Executive Summary

One of the hallmarks of the “breakthrough” era has been the rapid expansion of first-in-human trials into pivotal studies for efficacy submissions. In a new draft guidance, FDA offers some initial thoughts on safeguards to make hyperfast development pathways successful.

A US FDA draft guidance on expansion cohorts serves as a “starting point” memorandum to drug sponsors on how first-in-human (FIH) trials can be expanded and adapted to turn into pivotal trials to support a new drug application.

In the draft guidance, released Aug. 13, FDA defines expansion cohorts as a first-in-human trial with a single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives. The agency outlines eight potential expansion cohort objectives and offers its current thinking on best practices for each case.

“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 guidance states. “In general, comparison of activity between cohorts is not planned except where a prespecified randomization and analysis plan are part of the protocol design.”

FDA Commissioner Scott Gottlieb previewed the release of the guidance during a House hearing on the 21st Century Cures Act implementation process, highlighting it as an important milestone towards accelerating drug development. (Also see “US FDA’s Gottlieb Touts ‘Seamless’ Clinical Trials, Worries About Second-To-Market Products ” – Pink Sheet, 25 Jul, 2018.)

The reality is that FDA is already working with sponsors on development plans that essentially involve a single trial that rapidly expands from initial safety testing into proof of concept and ultimately serves as proof of efficacy for approval. Indeed, in the case of Merck’s Keytruda, a single trial (KEYNOTE-001) expanded into pivotal studies for more than one indication.

The guidance is therefore framed in terms of assuring appropriate safeguards and oversight to protect patients and preserve statistical integrity. The broader goal, however, is to enable more routine use of the “one continuous trial” model.

If that wasn’t already clear from his prior statements, FDA’s Gottlieb issued a statement on the draft guidance, saying it outlines how drug developers can “use an innovative seamless trial design in early stages of oncology drug development – specifically, the first time they’re tested in humans – that compresses the traditional three phases of trials into one continuous trial, called an expansion cohort trial.”

Gottlieb added that “a lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials.” The guidance was put together by CDER’s Office of Hematology & Oncology Products in collaboration with CBER.

Oncology Center of Excellence Director Richard Pazdur offered similar thoughts in an Aug. 14 blog post.

“Trials with multiple expansion cohorts can be inherently more efficient and expedite early drug development,” Pazdur said. “They can allow for addressing multiple questions in a single trial that is amended as new objectives are identified, avoiding the time lag and additional resources experienced with the opening of new clinical trials.”

“The principal advantage of expansion cohort trials is efficiency in drug development, with the goal of making highly effective drugs widely available to the public as quickly as possible,” Pazdur continued. “Well-designed and well-conducted clinical trials help ensure patient safety while also obtaining quality data that may support drug approval. This new draft guidance describes our proactive steps to help industry design clinical trials for today’s highly complex cancer therapies—and to conduct these trials in cost-effective and timely ways.”

“It’s pretty big step for FDA to formalize this,” Friends of Cancer Research CEO Jeff Allen said. “It’s probably most applicable to breakthrough type technologies that have potential in a variety of indications.” FOCR organized a working group in 2015 to begin the process of formalizing the “one continuous trial” model. (Also see “Beyond Phase I: Expansion Cohort Trials Bring Efficiencies, Regulatory Challenges” – Pink Sheet, 30 Nov, 2015.)

In the draft, FDA makes clear the importance of mitigating risks to patients because expansion cohorts may enroll large numbers (“between a few hundred to more than a thousand”) of patients before the metabolism and pharmacokinetics of the drug are analyzed and with limited safety assessments.

Sponsors must establish 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, IRBs, and regulators.

FDA says that an independent safety assessment committee (ISAC) or an independent data monitoring committee structured to assess safety in addition to efficacy should be established for all FIH multiple expansion cohort protocols due to the complexity of the trials, different cohort objectives and populations, and simultaneous dosage evaluations.

Finally, the agency says, multiple expansion cohort protocols should contain all of the elements for clinical protocols but there will likely be a need “for a greater level of detail” to allow FDA and IRBs to ensure that the risks to patients are not unreasonable and that the goals for each expansion cohort are clear and can be met.

https://pink.pharmaintelligence.informa.com/PS123736/One-Continuous-Tri…