby providing our member sites with useful guidance that could be locally adapted to mitigate the effects of the pandemic on clinical research and ensure continuity of existing and new trials for CF treatments.
We identi ed 15 areas of risk that could be impacted by resurgences of Covid-19 (Table 1). Here, we present our recommended mitigations measures for each risk. These recommendations are not binding; rather they provide sites with a list of items to consider and to potentially adapt to their local situation and institutional guidelines, along with any protocol amendments for speci c studies. Patients could be infected or have been exposed to SARS-CoV-2.
Physical site visit A physical visit at the site is not possible/inadvisable due to the risk of infection.

Consenting of patients
Informed consent process may not be possible if patients are not allowed to attend trial visits in clinic.

Study drug
Study drug cannot be provided if the patient is not allowed to come to the site.

Logistics
Source data veri cation (SDV) SDV needs to be performed remotely if monitors are not allowed to come to the trial site.

Handling protocol amendments
Mitigation measures may lead to more protocol amendments than usual.

Changing location of trial site
Reorganization of hospitals may mean that the trial site is effectively moved to another location within the hospital or even to another hospital. Preventing Sars-cov-2 Infection Ensuring the safety of study participants and staff is key. Patients may be wary of coming to clinic for trial visits and becoming infected. Conversely, they could be asymptomatic or pre-symptomatic transmitters of SARS-CoV-2 and infect staff when they come to clinic.
Pre-screening for SARS-CoV-2 before trial visits We recommend that before patients attend trial visits in clinic, they are pre-screened for Covid-19 associated symptoms via email, telephone or a video call. Alternatively, they could provide a recently negative SARS-CoV-2 PCR test result (≤ 24 to 48 hours before the planned visit), especially if the trial visit involves aerosol-generating procedures. Self-administered rapid antigen diagnostic tests may be permitted in some countries and institutions, but PCR-testing remains the gold standard.

Electronic consent
The use of electronic consent (eConsent) can facilitate remote clinical assessments. Several apps and platforms exist for electronic consent, however regulations governing their use vary by country and even by institution. Use of eConsent platforms may need to be approved by local ethics committees. Sites should check if study sponsors can offer technical solutions for eConsent.

Shipping study drug
The shipment of study drug directly to patients' homes can also reduce clinic contact time. Again, not all national and local regulations allow this. Patients may need to be educated on proper storage of study drug and administration. Temperature requirements for transport of study drug must also be considered. Some trial staff, who have more administrative, regulatory or data management roles, may be forced by institutional regulations to work from home to reduce exposure to the virus. Sites and their institutions should develop home working policies as a priority, with technical solutions such as providing homebased staff with encrypted computers and secure networks to access documents. Home working policies should provide staff with guidance on data protection.
The pandemic may also disrupt the clinical trial supply chain, creating a shortage of ancillary supplies for clinical trials. Sites should be aware of their inventory of clinical trials related materials and should interact with sponsors and CRO to adequately forecast patient recruitment.

Finances
The SARS-CoV-2 pandemic and the mitigations measures suggested in this paper will invariably have a nancial impact. We have focused on industry-sponsored trials here, and advise sites to discuss the cost of mitigation measures upfront with sponsors. However, many trials are investigator-initiated and funded by academia or grants from charities, national research bodies or European programs. We advise sites participating in such trials to immediately open communications with the trial funder to discuss extra funding for mitigating the impact of the pandemic, or for grant extensions to account for delays caused by the pandemic.

Protecting Trial Outcomes
Pandemic-related disruption of ongoing trials could prevent the robust assessment of outcomes, in particular safety and the primary outcome. It is critical to minimize trial disruption to preserve the integrity of ongoing trials, and to avoid the delayed introduction of potentially life-extending medicines. This is particularly important for life-threatening rare diseases with limited treatment options such as CF. It is also an ethical obligation to ensure that trials avoid research waste by adequately answering the research question.

