FDA Guidance for Clinical Research Projects Using Expansion Cohorts in First-In-Human Clinical Trials to Expedite the Development of Oncology Drugs and Biologics

Rae Hintlian

Associate Editor

Loyola University Chicago School of Law, JD 2019


In early August 2018, the Food and Drug Administration (“FDA”) announced the availability for guidance in Clinical Research projects relating to expansion cohorts used in first-in-human (“FIH”) clinical trials that are used to expedite the development of Oncology Drugs and Biologics.  The guidance is directed towards clinical sponsors in their design and conduct of FIH clinical trials intended to expedite the development of cancer drugs, including biological products that use multiple expansion cohort study designs. These studies typically employ multiple, concurrently accruing, patient cohorts, which use individual cohorts that assess the different aspects of the safety, pharmacokinetics, and antitumor activity of the drug.  The FDA provides guidance for (1) the characteristics of drug product best suited for consideration for development under a multiple cohort study; (2) information to include in investigational new drug application submissions to justify the design of multiple expansion cohorts; (3) when to interact with FDA on planning and conduct of multiple expansion cohort studies; and (4) safeguards to protect patients enrolled in FIH expansion cohort studies.

Overview of the Draft Guidance on Multiple Expansion Cohorts

The draft guidance was approved under 21 CFR part 312at OMB control number 0914-0014.  Phase 1 Clinical trials are designed to determine the metabolism and pharmacologic actions of an investigational drug in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness when possible. Typically, the number of patients included in a phase 1 clinical trial is approximately 20 to 80 patients.  In a multiple expansion cohort trial, the trial is designed to expedite the development of the drug by proceeding from an initial determination of potentially effective dose cohorts, which are initiated prior to the analysis of the metabolism and pharmacokinetics of the investigational drug and a limited safety assessment. These trials may enroll between a few hundred and a few thousand patients. To mitigate the risks of rapid patient enrollment and the exposure to drugs with unknown efficacy and minimally characterized toxicity profiles, the FDA sought a method to establish an infrastructure to protect patients while streamlining trial logistics.

Designing a Trial Utilizing Expansion Cohorts

For the purposes of the guidance provided, a FIH expansion cohort trial is comprised of a FIH trial with a single protocol using an initial dose-escalation phase containing three or more additional patient cohorts with cohort-specific objectives. The objectives may include anti-tumor activity in a disease-specific setting, assessment of a reasonably safe dose in specific populations, evaluation of alternative doses or schedules, establishment of dose and schedule for the investigational drug administered with another oncology drug, or evaluation of the value of a potential biomarker. In balancing the potential benefits with the increased risk of the FIH trial design to patients, the trials are limited to investigational drugs for indications and patient populations where the potential benefits outweigh the risk to the patient.  Therefore, sponsors must provide a robust rationale for the use of expansion cohorts in a trial.  As the drug trial progresses, the FDA expects that the investigational drug may have the potential to qualify for breakthrough therapy designation to support continuation of the expedited clinical development program.  Therefore, clinical trials in which the drug product formulations contain drug substances with material attributes that allow for relatively straightforward bridging, early drug product formulations and marketing formulations may be more appropriate for expansion cohort trials.

FIH Trials Require Specific Objectives are Met

To ensure the above objectives are met, sponsors are requested to design key elements for each cohort, including specific endpoints, eligibility, monitoring plans, and statistical considerations to justify the sample size, in light of the limited safety information.  In FIH trials in which the trial is intended to further evaluate the safety beyond the initial dose-escalation, the trial should be supported by pharmacokinetic information made available in the dose-escalation phase.  If the therapeutic index is considerably narrow and the dose-limiting toxicities fatal, the expansion will be delayed until the recommended phase 2 dose is identified. The guidance provides suggestions on elements which should be present in order to properly assess the disease-specific cohorts of the FIH trial. Further, the guidance requires that specific protocols be followed when evaluating the changes in the drug product chemistry, manufacturing, and control information.  In amendments to the drug chemistry, the sponsor will need to identify the specific changes in the drug product quality attributes to bridge the earlier clinical trial drug products formulation, manufacturing, and impurity profile. Further, the sponsor must include clear objectives and analysis assessing the differences in the safety and pharmacokinetics; some of these changes may require that the new drug formulations be conducted under a new IND. Finally, the guidance provides that expansion cohort studies evaluating the investigational drug administered with an approved or another investigational drug should be initiated only after the preliminary safety profile. If an approved drug or another investigational drugare initiated after the preliminary safety profile, then the activity of each investigational drug is characterized as a single agent prior to being used in conjunction with each other.

Monitoring and Qualifying for an FIH Trial with Multiple Expansion Cohorts

Given the complexity of the trials and to ensure that FIH trials are being monitored properly, an independent safety assessment committee (ISAC)or an independent data monitoring committee (IDMC)structured to assess the safety of the investigational drug, in addition to the efficacy, should be established for all FIH multiple expansion cohort protocols. The ISAC/IDMC are responsible for analyzing incoming expedited safety reports, development of cumulative summaries of all adverse events, and making recommendations to sponsors regarding protocol modifications to reduce the risks to patients enrolled in the trial.


In order to qualify for a FIH clinical trial using expansion cohorts, which expedite development of oncology drugs or biologics, sponsors must establish that the potential benefits to the patients outweigh the increased risks.  Further, because the trial itself is conducted under an increased level of scrutiny due to the limited knowledge in the efficacy, pharmacokinetics, and toxicity of the investigational drug, the studies require a high level of monitoring and must continually update the FDA whether the drug qualifies for a breakthrough therapy designation.  To review the FDA guidance, sponsors may review the PDF file Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics