Guest Column | November 8, 2018

Key Takeaways From FDA's New Guidance On First-In-Human Multiple Expansion Cohort Trials

By Samantha Eakes, Greenleaf Health


The FDA published a new draft guidance on August 10, 2018 entitled, Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics.1 The comment period for the draft guidance closed on October 12, 2018 and approximately 20 comments were submitted to the docket.2 The guidance provides sponsors with recommendations for designing and conducting first-in-human (FIH) multiple expansion cohort trials within their oncology development programs. This specific type of trial design helps sponsors to expedite the drug development process by employing “multiple, concurrently accruing patient cohorts, where individual cohorts assess different aspects of the safety, pharmacokinetics, and anti-tumor activity” of the investigational drug or biologic.1 This trial design also allows sponsors to have a more seamless transition from pharmacokinetic/pharmacologic-based Phase 1 studies to individual cohorts with objectives typical of Phase 2 trials.

The major sections of the draft guidance include:

  • FIH Expansion Cohort Definition and Potential Opportunities and Challenges
  • Drug Product and Patient Considerations
  • Considerations Based on Cohort Objectives
  • Statistical Considerations
  • Safety Considerations
  • Protocol Content
  • Communications and Interactions with the FDA

FIH Expansion Cohort Definition and Potential Opportunities and Challenges

The guidance defines an FIH multiple expansion cohort trial as “an FIH trial with a single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives.”1 The main benefit of this trial type is to improve efficiency in drug development and ultimately allow for faster patient access.

Despite this major benefit, the complexity and fast-paced nature of this trial design also causes many challenges and risks for sponsors and patients. Examples include:

  • Investigators, institutional review boards (IRBs), and regulators need to receive new safety information in time to ensure adequate oversight and patient protection.
  • A large number of patients could be exposed to potentially suboptimal or toxic doses of the investigational drug.
  • More patients may be exposed to the investigational drug than necessary to achieve study goals.
  • Preliminary trial findings could be misinterpreted, leading to delays in drug development.

Drug Product and Patient Considerations

Due to the increased risk associated with multiple expansion cohort trials, the FDA explains that this trial design should only be used in situations where the potential benefits justify the increased risk, and that “the patient population should be limited to patients with serious diseases for which there is no other curative therapy available.”1 Drugs and biologics that include “steep toxicity indices and large inter- and intra-patient variability (i.e., co-efficient of variability greater than or equal to 100 percent) in pharmacokinetics indicative of polymorphic enzyme mediated drug clearance for small molecules” are not suitable for study under a multiple expansion cohort trial.1 For this trial design, the FDA also expects “that the investigational drug has the potential to meet the criteria for breakthrough therapy designation to support continuation of the expedited development program.”1

Considerations Based on Cohort Objectives

Sponsors need to provide sufficient justification for utilizing a FIH multiple expansion cohort design as well as provide adequate rationale for conducting each proposed cohort.

The guidance also notes several considerations for specific cohort objectives:

  • When confirming the safety of the recommended Phase 2 dose, sponsors should provide detailed safety information and pharmacokinetic (PK) data from the preliminary dose-escalation phase. Sponsors should also provide safety data from other expansion cohorts.
  • When evaluating preliminary anti-tumor activity, sponsors should provide a rationale for inclusion of each population within a cohort, a statistical analysis plan including justification for sample size and stopping rules, and updated safety information from the dose-escalation phase and other expansion cohorts.
  • Based on the results of a disease-specific expansion cohort, sponsors aiming to continue development should either:
  1. Submit a new investigational new drug (IND) application “to the appropriate review division to discuss the adequacy of the development program for that indication;”1
  2. Ask to meet with the FDA “if preliminary clinical evidence suggests a substantial improvement over available therapies on a clinically significant endpoint;”1 or
  3. In situations “where data from an expansion cohort may support a marketing application, the protocol should contain provisions ensuring adequate data quality, independent review of tumor-based endpoints, and optimal dose selection, as well as a prespecified plan ensuring statistical rigor.”1
  • Additional FDA guidances are listed for sponsors to reference when assessing the effect of food, organ dysfunction, or drug interactions on exposure to the investigational drug.
  • Additional considerations are listed for sponsors intending to further assess optimal dose/schedule of the investigational drug.
  • Sponsors should justify the use of a biomarker when evaluating biomarker-defined populations and should utilize in vitro diagnostic (IVD) assays that are analytically validated.
  • The FDA expects that the level of information submitted for the chemistry, manufacturing, and controls (CMC) used to support expansion cohort studies should be appropriate for the product’s stage of clinical development. Sponsors should also notify the FDA of any major manufacturing changes in the cover letter of a protocol amendment.
  • If the bridging of clinical data is required, the FDA urges sponsors to meet with the appropriate review division to ensure that expansion cohorts are adequately designed.
  • Before evaluating more than one therapeutic drug within an expansion cohort, the preliminary safety profile must be characterized for each individual investigational drug on its own. Justification must be provided for combining multiple therapeutic drugs and an adequate safety monitoring plan must also be in place.
  • Sponsors should strongly consider an expansion cohort to evaluate pediatric populations “if the drug has potential relevance for the treatment of one or more pediatric cancers based on the drug’s mechanism of action.”1 In addition, sponsors can potentially shorten pediatric development if there is “prospective inclusion of one or more pediatric cohorts in a multiple expansion cohort trial, as an alternative to separate pediatric dose-finding and activity estimating protocols.”1

