Modernized Clinical Trials Include Diverse Representation, Decentralization, and Real-World Data in Post–COVID-19 Era

Donna R. Rivera, PharmD, MSc

Although the COVID-19 pandemic caused significant challenges across the health care paradigm, silver linings, including the rapid issuance of clinical trial guidance, trial modifications to ensure the risk of COVID-19 transmission was limited to patients with cancer, and the emphasis on inclusivity of diverse racial and ethnic patient populations, have opened the door for new opportunities for decentralized clinical trials and real-world data in a post–COVID-19 world, according to a panel discussion that took place during week 2 of the 2021 AACR Annual Meeting.¹

The session and panel discussion titled, “Lessons Learned from COVID-19: Adaptations and Approaches for Trial Modernization,” featured key speakers:

• Donna R. Rivera, PharmD, MSc, co-chair and panel moderator of the session, associate director for pharmacoepidemiology, Oncology Center of Excellence, FDA
• Sundeep Agrawal, MD, co-chair of the session, team lead, Division of Oncology I, clinical lead, Project Renewal, FDA
• Susan Winckler, RPh, Esq., panel moderator of the session, CEO, Reagan-Udall Foundation, FDA
• Nicole Gormley, MD, director, Division of Hematologic Malignancies II, FDA
• Elizabeth Barksdale, PhD, director of regulatory affairs, LUNGevity Foundation
• Jill Feldman, co-founder, EGFR Resisters
• James H. Doroshow, MD, senior investigator, Developmental Therapeutics Branch, director, Division of Cancer Treatment and Diagnosis, deputy director for clinical and translational research, head, Oxidative Signaling and Molecular Therapeutics Group, Center for Cancer Research, National Cancer Institute
• Noolie Gregory, vice president, Decentralized Clinical Trials Operations, Syneos Health

“One needs to understand just how far we have [come] in a short time because…there have been extensive changes that have occurred over the past several months. I don’t want anyone to miss the opportunity to realize that these are changes that might have taken a decade or more in the absence of the pandemic. There are real silver linings that [have] a great deal of substance,” said Doroshow during the panel discussion.

The goals of the session were to understand what has changed since the onset of the COVID-19 pandemic, what patient populations have been affected by the pandemic, where clinical trial modernization can be increased, and how the oncology field can sustain what was learned in a post-COVID landscape.

COVID-19 Leads to a Rapid Change in Clinical Trial Guidance

During the COVID-19 pandemic, clinical trial conduct was significantly affected, explained Agrawal. Patients were often unable or unwilling to come to the clinical trial site; more staff time was needed to organize, implement, and conduct patient visits; ancillary services, such as radiology and surgery, were limited; trial procedures needed modification; and communication to trial programs were variable and inconsistent.

As a result, the FDA issued a guidance document on conducting clinical trials during the public health crisis that advised sponsors on how to ensure trial participants were kept safe during the pandemic, considerations for common issues, and when to contact the FDA for trial conduct guidance.²

“It’s been a year filled with hardships and loss for many, including the patients with cancer we serve. Looking back at this past year or so, there have been a few silver linings. One being the rapid implementation of new clinical trial conduct, eligibility, and data use,” said Agrawal.

Common issues include the use of off-site methods, such as remote monitoring, changes for patient safety without approval from the FDA or Institutional Review Board, COVID-19 contingency measures documentation, and exclusion criteria based on prior COVID-19 therapy.

The FDA suggests that contact between the regulatory agency and investigators is advised if protocol modifications related to efficacy end points are needed and if changes are needed with regard to data management for statistical analysis plans.

“The speed in which the FDA has had to create guidelines that modify the trials to be flexible without compromising patient safety or scientific integrity of trials [has been remarkable]. It can allow us to move forward with some of the adjustments that have been made,” said Feldman during the panel discussion.

COVID-19 Opens the Door to Address Racial and Ethnic Disparities in Clinical Trials

Disparities in clinical trials was a known problem prior to the COVID-19 pandemic, said Gormley. However, looking beyond the COVID-19 era, broadening eligibility criteria to address representation throughout drug development should be a focus of clinical trial development.

Gormley used multiple myeloma clinical trials as an example. Although African Americans are twice as likely to develop multiple myeloma compared with Caucasians, African Americans are historically underrepresented in clinical trials, she explained. Moreover, the disease biology of multiple myeloma differs between races, which further underscores the need for adequate representation across all races to fully understand the efficacy of an investigational therapy.

Findings from a randomized phase 3 study (NCT01169337) demonstrated that early intervention with lenalidomide (Revlimid) led to significant delays in progression to symptomatic disease in patients with smoldering multiple myeloma.³ However, this benefit did not appear to translate to African American patients included on the trial (17.9% of total population; black vs white, HR, 0.62; 95% CI, 0.19-2.07; P = .440).

“Despite the comparatively robust representation of African Americans in this clinical trial…this was still not enough information to draw meaningful conclusions. This does highlight the importance of having adequate representation to assess the safety and efficacy of a therapeutic in populations that will ultimately receive the product,” said Gormley.

Bridging the conversation between typical clinical trials in multiple myeloma and those that were required to develop vaccines for the COVID-19 pandemic, Gormley highlighted that the clinical trial, which led to the FDA approval of the Janssen COVID-19 vaccine comprised a robust and diverse patient population.⁴ This proves that increased representation is possible in clinical trials, explained Gormley.

