Meeting a Need

The newly proposed guidance for expansion cohort trials was released with the hope of meeting several ongoing challenges within oncology clinical trials, according to Jennifer Miller, PhD, assistant professor at Yale University School of Medicine in New Haven, Conneticut.

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The first challenge is that a lot of patients with cancer do not qualify for treatment within clinical trials because inclusion and exclusion criteria are very narrow.

“This puts pressure on the system to speed research and development and get approval for experimental therapies more quickly,” Dr Miller said.

The next challenge in oncology trials is the drive to obtain real-world evidence on investigational therapies.

“Because trials have narrow exclusion and inclusion criteria, the results often apply only to a narrow subset of patients,” Dr Miller said. “These patients tend to be healthier and younger than patients that end up taking the drug in the real world. There is a push to come up with innovative adaptive trial designs that include more generalizable data.”

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Finally, the third challenge within oncology clinical trials is speeding up the entire process to allow for greater access to drugs for patients in need. There are 2 available avenues for this access outside of clinical trials: the FDA’s expanded access program and the recently approved right-to-try access.

The use of expansion cohort trials is another effort intended to speed access to drugs, Dr Miller said. However, it is still unknown if the establishment of expansion trials will fulfill this need.

A 2017 study from the Cleveland Clinic reviewed data from 252 phase 1 studies that were published in the Journal of Clinical Oncology from 2004 to 2014 to see if there was an association between the use of expansion cohorts and subsequent clinical development.3 The results showed that the addition of a phase 1 expansion cohort had no effect on phase 1 maximum-tolerated dose, recommended phase 2 dose, subsequent phase 2 trial, or FDA approval.

Another 2017 study looked at 533 single-agent dose-finding adult oncology phase 1 trials published from 2006 to 2011 and subsequent phase 2 trials.4 Of the 381 drugs evaluated in these trials, 112 drugs had at least one phase 1 trial with an expansion cohort. This study showed that phase 1 trials with expansion cohorts of 2 to 20 patients had twice the rate of success in phase 2 trials compared with trials that did not include expansion cohorts.

According to Dr Gottlieb, “a lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials. Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time.”2

But, according to Dr Miller, it is too early to know what effect this FDA guidance will have, or whether or not increased use of expansion cohorts will help speed access to drugs.


  1. US Food and Drug Administration. Expansion cohorts: use in first-in-human clinical trials to expedite development of oncology drugs and biologics. Guidance for industry. RegulatoryInformation/Guidances/UCM616325.pdf. Accessed September 4, 2018.
  2. US Food and Drug Administration. FDA in brief: FDA advances efforts to help modernize oncology drug trials. Updated August 10, 2018. Accessed September 4, 2018.
  3. Norris RE, Behtaj M, Fu P, Dowlati A. Evaluating the role of phase I expansion cohorts in oncologic drug development. Invest New Drugs. 2017;35(1):108-114.
  4. Bugano DDG, Hess K, Jardim DLF, et al. Use of expansion cohorts in phase I trials and probability of success in phase II for 381 anticancer drugs. Clin Cancer Res. 2017;23(15):4020-4026.