Statistical Considerations

The guidance reiterates that for each expansion cohort, sponsors should provide a scientific rational, prespecified stopping rules, and an analysis plan justifying the planned sample size. The FDA also notes that for cohorts evaluating anti-tumor activity, sponsors “should specify the magnitude of anti-tumor activity that would warrant further evaluation of the drug.”1 Sponsors should ensure that the design of each trial for an individual cohort will meet the trial’s objectives.

Safety Considerations

Sponsors are required to implement adequate safety monitoring and reporting plans. Within these plans, the sponsor should outline their communication protocol for when serious safety issues arise as well as their plan to inform clinical investigators and regulatory authorities for activation of protocol amendments to address these issues. In the case of a multiple expansion cohort trial, cumulative safety data should be reported more frequently than annually.

The complexity of these trials and the increased safety risks cause it to be critical for sponsors to establish an independent safety assessment committee (ISAC) as well as an independent data monitoring committee (IDMC). The responsibilities of these two committees “should include, but not be limited to, analysis of incoming expedited safety reports, development of cumulative summaries of all adverse events, and making recommendations to the IND sponsor regarding protocol modifications.”1 These committees should also be tasked with the real-time review of all serious adverse events and should perform prespecified and ad hoc assessments of safety and futility for each cohort.

In addition, sponsors must establish an IRB to review the clinical trial protocol and patient safety information prior to trial initiation. The IRB should also continue its oversight throughout the entirety of the clinical trial. To address the complexities of this trial design, the FDA recommends the use of a central IRB when appropriate. The agency also suggests that the IRB should consider convening additional meetings or that a separate, specialty IRB should be established to handle short-term review of new information or protocol modifications.

Lastly, the guidance notes that all patients should receive adequate informed consent and that informed consent documents should be continually updated based on new trial information or protocol modifications.

Protocol Content

Given the complexity and risks associated with this trial design, the guidance recommends that sponsors should include greater detail than is typically required for a clinical trial protocol. A more detailed protocol will allow both FDA and others (investigators, IRBs) to determine if the potential benefits outweigh the risks to patients and if all possible risks are addressed. The guidance also outlines what content to include for an initial protocol and protocol amendments.

Communications and Interactions with FDA

The FDA closes the guidance by suggesting that all sponsors consult the following guidance for industry for recommendations on communication with the agency: Best Practices for Communication Between IND Sponsors and FDA During Drug Development.3 The FDA also provides several suggestions specifically for communication regarding FIH expansion cohort designs, including requesting a pre-IND meeting and submitting protocol amendments to the agency at least 30 days prior to planned activation.

Docket Analysis

Several key themes emerged across the comments submitted to the docket.2 Stakeholders suggested that the FDA should revise the guidance definition of FIH multiple expansion cohorts to include trials consisting of “one or two additional cohorts” rather than “three or more,” as is currently stated in the guidance. In addition, stakeholders asked the FDA to further explain the possibilities for comparing data between cohorts and when a comparison is not appropriate.

Sponsors asked for additional clarity surrounding the specific types of drug and biological products that are and are not appropriate for use in a multiple expansion cohort trial. They also questioned the FDA’s reasoning behind the statement that results from these trials should meet the criteria for breakthrough designation (BTD) and asked the agency to clarify whether trials that do not meet BTD criteria will be allowed to proceed.

With regard to safety reporting, sponsors asked the FDA to provide additional detail as to what is meant by “more frequently than annually,” and some felt that the requirement to establish an IDMC is overly burdensome to sponsors. Sponsors also requested that the FDA not specify the use of the Simon 2-stage design for statistical analysis. Several comments noted that the FDA should provide sponsors with flexibility in choosing appropriate statistical methods and that there are several accepted and validated methods other than the Simon 2-stage design.

Stakeholders praised the FDA for the inclusion of pediatric considerations but asked for additional clarity surrounding the inclusion of pediatric expansion cohorts as part of pediatric study plans (PSPs), and the specific requirements for initial dosing. Others suggested that the FDA should expand this section to address considerations for all “special populations” including the elderly.


  1. United States Food and Drug Administration (2018). Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry. Accessed at
  2. Docket ID: FDA-2018-D-2777. Accessed at
  3. United States Food and Drug Administration (2017). Best Practices for Communication Between IND Sponsors and FDA During Drug Development. Accessed at

About The Author:

Samantha Eakes is senior manager of regulatory affairs at Greenleaf Health, Inc. She specializes in developing communications and advocacy strategies, conducting research, and providing regulatory insight. She recently received her master’s in public health (MPH) from Boston University. You can contact her at