Moreover, recommendations for eliminating racial disparities in multiple myeloma were published based on an FDA-AACR workshop in Blood Cancer Discovery, outlining considerations for pre-approval clinical trials, post-approval clinical trials, and real-world studies.⁵

Developing a Greater Understanding of Decentralized Clinical Trials

The rise of decentralized clinical trials, or studies in which some or all trial-related procedures and data acquisition take place locally rather than in the clinic, has been another silver lining of the COVID-19 pandemic, explained Barksdale. Utilizing decentralized clinical trials or a hybrid format rather than a traditional clinical trial could be a key step in increasing accessibility of clinical trials to patients.

“The worldwide health crisis created by the novel coronavirus necessitated a rapid shift from traditional, in-person clinical trials, to decentralized and hybrid trials. Prior hesitancies and objections around decentralization were put aside in a matter of weeks in order to reduce patients’ exposure to COVID-19 while preserving their access to life-saving investigational medicines through clinical trials,” Barksdale said.

There will likely always be a role for traditional clinical trials because they have an established track record and provide many benefits to patients, including highly trained clinical trial sites and investigators, operational efficiencies, control over data quality and variability, and sponsor control, Barksdale explained. However, decentralized trials offer less burden to patients, which leads to more rapid patient accrual and lower-cost trials. This approach also leads to less attrition, increased convenience of long-term follow-up, and the potential ability to enroll more representative patient populations.

Surveys conducted by the LUNGevity Foundation, a nonprofit, survivorship-focused organization, revealed that patients cited travel and logistics as a top concern with regard to clinical trial enrollment, Barksdale said. Additionally, thoracic oncologists said that tests, such as CT scans and blood panels, can likely be done via local labs if data are not compromised. Taken together, decentralized clinical trials could lessen the burden on patients while maintaining investigator comfort in acquiring data, Barksdale explained.

“[Decentralized clinical trials] are things that people like the idea of but are a little bit concerned and hesitant about [when it comes to] data integrity and, logistically, how to organize that. How do we ensure an efficient transfer of data?” asked Gregory during the panel discussion.

In order to further integrate decentralized elements into drug development programs, principal investigators and sponsors need clarification on who is responsible for overseeing an investigation. Investigators and sponsors may not want to take responsibility for results acquired by local labs or providers not under their direct supervision, Barksdale explained.

As such, academic and industry professionals are ironing out these details and LUNGevity is in the process of assigning risk levels to common lung cancer procedures to determine what elements could be decentralized and what elements should remain on-site. Remote consent may also be a next step to further this approach.

What Does Clinical Trial Modernization Mean for a Post­–COVID-19 World?

Taken collectively, the lessons learned from the COVID-19 pandemic have opened a door for real-world data opportunities, explained Rivera. Real-world data can offer rapid responses to emerging public health issues, inform innovative clinical trial designs, and facilitate a “learning health care system,” Rivera said.

The Reagan-Udall Foundation and Friends of Cancer Research COVID-19 Evidence Accelerator and Project Post COVIDity are two examples of collaborative efforts to acquire real-world data on public health.^6,7

“Real-world data can be complementary and contextualize randomized-controlled trials. To really harness the potential of real-world data, [optimizing] ‘a learning health care system’ can be a foundation to increase the quality of available real-world data through methods, such as better interoperability, and establish minimal common data elements. COVID-19 has disrupted health care and forced flexibility and considerations of alternative strategies for trial conduct,” Rivera said.

Challenges in utilizing real-world data, such as characterization of data quality, end point development and validation, and bias quantification, need to be standardized.

“While the world has endured unparalleled public health and global humanitarian challenges [in 2020 and 2021] because of COVID-19, it has also been a catalyst for innovation and change in the scientific, patient care, and regulatory communities. The pandemic has fundamentally changed us [and] forced us to adapt, work differently, and think differently,” concluded Rivera.

References

1. Rivera DR, Agrawal S, et al. Lessons learned from COVID-19: adaptations and approaches for trial modernization. Presented: 2021 AACR Annual Meeting; May 17-21, 2021; week 2; virtual. Session: REGSC102
2. Conduct of clinical trials of medical products during the COVID-19 public health emergency. FDA. Updated January 27, 2021. Accessed May 18, 2021. https://www.fda.gov/media/136238/download
3. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020;38(11):1126-1137. doi:10.1200/JCO.19.01740
4. Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1-2a trial of Ad26.COV2.S covid-19 vaccine. N Engl J Med. 2021;384(19):1824-1835. doi:10.1056/NEJMoa2034201
5. Gormley N, Fashoyin-Aje L, Locke T, et al. Recommendations on eliminating racial disparities in multiple myeloma therapies: a step toward achieving equity in healthcare. Blood Cancer Discov. 2021;2(2):119-124. doi:10.1158/2643-3230.BCD-20-0123
6. COVID-19 evidence accelerator. Reagan-Udall Foundation for the Food and Drug Administration; Friends of Cancer Research. 2021. Accessed May 18, 2021. https://evidenceaccelerator.org/.
7. US FDA ‘Project Post COVIDity’ will track infection impact on cancer patients using real-world data. Pink Sheet. February 15, 2021. Accessed May 18, 2021. https://bit.ly/33VlN3a.