FDA Unveils Guidances on Innovative Trial Design
The FDA late last week issued two new draft guidances — one on adaptive clinical trials and the other on master protocol designs — that it hopes will help sponsors innovate and get treatments to market more swiftly and efficiently.
“The standard approaptive clinical trials can give sponsors the flexibility to react to clinical evidence as it’s being collected, and modify the design and enrollment in trials by including more patients ch to generating evidence — a series of clinical trials, each investigating one or two interventions in a single disease — has become more expensive and challenging to execute,” FDA Commissioner Scott Gottlieb said in announcing the guidances.
“Adawith characteristics that help predict that they’re more likely to derive a benefit,” he added.
The FDA for months has been signaling interest in creative trials that stray from the traditional Phase I, II and III model. The 36-page guidance on adaptive design, which replaces a 2010 document, recommends the following approaches:
- Group sequential designs, which can reduce the sample size and length of a clinical trial by setting, in advance, the criteria for stopping the trial if it hits its goals or seems destined to flop.
- Sample size adaptations, in which investigators lay out in advance a plan to adjust sample size depending on what they learn from ongoing data. These types of trials might be best “when there is considerable uncertainty about the true treatment effect size,” the FDA says.
- Adaptive enrichment, where investigators can change their patient pool to focus on a subpopulation in response to early results.
- Treatment arm selections, in which investigators can either add or end an experimental treatment depending on data.
- Patient allocation adjustments. There are two kinds of these, according to the guidance. The first, a covariate-adaptive treatment assignment, puts a patient in a treatment arm based on his or her baseline characteristics and how they compare to those of earlier patients. The second, a response-adaptive randomization, allows patients to be moved from one treatment arm to another over the life of the trial.
The key to making any of the methods work, suggests the FDA, is careful planning and communication with regulators.
The biggest danger is the risk of false positives, the agency says. But it’s also clearly worried about bias creeping into adaptive trials. In an effort to prevent this, the document “strongly” recommends that access to interim trial data be limited.
One way to keep interim data under wraps is to create a separate “adaptation body” outside of the usual data monitoring committee — although that approach might work best for group sequential designs or other trial designs that have “simple adaptation algorithms.”
“Regardless of the chosen approach, the committee tasked with making adaptation recommendations should have members with the proper expertise, including a statistician or statisticians who are knowledgeable about the adaption methodology, the monitoring plan, and the decision rules,” the guidance states.
Sponsors and their employees or agents, too, should “generally” be kept away from interim data. But the FDA says it can envision situations — dose selection, for instance, which could “have important long-term implications for the drug development program” — where a sponsor’s staff might be entitled to a “limited” briefing.
The guidance on master protocols is similar in spirit but focuses on cancer trials.
It lays out a brief definition of the three, main types of master protocols: platform trials, in which researchers study multiple, targeted therapies for a single disease more or less perpetually, with treatments allowed to drop in or out of the platform depending on how well they perform in the trial; umbrella trials, which study several therapies for a single disease but focus various subgroups (usually determined by biomarkers) of a disease; and basket trials, in which researchers zero in on a single, targeted therapy for several diseases or disease subtypes (for instance, by focusing on a cancer mutation and seeing how a given drug treats the mutation when it appears in different types of cancers).
It also acknowledges that some clinical trials may combine the different approaches.
Whatever tack they take, sponsors conducting master protocols should create a separate safety or data monitoring committee responsible for gathering and disseminating urgent safety information as part of “a systemic approach that ensures rapid communication of serious safety issues to clinical investigators and regulatory authorities,” the guidance says.
The safety plan, as well as the committee’s make-up, should be part of the sponsor’s IND application. The FDA also urges a central IRB, which meets frequently to review the trial’s safety, to oversee master protocols. Institutions should also consider creating a “specialty” IRB to meet “on short notice to review new information and/or modifications to trials with master protocols” just in case there’s an urgent need and the central IRB can’t gather a quorum for a meeting.
In trials involving children, at least one person on the IRB should be an expert in “managing pediatric oncology patients and have experience with the regulatory requirements, including parental permission and assent requirements.”
Among the FDA’s other recommendations:
Those conducting umbrella trials should probably use a common control arm (in most cases the disease’s currently accepted standard treatment) “to improve efficiency.”
In platform trials testing more than one investigational drug, sponsors will probably have to offer “strong scientific rationale” to create a combined drug regimen; the FDA “strongly recommends” that the recommended Phase II dose for each drug has already been established.
If a master protocol is trying to find an appropriate dose for novel combinations, the FDA will require safety data for a proposed dose from at least six patients before allowing researchers to test the combo’s efficacy.
If protocols have substudies that target multiple biomarkers, sponsors must come up with a plan on how to assign patients potentially eligible for more than one of them.
Trials focused on patients’ biomarkers should not only explain why a given biomarker is worthy of study, but also be careful to use blood or tissue tests “that are analytically validated.”
Read the adaptive trials guidance here: www.fdanews.com/09-28-18-AdaptiveTrials.pdf.
Read the master protocol guidance here: www.fdanews.com/09-28-18-Masterprotocols.pdf.