Moving Clinical Operations Forward During Pandemic
Applied Clinical Trials
Lockstep with regulatory guidance on conducting trials amid crisis, here are four key actions sponsors can take to minimize disruptions.
As of the beginning of the month, in many parts of the world, the number of COVID-19 cases continued to rise rapidly as countries enacted strict lockdown and social-distancing countermeasures. Like many sectors of the world economy, the biopharmaceutical industry has been impacted with significant disruptions to clinical development, many of which have been well-documented in recent weeks.
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Patients are less able to travel to sites and comply with studies. Enrollments are drying up. Many resources, supplies, and personnel aren’t available. Studies are missing critical data points and are delayed. Ultimately, important treatments are delayed.
To combat these disruptions, FDA recently released guidance on the conduct of clinical trials during the COVID-19 pandemic.2 In particular, the agency repeatedly emphasized prioritizing safety for all participants. For example, due to global travel restrictions, the agency recommended that sponsors look for substitute methods to conduct patient safety assessments, and use remote technology where possible. FDA also recommended that sponsors explore alternative delivery methods for investigational products where feasible, such as patients self-administering drugs or visiting other sites, and pursue site monitoring remotely. For patients unable to access trial sites or necessary medications, the agency advised sponsors to put additional safety monitoring programs in place.
In accordance with FDA’s recommendations, there are four key actions that biopharmaceutical sponsors can take immediately to offset disruptions.
1. Virtualize clinical trials. A survey of U.S. and EU sites have reported that many of their patients are less willing to participate in the clinical trials that they’re already enrolled in. This patient sentiment is only worsening as the crisis continues.3 For clinical studies currently in flight, sponsors need to virtualize their trial operations to avoid jeopardizing the safety of patients as well as site staff.4 In a purely virtual setting, patients are in contact with study teams and trial physicians through smartphone technologies5, and investigational products are shipped directly to patients’ homes. Patients can self-administer therapies, if feasible. For more complex procedures and interventions, sponsors can collaborate with third-party home-trial vendors6 or incorporate at-home nurse visits. Obviously, the feasibility and logistics of this approach need to be analyzed thoroughly. For example, does a protocol involve procedures that cannot be conducted outside of a hospital setting?
2. Monitor sites remotely. If clinical research associates (CRAs) are unable to access sites because of global travel restrictions or local quarantines, sponsors should enable remote monitoring and oversight as the FDA recommends. If not already in place, sponsors may need to enable virtual workspaces for sites to upload the necessary documents for centralized monitoring. The Association of Clinical Research Organizations (ACRO) recently laid out emergency guidelines for sponsors, contract research organizations (CROs), and sites on conducting trial oversight during the pandemic.7 A few of the recommendations include:
- Continuing periodic communication with sites over telephone.
- Using key risk indicators (KRIs) and key performance indicators (KPIs) to identify trends that may require short-term interventions. Indicators could include protocol deviations, missed visits, adverse event reporting cadence, etc.
- Using an electronic data capture (EDC) system to enable remote reviews of patient visits, with particular emphasis on patient safety data and data quality issues. ACRO notes that it does not recommend accessing patient electronic health records remotely unless protocols and procedures for maintaining patient privacy are already in place. Additionally, it does not recommend using fax machines for critical source documents.
3. Engage patients and investigators through proactive communication. Developing a communication and remote engagement strategy with patients and investigators that can be sustained throughout the pandemic is vital to ensure motivation and reduce burden. Virtualizing trials or monitoring sites will only be successful if
sponsors frequently engage and empathize with patients and sites in order to assuage concerns caused by COVID-19.
4. Assess the overall clinical portfolio and evaluate study design, feasibility, and operations as the pandemic evolves. For each clinical trial in the portfolio, sponsors need to conduct a thorough assessment exercise aimed at answering key questions related to design, feasibility, and operations in the immediate term, short term, and long term. For example, in the immediate term, sponsors should determine which of their in-flight trials need to pause enrollment and which of their new planned trials need delayed starts. In the short and long term, sponsors should think through:
- Protocol modifications to incorporate remote patient and site assessments or other virtual elements.
- Patient visit requirements and anticipated data collection challenges.
- Effective resumption of activities when the pandemic situation improves.
- Improvements to risk management planning.8
- Overall impact on clinical trial and clinical program timelines (including time to approval).
Adapting, adjusting as we go
These are just a few questions among many that need to be sorted out. Moreover, each passing day brings new information about the spread of COVID-19 globally. China and South Korea seemed to have gotten a grip on the spread of the virus (as of early April), while the U.S. and countries in Western Europe continued to struggle as cases rose exponentially. Therefore, to plan for the short and long term, sponsors should go back to the drawing board and reevaluate overall clinical study design, including patient eligibility, feasibility, enrollment, timelines, and budgets against the evolving global landscape.
Sponsors should note that these strategies may require amendments to study protocols, and FDA guidelines urge sponsors to engage with institutional review boards (IRBs) as soon as possible. However, in cases where protocol changes are made to directly eliminate hazards to patients, these may be implemented without IRB approval. Finally, alarming projections indicate that social-distancing countermeasures may need to be in place well into 20219, which means that biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.
Sharma Ramanathan is a manager in ZS’s San Francisco office; Ronald Du is a manager in ZS’s Los Angeles office; Mike Martin is ZS’s global clinical lead, based out of the company’s Princeton office; Arvind Chavali is an associate consultant in ZS’s San Francisco office
References
1. https://www.jdsupra.com/legalnews/the-global-impact-of-covid-19-on-72027/
3. https://continuumclinical.com/blog/covid-19-live-updates
5. https://www.science37.com/blog/siteless-clinical-trials-changing-the-game-for-patients/
6. https://www.clinicalleader.com/doc/the-benefits-and-challenges-of-siteless-clinical-trials-0001
8. https://info.zs.com/activeingredient/clinical-development-risks-and-issues-in-a-covid-19-world
9. https://www.washingtonpost.com/health/2020/03/19/coronavirus-projections-us/
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