September 29, 2020 PAP-Q3-20-CL-025
Recruitment and patient retention were challenging before COVID-19, but they have been exacerbated during the pandemic; people are afraid to go to doctor’s offices and investigator sites, particularly those that rely on public transportation, where social distancing is difficult. In addition, more people are working from home while caring for children and/or elderly relatives, yet most doctors’ offices continue to maintain policies prohibiting extended family from attending visits.
Between this reticence and an inability or unwillingness to visit the doctor, the closure of sites during lockdowns, and the reallocation of industry personnel to trials focused on COVID-19 therapeutics and vaccines, recruitment and retention have quickly become critical issues for clinical trials. As of the end of June, the number of new subjects entering clinical trials worldwide had dropped by approximately 30% compared with the end of October 2019.1
In an April 2020 survey of 1,000 clinical site personnel, over two-thirds of respondents indicated that they have halted, or would soon halt, patient recruitment for ongoing trials, a third were halting randomization, and about half were delaying studies.1 Similar results were evident across multiple surveys, including those by the Cancer Research Institute, IQVIA, and the American Society of Clinical Oncology. Furthermore, the failures of some trials have been directly linked to COVID-19.
One solution to reverse this trend is to pursue decentralized trials with virtual patient participation and site management. Half of the sites covered in a survey by Medidata indicated they were switching in-person visits to virtual ones and using telemedicine to interact with patients to continue existing studies and initiate new trials.1
To gain further insight, PPD’s Accelerated Enrollment Solutions (AES) group conducted a survey using their database of 100 million households, which includes individuals that have given preconsent or expressed interest in participating in clinical trials. A majority of those surveyed indicated a willingness to participate in a virtual trial due to the high prevalence of the SARS-CoV-2 virus across many communities.
Patients still need to be made aware of these digitally-enabled trial options, however. To familiarize subjects with this option, digital technologies for education and recruitment can be utilized, including social media platforms and online communications via patient advocacy groups and patient communities. Another important approach that PPD is pursuing is encouraging physician practices to open up their practices to clinical research, which would result in greater numbers of investigator sites and more care options for patients closer to home in a time where many sites are operating at diminished operating capacity.
On the other hand, COVID-19 has created a greater awareness of the effectiveness of various digital tools in enabling clinical trials and the collection of patient data. In particular, eConsent has become essential to trial continuity, allowing consent to take place remotely in a clear, trackable, traceable manner, as well as providing a key method to re-consent patients.
The pandemic has also accelerated the development and deployment of televisits as a standalone solution for clinical trials with research timelines in peril. The ability to deploy simple 21 CFR Part 11–compliant patient applications that can be downloaded onto smartphones has boosted patient access and made it possible to connect patients with site coordinators or investigators around the world in a secure way that increases patient retention.
Regulatory guidelines for clinical trials are constantly evolving, and developments must be continually monitored by regulatory professionals and conveyed to clinical teams to ensure ongoing compliance. Throughout the COVID-19 pandemic, the pace at which new guidelines have been issued by various regulatory authorities has greatly accelerated. The volume of information related to regulatory concerns has also grown exponentially in recent years as trials are being conducted in more countries, with a greater number of regulatory authorities determining specific regulations. In parallel with this rapid evolution are the introduction and advancement of new technologies designed to facilitate clinical trials. In addition, the burgeoning consideration for patient-centricity is having an impact on trial design, creating further intricacies in regulatory guidance.
The pandemic has proven even more challenging in this respect. In the United States, previous FDA Commissioner Scott Gottlieb made decentralized trials a priority for the agency when he took the helm, and the EU launched the Trials at Home project in late 2019 to provide guidelines for decentralized trials.
The need for such guidance and advocacy has greatly increased in light of COVID-19. Hybrid and fully decentralized trials are no longer novel options but rather necessities to protect trials that start later this year and into next year. Agencies across the world have swiftly issued guidances for conducting trials during the pandemic, but at many different levels of granularity, with considerable detail being provided by the FDA, the MHRA, and the EMA.
Most guidances share the top priority of protecting patient safety and maintaining data integrity, which they generally look to achieve using a risk-based approach. Digital tools that the agencies have assessed include telemedicine, eConsent, electronic data capture, direct patient supply, in-home nurse visits, and remote monitoring. Common themes include proper planning, establishing contact with the relevant authorities, and complying with data protection, and security.
Acceptance of decentralized trials must come not only from the sponsor, but also key stakeholders, such as investigator sites and study participants. One of the challenges in transitioning conventional trials into decentralized solutions during the pandemic has been the training and adoption by individual sites. Hospitals, for instance, have their own data privacy and security requirements.
