FDA drafts guidance on seamless clinical trials for cancer drug developers

The FDA on Friday released draft guidance to help sponsors design and conduct first in human (FIH) clinical trials that speed the clinical development of cancer drugs through multiple expansion cohort study designs.

The guidance provides the FDA’s thoughts on the characteristics of drugs and biologics appropriately suited for such an expedited plan, information to include in such investigational new drug (IND) application submissions, when to interact with the FDA and safeguards to protect patients enrolled in FIH expansion cohort studies.

FDA Commissioner Scott Gottlieb explained how the draft guidance discusses ways sponsors can compress the traditional three phases of trials into one continuous trial, called an expansion cohort trial. “A lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials. Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time,” he said.


Phase I clinical trials, which are expected to include between 20 and 80 patients, are designed to determine the metabolism and pharmacologic actions of an investigational drug, the side effects associated with increased doses, and, if possible, to gain early evidence of effectiveness, according to the FDA.

FIH multiple expansion cohort trials, defined as trials with a single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives, are intended to expedite development by proceeding from initial determination of a potentially effective dose to individual cohorts that have trial objectives typical of Phase II trials (i.e., to estimate anti-tumor activity), the FDA says.

The objectives of these expansion cohorts can include “assessment of anti-tumor activity in a disease-specific setting, assessment of a reasonably safe dose in specific populations (e.g., pediatric or elderly patients or patients with organ impairment), evaluation of alternative doses or schedules, establishment of dose and schedule for the investigational drug administered with another oncology drug, or evaluation of the predictive value of a potential biomarker,” the draft says.

But challenges are to be expected because of the nature of these trials.

“Because of the rapid enrollment and evolving nature of the information obtained in these trials, large numbers of patients are exposed to drugs with unknown efficacy and minimally characterized toxicity profiles,” the FDA explains. “To mitigate such risks and to protect patients, it is imperative that sponsors establish an infrastructure to streamline trial logistics, facilitate data collection, and incorporate plans to rapidly assess emerging data in real time and to disseminate interim results to investigators, institutional review boards (IRBs), and regulators.”


FIH multiple expansion cohort studies pose unique challenges and risks, according to the FDA, including exposing patients across multiple, simultaneously accruing, cohorts to potentially suboptimal or toxic doses of an investigational drug or exposing more patients than required to achieve certain objectives.

“Inefficient drug development based on possibly missed interpretation of preliminary trial” was also cited as a potential challenge in the draft.

To ensure such studies are worth the added risk, the FDA says, “The patient population should be limited to patients with serious diseases for which no curative therapies are available.”

The 14-page draft guidance also features sections on considerations based on cohort objectives, statistical and safety considerations, as well as protocol content and communications and interactions with the FDA.

“Sponsors should request a pre-IND meeting to discuss their plans to conduct an FIH multiple expansion cohort trial,” the draft says.

First published here. Regulatory Focus is the flagship online publication of the Regulatory Affairs Professionals Society (RAPS), the largest global organization of and for those involved with the regulation of healthcare and related products, including medical devices, pharmaceuticals, biologics and nutritional products. Email for more information. 

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