FDA issued draft guidance Friday (Aug. 10) intended to help streamline the drug development process for cancer drugs and biological products by providing sponsors with advice on how they can design and conduct seamless clinical trials, which allow drug developers to conduct one continuous trial and avoid the stops and starts associated with traditional three-phase trials.

While seamless trials pose risks, the agency says sponsors can mitigate those risks by monitoring and assessing data in real-time; quickly responding to and reporting adverse events; and maintaining consistent communication with institutional review boards (IRBs), reviewers and regulators. The agency also recommends continuous trials be limited to drugs that fulfill an unmet clinical need for serious diseases and that can treat multiple pediatric cancers.

Encouraging the use of seamless trial designs ties into the agency’s efforts to streamline the clinical trial process. Chiefly, seamless trial designs could potentially reduce the cost of drug development by eliminating the “starting and stopping” that typically happens between the three phases of clinical trials, FDA chief Scott Gottlieb said during a House Energy & Commerce health subcommittee hearing July 27.

Gottlieb echoes those thoughts in a press statement released Friday. “The approach we’re describing in new guidance today is to help innovators to evaluate drugs in trials that are potentially lower cost, more efficient, and could enable us to learn more about the safety and efficacy when compared to traditional trial designs,” he says.

“Expansion cohort trials can bring efficiency to drug development, potentially reducing development costs and time,” Gottlieb continues. “These clinical trial improvements can help ensure that innovative new therapies can be advanced efficiently to patients confronting a cancer diagnosis.”

Because first-in-human (FIH) multiple expansion cohorts are intended to expedite drug development, there are risks associated with them, FDA writes in the draft guide, “Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics.” In these types of studies, groups of patients are sometimes brought in before an investigational drug’s metabolism and pharmacokinetics have been full assessed for safety. Those assessments are designed to take place during Phase 1 studies, in which there are typically 20 to 80 patients enrolled.

However, FIH multiple expansion cohort trials transition straight from initial determination of a potentially effective dose into Phase 2 trial objectives, “i.e., to estimate anti-tumor activity,” FDA writes.

“Such trials have enrolled between a few hundred to more than a thousand patients. 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 guide states.

FIH multiple expansion cohort studies also can pose challenges with regard to: ensuring safety information is disseminated to investigators, IRBs and regulators in a timely manner; and the possibility of “inefficient drug development based on possibly missed interpretation of preliminary trial results and unplanned analyses that can lead to delays in proper clinical development.”

These risks, FDA writes, can be mitigated by establishing an infrastructure that allows sponsors to streamline logistics; gather data; rapidly assess emerging data in real-time; and disseminate information to investigators, institutional review boards and regulators.

The agency also says that because of the potential risks, FIH multiple expansion cohort studies should be “limited to investigational drugs for indications and patient populations in which the potential benefits justify the increased risks.” In other words, these types of studies should only enroll patients with serious diseases for which there is no other therapy available. Additionally, FDA says investigational drugs for which sponsors aim to use seamless studies should have potential to go through the agency’s breakthrough therapy pathway.

“Sponsors should provide a robust rationale for use of an expansion cohort trial,” the guide says. “As drug product development progresses, FDA expects that the investigational drug has the potential to meet the criteria for breakthrough therapy designation to support continuation of the expedited clinical development program, such that the potential benefits of enrollment in these complex clinical protocols continue to outweigh the potential for the increased risks to patients.”

Drugs with substances that allow for straightforward bridging studies between early formulations and marketing formulations may also be eligible for expansion cohort trials.

FDA also suggests sponsors “strongly” consider expansion cohorts for pediatric populations if the drug can potentially treat one or more pediatric cancers.

“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 provides an opportunity to shorten the timeline to begin pediatric development,” FDA says.

The guidance adds that pediatric patients should only be enrolled after a safe dose has been established in an adult population.

“To ensure the prospect for direct clinical benefit from participation on a research study where there is a greater than minor increase over minimal risk, sponsors should enroll pediatric patients in dose-finding and activity estimating cohorts after a reasonably safe dose and preliminary activity have been established in adults,” the guide says.

Sponsors should establish a system — to be included in the investigational new drug application — whereby they can quickly communicate any serious safety issues that arise to clinical investigators and regulators.

“The IND should contain a proposed plan for submission of a cumulative summary of safety, on a periodic basis that is more frequent than annually,” the guidance says. “New safety data that further identify, characterize, and provide insight on management of adverse reactions should be periodically assessed and submitted to the IND in support of modifications of one or more cohorts within the protocol.”

FDA says sponsors also should put together an independent safety assessment committee (ISAC) or independent data monitoring committee (IDMC) that can assess safety and efficacy by analyzing incoming expedited safety reports, developing summaries of adverse events and recommending modifications to the IND sponsor that can help reduce risks to patients in the trial.

The agency recommends sponsors use a central IRB that can review multicenter FIH multiple expansion cohort trials. “The central IRB should have adequate resources and appropriate expertise to review FIH multiple expansion cohort trials in a timely and thorough manner,” the guidance states, adding that IRBs should consider holding additional meetings to review any new safety information.

Friends of Cancer Research CEO Jeff Allen said that whether expansion cohort trial designs can reduce overall drug development costs remains to be seen, adding that flexibility is an important part of the discussion.

“I think a key element of this concept is flexibility. Each situation may be a little bit different and require different considerations,” he said in a statement to Inside Health Policy. “The FDA’s proposed guidance on the topic is helpful by laying out a variety of different aspects (safety, dosing, biomarker use, consent/IRBs, etc) that need to be considered. The use of expansion cohorts can provide broader, rapid access compared to traditional approaches because the trials remain open and modify to things like including different patient populations or cancer types that the drug may be effective in treating. This is an important strategy particularly for highly effective drugs that could be beneficial in treating numerous conditions. But it comes with added complexity in implementation and the guidance identifies the numerous aspects that may need to be examined on a case by case basis.”

The Pharmaceutical Research and Manufacturers of America (PhRMA), although still in the process of reviewing the draft, commended FDA for its efforts to encourage innovative trial designs.

“PhRMA applauds the Food and Drug Administration for continuing to explore innovative clinical trial designs to reduce the time and cost associated with drug development,” a spokesperson for PhRMA wrote in a statement to IHP. “We look forward to reviewing the newly released guidance in full.”

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