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The FDA published a new draft guidance on August 10, 2018 entitled, Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics.1 The comment period for the draft guidance closed on October 12, 2018 and approximately 20 comments were submitted to the docket.2 The guidance provides sponsors with recommendations for designing and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The major sections of the draft guidance include: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
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:
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:
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.
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.
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.
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.
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 firstname.lastname@example.org.