Over the course of the pandemic, sites needed to reconfigure their patient engagement strategies within a few weeks to enable critical patient visits to continue. It was often necessary to demonstrate to site leadership that the novel technologies deployed as part of a decentralized solution met strict data privacy requirements. In another instance, a study was redesigned with a reformulated drug that would allow participants in the trial to self-administer the medicine without any need for a site visit. The experimental drug ingredients were not altered — just the way in which the drug was administered changed to circumvent initial site roadblocks. These examples highlight the opportunity for sites to play a role in decentralized trial design and technology selection.
Similarly, patients need to be comfortable with accessing and using the technology assigned through decentralized trials while being reassured that they are receiving a level of care equivalent to that provided in a conventional trial. PPD has addressed this issue by focusing on the patient journey. Our dedicated patient-centricity team carefully considers which aspects of a decentralized trial are most beneficial and potentially challenging, raising concerns and suggestions with the sponsor. For example, in a trial involving patients with complex pain, PPD would most likely not recommend in-home use of ECG devices, as doing so would require consistent and advanced dexterity, and would propose alternative options to gain the same endpoints.
With PPD’s Patient Concierge Service, patients establish a relationship with their dedicated “concierge” who provides ongoing support and engagement throughout the trial by scheduling visits, sending reminders of visits or other activities that need to be completed, and answering questions about how to use different technologies. The service allows patients to feel a deeper connection to the study, which is beneficial for retention and satisfaction.
We expect that all stakeholders — from regulatory authorities and investigator sites to sponsors and CROs — will learn from the experience of switching to decentralized trials as a matter of necessity during the COVID-19 pandemic and continue to implement them. Slowly, but surely, sponsors have come to view decentralization not just as a risk-mitigation tactic, but as an effective way to conduct clinical trials under any circumstances.
In the interim, the needs of a study and its patient population will determine whether a decentralized trial is appropriate, which is largely dependent on the schedule of events and the assessment of needs within the trial — such as whether certain devices can be used or if certain patients will need to be treated in a hospital setting due to their fragile conditions. Smaller protocol details are also important, such as if blood draws need to be performed at a specific temperature or centrifuged immediately. Whether local laboratories and other facilities are available is another consideration. However, sponsors can rely on the expertise of PPD® Digital to guide them on protocol adaptations and design.
When devising schedules of events, sponsors should assess what is absolutely required at each visit and what can be conducted remotely to design protocols. They should also consider the patient journey — whether they will need more personal interaction with their physicians and if that can be accomplished with televisits. As decentralized trials become more accepted, we anticipate the increased standardization of technologies, from geofencing to compliance technologies, such as new sensors, blood pressure cuffs, or smart pills that connect via Bluetooth and register if a medicine has been taken. All of these factors should help determine the optimal distance along the decentralized spectrum.
Knowing that decentralized trials are not one-size-fits-all, PPD has adopted a multi-platform approach to provide optimum solutions for every trial. Rather than acquire a single platform and force-fit trials to that technology, we work with many different vendors — our anchor partners — offering a range of solutions. We evaluate each protocol and the patients involved to identify the platform that best fits each study’s unique set of needs.
To ensure ongoing compliance, PPD also has an internal regulatory intelligence function that continuously monitors and interprets regulatory changes in real-time. When COVID-19 emerged, our dedicated staff increased focus in this area, monitoring the rapidly evolving regulatory environment around the clock to keep study teams up to date so all clinical trials and customer projects stayed on the right path.
Our multiplatform approach and internal regulatory intelligence capabilities, combined with an awareness of what features, functions, and devices will be available tomorrow, enables PPD to design compliant, customized trials using conventional, decentralized, and hybrid strategies as appropriate and with the flexibility to leverage all possible technology options.
Note: Additional insight contributed by Charity-Anne Schuller, Pharm.D., Senior Director, Regulatory Affairs, PPD; and Ilse-Maria Nolan, Senior Director, Regulatory Affairs, PPD.
In his current role, Alistair supplies strategic intelligence and insight to the technical direction of the regulatory affairs team. He interacts with internal and external stakeholders in the offering and provision of services and oversees relationships with regulatory authorities. Alistair provides operational oversight for the creation of quality submissions and building solutions that offer clients maximum flexibility, quality and cost effectiveness. Before PPD, he served as senior director of global regulatory affairs for another CRO and vice president of international regulatory affairs for GlaxoSmithKline. Alistair earned a bachelor’s degree in agriculture from Queen’s University Belfast.