Managing Continuity in Clinical Trials in the COVID-19 environment: The Decentralized Option and Regulatory Flexibility
Introduction/Situation
COVID-19 has created a number of challenges in managing clinical trials for acute, chronic, life-threatening, and rare diseases.
Due to the pandemic, as many as 90% of the world’s clinical research sites are partially or totally inaccessible as of early May 2020. Enrollment is slowing or even stopping in some cases to prioritize patient safety; travel restrictions are preventing in-person patient site visits and CRA monitoring visits; regulators and industry staff who once traveled widely are working from home; some IRBs are deferring protocol review meetings, and investigator sites and hospitals are justifiably prioritizing care over clinical research activities.
However, to ensure that patients who participate in clinical trials – especially those for whom clinical research is really their only care option – are supported as much as possible, companies can navigate this crisis successfully by re-examining and adapting their clinical research operations to ensure patient safety, sustaining and supporting patient enrollment, increase communications with regulators, assess risks, preserve data integrity, and comply with fast-changing regulations.
Regulatory Authorities have issued guidance documents for industry on how to conduct trials during the coronavirus pandemic. Sponsors face complex choices, among them extending the duration of trials, halting or postponing trials or closing trial sites, transferring patients from sites hit hard by COVID-19, conducting procedures at new locations, suspending the enrollment of new patients, and modifying trial protocols. But more can be done. The fact that regulators are quickly showing a degree of flexibility and tolerance under the new circumstances provides to sponsors a basis (an “open door”) for creative thinking.
For example, FDA’s March 2020 Guidance on clinical trials during the pandemic states: “Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants”.
The implication is not subtle: regulators are open to industry ideas on how to keep clinical trials going and start new trials, and to considering revised processes such as remote monitoring, remote source data verification (SDV), direct-to-patient delivery of investigational products, and decentralized clinical trials. These ideas have been around for a while, but they gain fresh relevance and new urgency during this unexpected pandemic. Sponsors are well advised to take advantage of this opportunity, for the sake of their clinical trials and of patient benefit.
Importantly, regulators worldwide have mobilized to streamline requirements for developing diagnostics and products to treat COVID-19. For example, the FDA’s new Coronavirus Treatment Acceleration Program (CTAP) (launched March 31) is reviewing COVID-19 study protocols within 24 hours, approving single- patient expanded access requests in 3 hours, and showing renewed interest in the use of real-world data (RWD) and Real World Evidence (RWE) for illness patterns and treatment outcomes. Therefore, it is imperative that the clinical trial ecosystem continue to be strong, functional, increasingly efficient and able to accommodate vast numbers of patients suffering not only from COVID-19 but from myriad other diseases as well.
The challenge of COVID-19 is daunting but it is not insurmountable. To the contrary, it offers fresh opportunities to improve clinical research and benefit many more patients.
The Solution
Pandemic aside, the state of clinical trials today is in urgent need of greater efficiency. Eighty percent of clinical trials are delayed due to recruitment problems; the dropout rate across all trials is 30%; 85% of trials fail to retain a sufficient number of patients. Part of the cause is arguably related to patient convenience: 70% of potential participants live more than 2 hours away from their nearest study center, which limits their recruitment and retention.
In the context of the pandemic crisis, decentralized trials offer a just-in-time opportunity to address some of these problems in patient-centric ways, coupled with maintaining needed continuity in the clinical trial enterprise.
For example, the following tools can be implemented effectively both in ongoing and in newly initiated trials:
- Telemedicine: Virtual study visit using video calls through the patient’s smartphone
- Telephone Contacts
- Home Nursing: Study tests/ procedures provided in the patient’s home
- Simple eSource: tool to allow sites to document assessments/ interactions while conducting a remote visit when they cannot conduct the visit at the site. Data collected would be later entered into the EDC system.
