Michelle Grienauer

by Michelle Grienauer

How Adaptive Clinical Trial Models Move Research Forward

For the past four years, the Kinetiq regulatory consultant team has led an introductory course on research ethics to high school students participating in Camp BIOmed, a science summer camp hosted by the Northwest Association for Biomedical Research (NWABR). Part of this course includes students participating in a mock IRB review, which usually requires a brief overview of the drug development process. To date, we have focused on the traditional framework for clinical trials phases. However, given continued efforts by the Food and Drug Administration (FDA) to advance innovative trial designs and the recent draft guidance on the use of expansion cohorts, we will need to update our Camp BIOmed course to stay current and take into account adaptive trial designs. After all, these types of studies will likely be much more common by the time these high school students become full-fledged investigators submitting their own protocols for IRB review.

A New Model Rivals the Traditional Model

In the draft guidance, the FDA recognizes the need to expedite the cancer drug development and approval process while maintaining safety and efficacy standards. The FDA provides direction to sponsors, the academic community, and the public on the design and conduct of first-in-human (FIH) expansion cohort studies—trial designs that include multiple, concurrently accruing patient cohorts, with each individual cohort assessed on different aspects of safety, pharmacokinetics, and drug anti-tumor activity.

Under the traditional model, each clinical trial phase is conducted separately and in order, but FIH expansion cohort studies blur the separation between phases. One protocol may include objectives typical of both Phase 1 and Phase 2 trials, with an initial dose-escalation phase, followed by multiple individual cohorts with separate objectives (e.g., assessment of anti-tumor activity in a disease-specific setting, testing reasonably safe doses in specific populations, and evaluation of alternative doses or schedules). Because FIH expansion cohort studies may involve the initiation of new cohorts before safety assessments are completed for prior cohorts, a large number of patients may be exposed to drugs with unknown efficacy and toxicity. Therefore, the FDA emphasizes that, when designing FIH expansion cohort studies, sponsors must establish adequate infrastructure to efficiently obtain, analyze, and act on emerging study data and to share interim results with investigators, IRBs, and regulators in a timely manner.

Given the complexities related to combining multiple cohorts into one research protocol, the guidance is specifically intended to state the FDA’s current stance on the following:

The Characteristics of Drug Products Best Suited for Consideration for Development Under a Multiple Expansion Cohort Trial

In its guidance document, the FDA describes the characteristics of drug products that may or may not be suitable for expansion cohort studies.  For example, appropriate drug products would include those formulations that allow for straightforward bridging between the early and marketing version.  Drugs with steep toxicity indices or large inter/intra-patient pharmacokinetic variability may not be suitable for multiple expansion cohorts.

Importantly, when it comes to the characteristics of the most appropriate participant populations for expansion cohort studies, the FDA states that these trials should be limited to investigational drugs for indications and populations in which the potential benefits justify the increased risk that comes with this trial design. In other words, the participant population should be limited to those individuals with serious diseases for which no curative therapies are available. The agency even indicates it expects these investigational drugs have the potential to meet the criteria for breakthrough therapy designation.

The Information to Include in Investigational New Drug Application (IND) Submissions to Support the Use of Individual Cohorts

The new guidance document covers the main elements and considerations for each cohort within a multiple expansion cohort trial. These include ensuring robust and detailed information if further safety evaluation is required for the recommended Phase 2 dose, providing scientific rationale for each disease-specific cohort assessing anti-tumor activity, using analytically validated in vitro diagnostic (IVD) assays for cohorts evaluating biomarker-defined populations, and only enrolling pediatric populations after a reasonably safe dose and preliminary anti-tumor activity have been established in adults.

The Safeguards to Protect Patients Enrolled in FIH Expansion Cohort Studies

Under the FDA Investigational New Drug (IND) safety reporting regulations, sponsors must ensure timely communication of serious safety issues to clinical investigators and regulatory authorities. Given the complexity of design and potential increased risk presented by FIH expansion cohort studies, the FDA recommends the IND include a proposed plan for submitting cumulative safety data more frequently than on an annual basis. The exact interval should be agreed upon with the FDA. Additionally, independent safety assessment committees (ISACs) or independent data monitoring committees (IDMCs) should be structured to assess safety and efficacy.

The FDA guidance also explicitly addresses IRB responsibilities in reviewing FIH multiple expansion cohort studies. The FDA notes that, as part of an investigator’s continuing review requirements, cumulative safety information provided by the IND sponsor must be communicated to the IRB. Given the increased safety assessments performed for FIH expansion cohort studies, investigators may regularly be required to provide safety information before continuing review. In order to facilitate this review, the FDA’s guidance states that the use of a central IRB may be appropriate. Such central IRB should have sufficient resources and expertise to review FIH expansion cohort studies, including the timely and thorough review of more frequently submitted safety information. This may include the convening of additional IRB meetings or establishing a separate, duly constituted specialty panel composed of experienced members.

When to Interact with the FDA on Planning and Conduct of Multiple Expansion Cohort Studies

The FDA encourages sponsors to request a pre-IND meeting to discuss plans for conducting an FIH multiple expansion cohort trial. FDA also recommends sponsors notify the FDA before submitting any protocol amendment that substantively affects the safety or scope of the protocol. Importantly, although an amended protocol may proceed upon submission to the IND, the FDA strongly recommends sponsors submit amendments at least 30 days before planned activation – in order to give the FDA time to conduct a safety review.

Readying the Industry

The agency’s new draft guidance document provides important advice to the research community regarding the parameters for when expansion cohort studies may be appropriate, and the elements and rationale required to provide justification for each additional cohort. This information should help sponsors and investigators in the design and conduct of such trials. It may also provide IRBs with useful guidance when reviewing such protocols against the criteria for approval of research.

At Kinetiq, we are excited by the advances in cancer drug development, and the FDA’s efforts to advance innovative clinical trial designs. Our regulatory consultants are already considering using a FIH expansion cohort protocol for next year’s Camp BIOmed mock IRB review. In any event, we arm the investigators of tomorrow with the most current information on the drug development process.

Need to develop a protocol for an adaptive clinical trial or determine if this is the right approach for your research? Kinetiq can help.

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