Innovative Clinical Trial Designs Emerge from Pandemic

Pressure to quickly and efficiently develop and test potential treatments for COVID-19 has led sponsors and research organizations to implement new strategies for determining product safety and efficacy in a broad range of patients. Collaboration is a leading theme as multiple biopharma companies look to study candidates in master protocols designed to compare several test therapies at the same time. More decentralized trials and adaptive studies and greater use of real world data and real world evidence (RWE) are shaping protocols and revising patient recruitment and enrollment practices.

One approach is for clinical studies to identify and enroll more high-risk patients in order to accelerate data collection on product effectiveness. Eli Lilly, for example, made waves last month with its plan to test an experimental neutralizing antibody in nursing homes where residents and staff have been exposed to the virus [see https://investor.lilly.com/news-releases/news-release-details/lilly-initiates-phase-3-trial-ly-cov555-prevention-covid-19-long]. The aim is to see if the test drug (LY-CoV55), developed by AbCellera, can block the spread of infection among these highly vulnerable individuals. The plan is to enroll 2400 patients in a phase 3 study in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and utilizing its COVID-19 Prevention Network. Because long-term care facilities lack the infrastructure to conduct clinical trials, Lilly assembled a customized a fleet of recreational vehicles with lab equipment and research personnel able to provide intravenous infusion of the test drug to patients at selected sites.

Another strategy involves studying asymptomatic adults in households with an infected individual to determine if the test drug can prevent the spread of infection to healthy individuals. NIAID is jointly conducting a phase 3 trial with Regeneron Pharmaceutical that will enroll 2000 adults in such homes to study whether its investigational REGN-COV-2 double mAb combination therapy can block contagion compared to placebo based on assessment of results one month following administration [see https://www.nih.gov/news-events/news-releases/clinical-trials-monoclonal-antibodies-prevent-covid-19-now-enrolling].

The Lilly/AbCellera mAb also is being tested in hospitalized COVID patients as part of a larger RCT organized by NIAID and other research entities. Based on a master protocol, the study is designed to test multiple monoclonal antibody treatments, with flexibility to enroll additional patients later in the trial and shift study participants to another therapy that shows more promise. Initial participants are randomly assigned to receive a test drug or placebo and then assessed for symptom change after 5 days. These findings will determine whether investigators should administer the drug to larger patient cohorts and to more seriously ill individuals.

Biopharma companies are collaborating to support platform trials able to test multiple therapies. For example, the COVID R&D Alliance involving 20 biopharma companiesannounced in early August the launch of the I-SPY COVID platform trial to test three drugs from Amgen, AbbVie and Takeda on seriously ill, hospitalized individuals [https://www.covidrdalliance.com/pdf/ISPY_PressRelease_August_3_Final.pdf]. The aim is to determine if these anti-inflammatory treatments can provide relief by impacting the immune system of such individuals, as measured in their need for respiratory support. The trial utilizes Quantum Leap Healthcare Collaborative’s adaptive platform trial design, which aims to minimize the number of study participants and time required to obtain data by assessing multiple therapies at the same time. In utilizing features of adaptive trials, the sponsors agree to drop those drugs that don’t show effectiveness and to add new test products that show some promise, as has been applied to research on new cancer therapies.

Drive for minority participants

Another goal for the research community is to utilize innovative research strategies to enroll more diverse racial and ethnic populations in clinical trials for COVID-19 treatments and vaccines. Although FDA has issued guidance and emphasized the importance of such efforts for years, minority participation in clinical trials has remained low. At the same time, national tracking data indicates that hospitalization rates for Black and Latino groups are nearly five times that of whites. Main factors for these disparities is that minorities show a higher prevalence of debilitating health conditions (obesity, heart disease, diabetes), poor health care, and greater exposure to contamination through jobs and crowded living conditions.

Researchers are working to overcome decades of mistrust in government health institutions through community outreach efforts. Sponsors seek to locate clinical trial test sites in neighborhoods with high minority populations and are working with local church groups and community organizations to overcome fear of medical institutions.

Underlying these research efforts is a growing recognition of the importance of testing new therapies in large, randomized, placebo-controlled, double-blind clinical trials as necessary for determining whether an experimental medicine has any real impact on preventing or treating infection by the COVID-19 virus [see https://www.nejm.org/doi/full/10.1056/NEJMe2024638?query=TOC]. Data disproving effectiveness claims for some highly touted drugs have focused attention on the need for sound, well-controlled studies that may confirm effectiveness, but perhaps only in certain patients with less serious disease, or that treatment may lead to serious side effects for others.