be conducted, to include “dystrophin expression from muscle biopsies taken 22 weeks after patients enrolled in the OLE were transitioned to one of the Phase 2/3 doses of suvodirsen,” Wave said. Data from the interim analysis are “intended to be an important component” of an application for accelerated approval planned for the second half of 2020.
THE MUTABLE NATURE OF COMPLEX INNOVATIVE TRIALS
“Although CID has been referred to as complex adaptive, Bayesian, and other novel clinical trial designs, there is no fixed definition of CID because what is considered innovative or novel can change over time,” the draft guidance declares. “What is considered CID today could become routine in the future.”
For FDA’s purpose, CID includes trial designs that have “rarely or never been used to data to provide substantial evidence of effectiveness,” the guidance says.
“A common feature of many CIDs is the need for simulations rather than mathematical formulae” in order to “estimate trial operating characteristics or to optimize design parameters such as number and timing of interim analyses,” the draft observes.
FDA’s draft guidance and materials present a few examples of trial designs that could be considered CID, including:
- Trials that formally borrow external or historical information or borrow control arm data from previous studies to expand upon concurrent controls. “Use of Phase 2 control data to bolster the control group in a Phase 3 trial can lead to reduction in the total Phase 3 sample size and therefore of the time and cost to complete the Phase 3 trial,” FDA said.
- Sequential Multiple Assignment Randomized Trials (SMARTs), which are “designed to inform the development of adaptive interventions.” A SMART is “comprised of multiple intervention stages, and each stage corresponds to one of the critical decisions involved in the adaptive intervention,” FDA explained. “Patients move along multiple stages and are randomly assigned to one of several treatment options at each stage.”
- Master Protocols, which “allow multiple treatments or multiple diseases or disease subgroups to be evaluated within one overarching protocol that addresses numerous questions.” Master protocol designs include basket, umbrella and platform trials. Center for Drug Evaluation and Research director Janet Woodcock has long been an advocate of master protocols, including authoring a major article in the New England Journal of Medicine with Office of Biostatistics director Lisa LaVange in 2017.
Both Woodcock and FDA’s CID materials point to the ongoing National Cancer Institute-sponsored Phase II/III Lung-MAP trial as an example of master protocols. Lung-MAP, which is studying biomarker-matched therapies in rare squamous-cell subsets of non-small cell lung cancer (NSCLC), started 2014 with four molecular targets and four investigational drugs.
The trial was expanded to include all NSCLC types in early 2019. Clinicaltrials.gov now lists more than 10 studies under the Lung-MAP banner.
Bayesian statistics provide a common theme in many CIDs. Bayesian statistical approaches are “well-suited for some CID settings because they can provide flexibility in the design and analysis of a trial, particularly when complex adaptations and predictive models are used,” FDA said.
“In addition, Bayesian inference may be used in settings where it is advantageous to combine multiple sources of evidence, such as extrapolation from adult data to pediatric populations, or to borrow control data from Phase 2 trials to augment a Phase 3 trial.” Two key areas to discuss with FDA are prior distribution and study decision criteria for primary and key secondary endpoints, the draft guidance advises.
(INCREASINGLY LESS) RARE EXAMPLE
FDA repeatedly cited the PREVAIL II study of multiple therapies for Ebola virus as one of the few examples of a CID in practice. In fact, an agency Q&A notes, “the few examples of CIDs being used in trials intended to support regulatory decision making is one of the motivations behind creating the pilot meeting program.”
The COVID-19 criseis is expected to vastly increase the number of CIDs.
PREVAIL II was a master protocol trial conducted during the West African Ebola virus outbreak of 20142016. The outbreak presented a good setting for a CID allowing flexible design and analysis, FDA said, given “limited or intermittent drug supply for several potential therapeutic agents” and the “need to maximize information from limited data.”
PREVAIL II was constructed using a Bayesian adaptive design to test multiple therapies simultaneously using a shared control arm, with the potential to add new experimental candidates when they became available. If a treatment was proven efficacious, it could become the new standard of care for all trial participants.
Despite its innovative design features, the trial could not prevail over the natural cycle of the epidemic. As Ebola cases waned, the trial could not enroll enough patients to establish efficacy. It was ended early, having evaluated only one treatment, Mapp Biopharmaceutical’s ZMapp.
STATISTICAL INTENSITY
The high-level biostatistics behind complex innovative trials pose challenges for both sponsors and regulators. “FDA’s review of CID proposals often involves challenging evaluation of design operating characteristics, including extensive computer simulations, as well as detailed discussions across disciplines and FDA offices,” the draft guidance observes. “This may make it difficult for FDA to adequately review such designs under short timelines.”
The agency also pledged to “develop staff capacity to support the computationally intensive review work necessary to evaluate such designs and analyses.”
The recent draft guidance on interacting with FDA on CID will not be FDA’s last word of advice to sponsors with innovative trial designs. The agency is also planning draft guidances that will address complex adaptive clinical trial designs, best practices for conducting simulations and submitting the results, the types of quantitative information that should be provided to FDA, and analysis methodologies.
This article was first published on 1 April 2020 in The Pink Sheet.
Image: iStock/metamorworks