Lilly, Innovent and the Question of Clinical Trial Representation
Last week, when the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) recommended that Eli Lilly and Innovent Biologics must run another U.S.-based trial before lung cancer drug Sintilimab could be approved in this country, it set off alarm bells across the industry.
The precedent-setting 14-1 decision will surely impact the more than 25 applications already submitted to the FDA, or in the planning stages, based solely on clinical data from China, the agency said.
“Single country submission is a step backward in achieving the racial diversity that we need in the United States,” said Richard Pazdur, director of the FDA’s Oncology Center of Excellence.
SVB Leerink analyst Daina Graybosch indicated that the decision could be seen as precedent-setting, and not just for the PD-1 therapy space.
“Were [the trial] a one-off case, we sense that the FDA may be more willing to grant approval, but given its status as a leading example, we believe the FDA will draw a line in the sand to discourage this single-country trial approach," she said.
The rationale makes sense. It is not nationalistic or xenophobic. If anything, it’s the opposite. Drugs are sensitive entities and they have a unique impact on different races and ethnic (cultural) populations. Reasons for this include genetic, environmental and cultural factors, which can impact the metabolism, clinical effectiveness and safety profiles of the drugs.
Environmental factors can include climate or the propensity of practices like smoking or alcohol consumption, while psychosocial factors can influence adherence to a particular drug regimen. Precision cancer therapeutics is based partly in pharmacogentic profiles (testing for genetic variations). For example, testing for genetic markers of efficacy or toxicity of anticancer therapeutics can help to guard against severe side effects and help determine why a certain person, or group of people, respond well to a certain drug. Genes that could underlie (or spare) a certain group from disease, are constantly being uncovered.
So, to require Lilly and Innovent and the owners of those other 25 unnamed products to run a pivotal trial based on more than one ethnic group certainly is not out of the realm of reason. The unspoken challenge here is: how diverse can a trial run in the United States really be right now?
This important dilemma was spotlighted during the development of the COVID-19 vaccines. While Blacks and Latinos were likely to be more severely impacted by COVID-19, they were also less likely to participate in the clinical trials for the vaccines. Moderna’s private contractors struggled to recruit enough Black, Latino and Native American participants for its Phase III trial. The company eventually did achieve something close to parity, with 37% of the 30,000 participants being minorities.
“Underenrollment of racial and ethnic minorities reduces the generalizability of research findings and represents a disparity in access to high-quality health care,” said Lauren M. Hamel, Ph.D. and colleagues in a paper published in NCBI.
A 2018 ProPublica analysis found that Black participants made up less than 5% of the clinical trials for 24 of the 31 cancer drugs approved since 2015. This was a particularly glaring problem in the trials for Takeda’s Ninlaro for multiple myeloma. Twenty percent of multiple myeloma patients in the U.S. are Black, yet only 13 of the 722 participants in the trial determining its approval were Black. That’s 1.8%.
Gilles Gallant, SVP and global head of oncology development at Daiichi Sankyo, told BioSpace that his company ensures diversity by conducting clinical research in different sites across different countries. However, he shared that achieving this diversity is more challenging in the United States.
“If you look at our clinical trials, you will see that we enroll patients from Japan, from Asia, from Europe, from Latin America, from everywhere around the world,” he said. “So there is a diversity, but the challenge comes often more in the U.S. where the diversity in our clinical trials is often impaired by the ability to access the clinical care that we offer.”
Industry is taking steps to address these discrepancies. Recently, Medable and CVS forged a partnership aimed at improving patient access to clinical trial research. The collaboration links Medable’s decentralized trial platform with CVS MinuteClinic facilities across the country, placing most residents within a short drive of a decentralized clinical trial research site.
Lilly and Innovent’s key argument that they planned to offer Sintilimab to the U.S. market at a deep approximate 40% discount compared to PD-1 checkpoint inhibitors currently in the market, is ironic in the sense that it could actually help in achieving more equitable access to these drugs for underprivileged patients, who often happen to come from largely minority populations.
Lone ODAC dissenter, Jorge Nieva of the University of Southern California, pointed out another reason why having another PD-1 on the market could help to lower the cost.
“Having more drugs competing for those patients will have greater impact on health equity than the need for diversity in clinical enrolment,” he argued.
This begs the key question: yes, running clinical trials in China is cheaper, and pharmaceutical companies naturally want access to the country’s population of 1.3 billion people, but is offering Sintilimab in the U.S. at a 40% discount really putting the patient first if many patients will not ultimately benefit?
ODAC said no. It will be interesting to see the final arrangement struck between the FDA, Lilly and Innovent, and how this sets a new standard for global drug development going forward.