Opportunities of FDA’s Complex Innovative Trial Design Pilot Meeting Program

Posted by Cytel

Sep 7, 2018 9:55:00 AM

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On August 29th 2018, the FDA announced (1) that it would be establishing a Complex Innovative Trial Design (CID) Pilot Meeting Program. This follows the release earlier in August of a draft guidance (2) to help advance effective and innovative clinical trial designs early in drug development that can expedite new cancer therapies.

The stated goals of CID program, described by FDA Commissioner Scott Gottlieb as an “idea incubator” are to facilitate and advance the use of complex adaptive, Bayesian, and other novel clinical trial designs in late-stage drug development, and further innovation by allowing the FDA to publicly discuss those trial designs that are being considered through the pilot program. Gottlieb said:

“ ..adaptive clinical trial designs can allow us to more quickly learn which patients are most likely to benefit from a treatment, or experience a side effect. They can make it easier to target drugs to patients who are more likely to experience a benefit, based on the biological characteristics of their disease.”

The FDA in brief release characterizes innovative designs as:

Seamless trial designs
Modeling and simulations to assess trial operating characteristics
Use of biomarker enriched populations
Complex adaptive designs
Bayesian models and other benefit-risk determinations, and other novel designs

This news serves to further cement the position that the climate for adoption of innovative and adaptive approaches is becoming increasingly receptive. Cytel welcomes this milestone and looks forward to guiding our customers through the pilot program process by harnessing our trial design and regulatory interaction experience.

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So who’s eligible to participate?

In the development resources on the pilot program, (3) the FDA outlines the eligibility criteria and selection guidelines for the program. It’s important to note that any proposed CID for the program needs to be “intended to provide substantial evidence of effectiveness to support regulatory approval of the medical product” and should not be a first-in-human study.

On the basis that the agency expects to grant up to two meeting requests per quarter as part of the pilot program, the FDA advises that selection will be based on two key aspects
1) The novel aspects of the design, and particularly whether the innovation offers advantages over other approaches. In addition, the criteria state that “Initial priority will be given to trial designs for which (1) analytically derived properties (e.g., type I error) may not be feasible and (2) simulations are necessary to determine operating characteristics.”
2) The therapeutic need

Read the full eligibility and selection criteria, and submission guidelines on the FDA’s website here.

Below, we have compiled some materials and resources that may be helpful for sponsors considering designs that could potentially qualify for the program:

Seamless Trial Designs
The idea of a seamless trial is simple: Instead of conducting several phases of a study, plan one adaptive trial where the phases are separated by interim looks. In a speech last year, Commissioner Gottlieb highlighted the benefits, saying “By using one large, continuous trial, it saves time and reduces costs. It also reduces the number of patients that have to be enrolled in a trial.”
Napo’s Fulyzaq, the first drug ever approved using an adaptive two-stage "seamless" clinical trial was supported by Cytel statisticians. Since then, our Strategic Consulting team has supported numerous other clients with design and implementation of these confirmatory adaptive trials.

Click here to read our blog post: Seamless adaptive trials: Now that we get the statistics, what's really at stake?

Biomarker Enriched Populations
Population enrichment designs explicitly account for the possibility, especially applicable in oncology, that the experimental compound might result in different treatment effect depending on the biomarker subgroup. In an enrichment design, enrollment is initially open to a broad patient population but allows future enrollment, following an interim analysis, to be restricted only those biomarker subgroups that appear to be benefiting from the experimental therapy. While potentially beneficial, statistical and logistical design challenges need to be addressed and a complex trade-off negotiated between power, sample size, number of events, and study duration.

Read Cyrus Mehta’s article: Biomarker Driven Population Enrichment for Adaptive Oncology Trials with Time to Event Endpoints

Read the TAPPAS Poster co-authored with TRACON Pharmaceuticals

Complex Adaptive Designs

In 2017, Cytel Senior VP of Strategic Consulting and Software Solutions, Yannis Jemiai, was co-author on twin papers (4,5) discussing what the FDA characterize as 'less-well understood' adaptive designs as part of the Adaptive Designs Scientific Working Group (ADSWG). In Best practices case studies for “less well-understood” Adaptive designs, the group reviews 10 important case studies, with different 'less well-understood' features, and share details on their design and operational characteristics, as well as related regulatory interactions.  

To read more about the publication, and access the abstract, read our blog post here. 

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Considering an innovative design for your next trial?

Are you considering an innovative design for your next trial? Click the button below and request a consultation with one of our strategic consulting team.  We can help evaluate options, and work with you to explore the suitability of the CID pilot program.

Request consult

References:

1)FDA IN BRIEF: FDA launches new pilot to advance innovative clinical trial designs as part of agency’s broader program to modernize drug development and promote innovation in drugs targeted to unmet needs 
2) FDA in Brief: FDA advances efforts to help modernize oncology drug trials
3) Complex Innovative Trial Designs Pilot Program 

4) Miller, E., Gallo, P., He, W., Kammerman, L.A., Koury, K., Maca, J., Jiang, Q., Walton, M.K., Wang, C., Woo, K., Fuller, C. and Jemiai, Y. (2016) ‘DIAs Adaptive design scientific working group (ADSWG): Best practices case studies for “less well-understood” Adaptive designs’, Therapeutic Innovation & Regulatory Science, . doi: 10.1177/2168479016665434.

5) He, W., Gallo Paul, Miller, E., Jemiai, Y., Maca, J., Koury, K., Fan, X.F., Jiang, Q., Wang, C. and Lin, M. (2016) ‘Addressing challenges and opportunities of “Less Well-Understood” Adaptive designs’,Therapeutic Innovation & Regulatory Science, . doi: 10.1177/2168479016663265.

  

Topics: biostatistics, adaptive trials, adaptive sample size re-estimation, Seamless designs, FDA, Oncology

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