- Direct-to-Patient (DTP) drug shipments: Study drug/device delivered direct to the patient’s home (in most cases, from site to patient home)
- Specialized couriers can maintain required shipping/storage conditions
The time for a serious look at implementing decentralized trials where appropriate and feasible is now.
But Regulatory Compliance Is Not Going Away: Data Collection, Protocol Deviations and Missing Data
The FDA is showing remarkable flexibility on a range of issues, from how a sponsor may document informed consent, to conducting clinical trials virtually, to using real-world evidence in a marketing submission. This gives the industry permission to test the boundaries. If an unprecedented solution can meet regulatory requirements, as well as the needs of patients and sponsors, regulators may be more open to it today than in the past. It is up to industry sponsors to initiate these conversations.
Importantly, sponsors must keep in mind that compliance obligations remain in place and exist to protect both the rights of patients and the integrity of the data:
- Informing Regulators: Although regulators will never compromise on patient safety, or on the need to show efficacy with GCP-compliant data, there is now flexibility on how and when data are collected (for example, endpoints can be delayed), how study monitoring can be done, and how investigational drugs may be delivered to patients, to name just a few. Regulators need to be informed about any solutions sponsors may want to try, and companies can protect their drug development programs by communicating them effectively.
- Protocol Deviations and Recordkeeping: Where sponsors have to modify study protocols in response to the Coronavirus pandemic, regulatory agencies expect meticulous records of deviations in order to preserve the integrity and interpretability of trial data. Regulators around the world have indicated they will be more flexible than in the past. For example, new FDA guidance specifies that changes to a protocol or investigational plan meant “to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19)” may be implemented without IRB approval or before filing an IND/ IDE amendment—but are required to be reported afterwards.”
- Missing Data: Acknowledging that the disruptions caused by the pandemic may result in an increase in missing data, the FDA is requiring that missed visits, patient discontinuations, and similar changes in protocol- specified procedures must be tracked in case report forms and must include specific information explaining how the missing data relate to the COVID-19 pandemic. EMA has encouraged sponsors to “pre-plan” how protocol deviations related to COVID-19 are recorded and how reasons for missing data are captured, in order to distinguish between “affected” and “unaffected” data when interpreting trial results.
- Country Specificity: While the EMA have released an overall guidance for the EU, the National Regulatory Authorities of EU member states are directly responsible for the trials. Accordingly, sponsors need to check country- specific guidance documents.
Conclusion and Why Parexel?
A large number of clinical trials (though not all) will inevitably be paused until the Coronavirus pandemic subsides and sites reopen, but sponsors should stay engaged. For example, Parexel is currently involved in a high volume of regulatory work for clients who are getting everything in line for when their paused trials resume, and/or are preparing the groundwork for new trials. If the preparatory work is done now, studies can restart more efficiently. This crisis will not last forever.
Sponsors should immediately consider applying decentralized methodologies to ongoing and new trials with a view to improving enrollment and retention rates as well as data collection; the circumstances have created a compelling opportunity to try new approaches.
Parexel’s Clinical Research has already accumulated significant practical experience in this emerging space, including 70+ decentralized clinical trials, 200+ remote patient engagement strategies, 250+ Direct-To-Patient shipments, 300+ patient apps and e-COA projects, and 3000+ clinical technology integrations. And this is just the beginning of a significant new approach to clinical research.
In parallel, sponsors should pay particular attention to protecting the safety of patients who are currently enrolled in clinical trials, and to safeguarding the integrity of the data collected in those trials, whether traditional or decentralized. Although regulators are stretched and perhaps distracted due to the impact of the pandemic, sponsors should remain vigilant to the potential risks inherent in these unusual circumstances, should mitigate them and should keep regulators properly informed.
Parexel’s Regulatory Consulting experts have broad and deep experience arising from decades of work as agency regulators and industry regulatory professionals. They understand the expectations of regulators and how to meet those expectations. They stand ready to support sponsors with appropriate regulatory risk mitigation strategies and with effective and timely communications with regulators around the world.