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

The rapid issuance of clinical trial guidance, trial modifications and 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 at week 2 of the 2021 American Association for Cancer Research (AACR) Annual Meeting.

“One needs to understand just how far we have [come] in a short time…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. They have a great deal of substance,” James H. Doroshow, MD, of the National Cancer Institute, said. Doroshow serves as senior investigator in the Developmental Therapeutics Branch, director of the Division of Cancer Treatment and Diagnosis, deputy director for clinical and translational research, and head of the Oxidative Signaling and Molecular Therapeutics Group at the institute’s Center for Cancer Research.

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

COVID-19 Leads to Rapid Change in Clinical Trial Guidance

During the pandemic, clinical trial conduct was significantly affected, explained Sundeep Agrawal, MD, medical director, FDA and clinical collaborator, medical oncology, National Cancer Institute. Patients were often unable or unwilling to go 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 was variable and inconsistent.

As a result, the FDA issued a guidance document on conducting clinical trials during the public health crisis, advising 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 offsite methods, such as remote monitoring, changes for patient safety without approval from the FDA or the 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 regarding data management for statistical analysis plans.

“The speed [with] 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 Jill Feldman, cofounder of EGFR Resisters, during the panel discussion.

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

Disparities in clinical trials were a known problem prior to the COVID-19 pandemic, noted panelist Nicole Gormley, MD, acting director of the FDA’s Division of Hematologic Malignancies II. However, 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 as Caucasians, African Americans are historically underrepresented in clinical trials, she explained. Moreover, the disease biology of multiple myeloma differs among races, further underscoring 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 in the trial (17.9% of total population; African American 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 [from which] 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 that 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,” she explained.

Moreover, recommendations for eliminating racial disparities in multiple myeloma were published based on an FDA-AACR workshop in Blood Cancer Discovery, outlining considerations for preapproval clinical trials, postapproval 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 unforeseen prospect of the COVID-19 pandemic, explained Elizabeth Barksdale, PhD, director of regulatory affairs and scientific policy at LUNGevity Foundation. 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 to reduce patients’ exposure to COVID-19 while preserving their access to lifesaving investigational medicines through clinical trials,” Barksdale said.

A role will likely always exist 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 top concerns regarding 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 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 Noolie Gregory, vice president of decentralized clinical trials operations, Syneos Health, during the panel discussion.

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 which should remain onsite. Remote consent may also be a next step to further this approach.

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

The collective lessons learned from the COVID19 pandemic have opened a door for real-world data opportunities, explained Donna R. Rivera, PharmD, MSc, cochair and panel moderator of the session and associate director for pharmacoepidemiology, Oncology Center of Excellence, FDA. “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.

“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.

The use of real-world data, with challenges such as characterization of data quality, end point development and validation, and bias quantification, needs 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 at: 2021 American Association for Cancer Research Annual Meeting; May 17-21, 2021; virtual. Session REGSC102.}

_{2. FDA. Conduct of clinical trials of medical products during the COVID-19 public health emergency. 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):18241835. 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}