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The Importance of Conducting Diverse US Trials for US Cancer Patients

Since the early 1990s, overall cancer death rates have declined for most cancers in the US. According to the Annual Report to the Nation on the Status of Cancer – issued in March 2020 as part of a joint effort between the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the North American Association of Central Cancer Registries (NAACCR), and the National Cancer Institute (NCI) – rates decreased by 1.8% per year among men and 1.4% per year among women from 2001 to 2017.1 Children aged 0 to 14 years also experienced a decrease in deaths, down 1.4% per year. Among common cancers with declining death rates from 2014 to 2018, lung cancer and melanoma showed the largest decreases.2

Many factors have contributed to these decreases, such as tobacco cessation, early detection, genetic testing, and annual screening for high-risk individuals, but perhaps the largest contributor has been the introduction of targeted immunotherapies, such as CAR T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies, immune system modulators, and treatment vaccines. However, some cancers are experiencing increases despite these advancements.

When Accelerated Approval Gets It Wrong

When Accelerated Approval Gets It Wrong To help address the cancer burden in the US, the US Food and Drug Administration (FDA) offers various routes to accelerate the development of cancer treatments, the most notable of which is accelerated approval. Sponsors of drugs that treat serious conditions and fill unmet medical needs can seek considerably earlier FDA approval based on a surrogate endpoint.3 These companies must still conduct confirmatory studies to confirm clinical benefit; if that is not achieved, the FDA can withdraw approval, prompting the removal of the product from the market by the sponsor. The FDA’s Oncologic Drugs Advisory Committee (ODAC) met in April 2021 to discuss whether confirmatory trials have demonstrated clinical benefit for multiple immune checkpoint inhibitors approved under the accelerated approval pathway. The committee agreed that some of those products should remain on the market but recommended that others be removed after they did not demonstrate clinical benefit.

Two products were subsequently voluntarily withdrawn from the market: 1) Keytruda (pembrolizumab), from Merck Sharp & Dohme Corp, for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 and 2) Opdivo (nivolumab), from Bristol-Myers Squibb Company, for the treatment of patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib.

Trials Conducted Outside the US

After reevaluating multiple products to treat cancer in 2021, the FDA convened the ODAC in February 2022 to consider a new product to treat cancer – sintilimab from Innovent Biologics (Suzhou) Co, Ltd, for use in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of patients with stage IIIB, IIIC, or IV non-squamous non-small cell lung cancer (NSCLC) with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumour aberrations. In a new biologics license application (BLA) submission, the sponsor sought approval based on a single confirmatory trial conducted in China (ORIENT-11). The committee agreed that sintilimab appeared to be safe and effective, adding value over chemotherapy alone. The primary endpoint for the study was progression-free survival (PFS), but the standard endpoint for first-line treatments of NSCLC with immune checkpoint inhibitors is overall survival (OS).

The FDA’s primary issue with the BLA, however, was that the trial was conducted in a single country lacking the diversity of the US population. Ultimately, the ODAC voted 14–1 that additional clinical trial(s) demonstrating applicability to US patients and US medical care should be required prior to a final regulatory decision. The panelists also agreed that a lack of unmet needs in the associated patient population contributed to their decision. The FDA subsequently issued a complete response letter recommending that the sponsor conduct a multiregional clinical trial and use OS as an endpoint. At the ODAC meeting, the FDA noted an “increasing number of single-country trials” submitted to support US approval, which the agency considers “me-too trials.” This practice is “a departure from decades of multiregional clinical trials as the consistent approach to drug development.” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence (OCE), spoke about the lack of racial and ethnic diversity in ORIENT-11, which he stated was a “lack of diversity by design,” and said he was “very unhappy to have this discussion” during Black History Month in the US. He noted the importance of including racially and ethnically diverse populations in clinical trials designed to approve products for use in US patients.