FDA draft guidance addresses inclusion of adolescents in oncology trials

With an eye toward helping industry, investigators and institutional review boards (IRBs), the U.S. Food and Drug Administration (FDA) has unveiled draft guidance on the inclusion of adolescents—defined as those between the ages of 12 and 17—in adult oncology trials. Allowing adolescents in relevant trials would allow for earlier access to life-saving drugs in this patient population.

Released in June, the draft guidance, titled “Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials,” came more than a year and a half after the publication of a journal article by FDA officials that addressed the topic.1 Published first online October 25, 2016, the authors noted that enrollment of adolescents in oncology studies is lower than younger pediatric patients. “Adolescents are generally not eligible for enrollment in adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved,” they wrote. The draft guidance acknowledges this concern, adding that some cancers seen in adolescents, such as leukemias and soft tissue and bone sarcoma, are similar in histology and biologic behavior to what is seen in adults.

The article also cited statistics showing that enrollment in clinical trials tends to decrease with age in this younger population, bottoming out in older adolescents (i.e., those between the ages of 15 and 19). Further, while deaths from childhood cancer have declined more than 50% since 1975, adolescents and young adults have not benefitted as much as the younger pediatric cohort in terms of survival rates.


The National Cancer Institute (NCI) estimated that in 2017, 10,270 new cases of cancer would be diagnosed in those 14 years of age and younger, with about 1,190 succumbing to the disease.”


The National Cancer Institute (NCI) estimated that in 2017, 10,270 new cases of cancer would be diagnosed in those 14 years of age and younger, with about 1,190 succumbing to the disease. The American Cancer Society has estimated that about 5,000 U.S. teens between the ages of 15 and 19 are diagnosed with cancer each year. While that number represents less than 1% of all cancers, 600 adolescents die. In fact, cancer is the fourth leading cause of death in this age group, behind accidents, suicide and homicide. When one looks at patients between the ages of 15 and 39, roughly 70,000 individuals receive a cancer diagnosis each year in the U.S.—significantly more than the number of cancers diagnosed in those younger than 14, according to the NCI.


Inclusion, dosing

The draft guidance outlines when adolescents can be eligible for oncology studies at all stages of drug development. In first-in-human or dose-escalation trials, this patient population may enrol after adult pharmacokinetics and toxicity data are gained. The FDA has advised that sponsors discuss with the appropriate review division about the suitable amount of adult data needed before adolescent enrollment may proceed. Further, adolescents who are enrolled in these early phase trials should have cancers relapsed after or refractory to standard therapy with no other options. For activity estimating or confirmatory trials, adolescents are eligible for enrollment at the same time as adults.

In terms of dosing, the draft guidance notes that systemic exposure and clearance of drugs typically are similar in adolescents and adults. The document recommends that the election of an appropriate dose for adolescents should be based on whether the adult dose is adjusted based on body size or is a fixed dose. In addition, adolescent PK samples should be collected at the time patients are included in the development program and analyzed to verify similar drug systemic exposure. Of note, it is expected that adolescents with body weight of at least 88 lbs. (40 kg) can receive the same fixed dose administered in adults. Those weighing less than 88 should switch to a body weight or body surface area-adjusted dose.


Of note, it is expected that adolescents with body weight of at least 88 lbs. (40 kg) can receive the same fixed dose administered in adults.”


Finally, the guidance addresses safety monitoring and ethical considerations. Regarding the former, the FDA acknowledges that obtaining information on developmental toxicities that require long-term follow up, such as fertility problems, would prove difficult, if not impossible, for early phase trials. The agency urges sponsors to develop a plan for longitudinal evaluation of potential developmental toxicities when it is feasible. In terms of ethical considerations, IRBs reviewing adult oncology clinical trials with adolescents must ensure that the provisions of 21 CFR part 50, subpart D (Additional Safeguards for Children in Clinical Investigations) and 21 CFR 50.52 (Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects) are satisfied before approving the studies.



A search of ClinicalTrials.gov yields a number of studies with behavioral interventions. Among the drug trials, however, “A Study of Eribulin in Combination with Oral Irinotecan for Adolescent and Young Adult Patients With Relapsed or Refractory Solid Tumors,” is being sponsored by the University of Colorado, Denver, in collaboration with the University of Kentucky. The primary outcome measure is the recommended phase II dose of eribulin when used in combination with oral irinotecan over a two-year time frame. In this IND-exempt phase I trial, eribulin will be administered intravenously on days 1 and 8 of a 21-day cycle, while irinotecan will be administered orally on days 1-5.

Patients will be assigned an eribulin dose level at the time of enrollment using a 3+3 phase I design, and there will be no intrapatient dose escalation. Once the RP2D has been established, there will be up to 10 patients enrolled in a dose expansion cohort. In the absence of disease progression or toxicity, subjects may receive up to 17 cycles of therapy.



  1. Chuk MK, Mulugeta Y, Roth-Cline M, et al. Enrolling Adolescents in Disease/Target Appropriate Adult Oncology Clinical Trials of Investigational Agents. Clin Cancer Res. 2017; 23 (1): 9-12.


Editor’s Note: This analysis was developed with data from Cortellis Regulatory Intelligence and Cortellis Clinical Trials Intelligence. A version of this article was originally published in the Journal for Clinical Studies. Read it here.