Assessments
Assessments underpinning the primary endpoint should be prioritized. If sponsors do not proactively provide guidance, sites can ask sponsors to provide a minimal core data set (plan "B") outlining which outcome measures can be obtained remotely where possible.
If patients are provided with the relevant sterile equipment and instructions (written, by telephone or video), they can provide biological samples (e.g. urine, sputum) from home, which can be collected by courier and transported to the hospital. Other common assessments that can be performed at home include lling in any patient-reported outcome questionnaires, pregnancy testing, height and weight (ideally using equipment provided and calibrated by the sponsor). This will require close collaboration with the sponsor and consideration of extra costs. Ethics approval could be needed for such amendments.
Some assessments can be performed by private home-care services, hired by the sponsor, or in some cases, the site research nurse or coordinator. These include electrocardiogram, blood draws, vital signs, and pulse oximetry. Case report forms may need to be modi ed to account for such changes.
Spirometry is a key assessment parameter in CF and is often a primary outcome in clinical trials. Patients require training to perform this maneuver, therefore, the results are highly dependant on active cooperation of the patients. With recent technological advances, compact home spirometry equipment is now available, but is not yet implemented as standard in routine CF care. In addition, these devices have not yet been validated for assessment of spirometry endpoints for clinical trials. In face-to-face spirometry assessments, patients are coached by the research nurse or coordinator regarding the necessary technique required to perform a "valid" forced expiratory maneuver. Spirometry performed at home, even when utilizing remote coaching via video-link may therefore be qualitatively suboptimal as compared to an in-clinic assessment. This could lead to variable results, especially if some assessments are performed at home and others in clinic. A study sponsored by the Cystic Fibrosis Foundation is investigating how home spirometry results can be "corrected" in order to be comparable to spirometry performed in clinic (5). It is unknown at this point how regulators will evaluate the results of key outcome parameters obtained with unvalidated home equipment.

Study drug compliance
Checking compliance is an important way to ensure that patients are taking study drug as instructed. This is often monitored by the patients returning empty study drug packaging to the trial site. If patients are not attending clinic, they cannot bring back empty study drug packaging to assess compliance.
Alternative ways to document compliance include having the patient photograph packages of used and unused study drug packaging (blister packs) and send these photographs to the site or check online during video call and take pictures (screen shots) of patients demonstrating used and unused packages. Sites can also ask patients to collect all packaging to return to site when mitigation measures are no longer in place or can organize pick-up at home.

Adverse events
If trial participants become infected with SARS-CoV-2, there may be a rise in the number of adverse events (AEs) and serious adverse events (SAEs). Sites should discuss with the sponsor how to handle these AEs/SAEs. Patients should be reminded to call the trial team in case of any possible AEs. Phone/video calls can be performed to collect and record concomitant medications and AEs.

Protocol deviations
Similarly, restrictions related to the SARS-CoV-2 pandemic may lead to more protocol deviations, especially around missed visits and assessments. Sites should discuss how to handle, and report protocol deviations related to the pandemic prior to database lock with sponsors.

Recruitment
The pandemic may impact recruitment since patients may be more hesitant to enroll in new trials, may drop out of ongoing trials, or hospital rules may prevent patients from joining new trials. Sites should discuss with the sponsor in advance under which circumstances the study will be stopped due to low recruitment or whether the recruitment window can be extended.

Continued Access To Study Drug
Blanket bans on new trial initiation may block extension/rollover trials and continued access to investigational drugs. This is particularly important for patients for whom highly effective therapies do not exist or are not accessible. For the rare disease CF, we were concerned that this would block continued access to a new class of medicines called cystic brosis transmembrane conductance regulator (CFTR) modulators. We previously reported that most ECFS-CTN sites were allowing extension trials to start as planned, ensuring access to these study drugs (4).
Investigators, learned societies, clinical trial networks and patient organizations can advocate for these trials to be treated as high-priority trials.

Conclusions
These recommendations were co-created from the shared knowledge and experience of sites in our network and were subsequently distributed directly to all ECFS-CTN sites. We will also use this guidance to assist companies, academia and consortia with future protocol design and risk mitigation plans. Indeed, many of the mitigation measures proposed in this manuscript are di cult to implement at site level without the logistical and nancial support of the study sponsor. We also feel that industry, regulators, CF clinical trial networks and investigative sites, with the help of the patient organizations and with the experience gained during the SARS-CoV-2 pandemic could consider adopting virtual and remote technologies to promote improved patient-centricity in future clinical trials. Indeed, the rapid pivot towards home monitoring and other remote measures may pave the way for a shift towards more "remote" trial visits in the future. We hope that our manuscript might help trial sites who are not otherwise supported by a clinical trials network, and who would bene t from the collective knowledge and experience of our ECFS-CTN member sites. We also hope that our manuscript will serve as a starting point for continued conversation as well as sharing of experience and best practice. Availability of data and material: Not applicable.

List Of Abbreviations
Competing interests: FD, VB, KH and AV have no competing interests.
SvK and LD have no relevant con icts of interest to declare pertaining this manuscript.
HJ has received a speaker's fee and a research grant for an investigator-initiated study from Vertex.
NJS has received fees for consultancy and speaking from Vertex, Chiesi, Gilead, Roche, Teva, Zambon and Pulmocide.
DD has received honoraria from Vertex and Chiesi.
Funding: Not applicable.
Authors' Contributions: SvK, FD, VB, KH and AV planned, distributed and analysed the regular surveys, and prepared the manuscript. PdC, HJ, ND, NJS, LD and DD oversaw the project and survey results and contributed to the manuscript. All authors read and approved the nal manuscript.