The New Era of Clinical Trial Design

Jill Gilbert, MD

In this issue, I want to highlight a recent landmark decision by the FDA concerning trial design moving forward for cancer drugs. For over 100 years, the FDA has worked to ensure the safety and efficacy of human and veterinary medicines, biologics, and medical devices.

In particular, the Oncology Center of Excellence within the FDA was established in 2017 as authorized by the 21st Century Cures Act. The FDA’s Oncologic Drugs Advisory Committee (ODAC), comprising 13 voting members, evaluates data concerning the safety and efficacy of marketed and investigational human drug products for the treatment of patients with cancer. ODAC then makes a recommendation to the FDA commissioner.¹

The approval process is much more complex than it seems. I bring your attention to this process due to a recent landmark decision by ODAC and the FDA concerning the phase 3 AEGEAN trial (NCT03800134). On July 25, 2024, the FDA reviewed data from this trial, which evaluated perioperative and postoperative durvalumab (Imfinzi) for patients with stage IIa to IIIb non–small cell lung cancer without known targetable mutations or translocations. The randomized, placebo-controlled trial enrolled 740 patients using intention-to-treat rules (Figure).²

Figure. AEGEAN: Durvalumab Neoadjuvant and Adjuvant

By traditional standards, the completed trial was successful and demonstrated significant and clinically meaningful improvement in event-free survival (EFS). However, the FDA flagged this trial for review by ODAC in July 2024. Although the FDA did not question the EFS benefit, the critique concerned the study design, which did not separate the role of neoadjuvant vs adjuvant durvalumab in attaining the EFS. In other words, are both exposures necessary? Are we subjecting patients to higher costs and risks of toxicity?

The FDA has now required that 2-arm trial designs specifically address this issue. That means instead of 1 trial with 2 arms, this will necessitate either separate trials or a 3- or 4-arm trial design. It is anticipated that this decision may require more patients, more investment by drug companies, and more time to answer these clinical ques - tions. This may be a win for patient safety and financial toxicity. It may slow drug discovery and approval and thus slow progress for our patients. Time will tell.

Even if clinical trial design is not a primary topic of interest, it is important to recognize how design is incredibly important and must be considered when interpreting data. We live in a world of clinical trials. Small shifts in paradigms can greatly affect our patients and science.

On a related note, I strongly encourage any fellow to apply for the FDA-ASCO (American Society of Clinical Oncology) Hematology and Oncology Fellows Day Workshop. This in-person workshop occurs annually at FDA headquarters in Silver Spring, Maryland. Workshop participants are immersed in an informative deep dive into the complex steps of getting a drug from concept to trial and approval. The workshop is highly educational, and participants quickly realize that the people who work for and with the FDA have a true passion for patient safety and impactful drug discovery.

Durvalumab with platinum-containing chemotherapy as neoadjuvant treatment followed by single-agent durvalumab as adjuvant therapy was approved by the FDA for patients with resectable non– small cell lung cancer with no known EGFR mutations or ALK rearrangements on August 15, 2024.

Reference

FDA YouTube page. July 25, 2024, meeting of the Oncologic Drugs Advisory Committee. https://www.youtube.com/live/smUHtK5wdic