Talking with Dionne Price, Ph.D., Director, Division of Biometrics IV, Office of Biostatistics, CDER, Office of Translational Sciences/Office of Biostatistics.
Complex innovative trial designs (CID) – including the use of adaptive, Bayesian, and other novel statistical approaches – may help streamline and advance drug development and inform regulatory decision-making. Both the Prescription Drug User Fee Amendments of 2017 (PDUFA VI) and the 21st Century Cures Act contain provisions to make the use of CID in drug development and regulatory decision-making easier.
As part of a new initiative to advance the use of CID, FDA launched a pilot program in August 2018 for sponsors planning to use innovative trial designs that would provide substantial evidence of effectiveness. The CID pilot program is a joint initiative between CDER and FDA’s Center for Biologics Evaluation and Research, with CDER’s Office of Biostatistics leading the program for CDER. Sponsors participating in the CID pilot will have additional opportunities to meet with FDA staff through two focused meetings. To encourage expanded use of CID across therapeutic areas, acceptance into the pilot requires the sponsor to agree that FDA can publicly disclose certain study design and analysis elements of the CID even before the product is approved.
Dionne Price, Ph.D., who is the Director of the Division of Biometrics IV in CDER’s Office of Biostatistics, describes the latest developments in this rapidly advancing area.
How does FDA define complex innovative trial designs?
CID includes complex adaptive, Bayesian, and other novel clinical trial designs. CID has design elements and/or analysis approaches which are not trivial and generally will require computer simulations to determine the statistical properties of the trial (e.g., power, Type I error). Examples of design features include:
- innovative use of external or historical control data,
- formal incorporation of prior knowledge into the study design, and
- ability to make prespecified adaptations to multiple design aspects and criteria of a trial if accumulating data warrant it.
What is the role of CID in drug development?
The drug development landscape is evolving and as a result, we are faced with both challenges and opportunities. We need to maximize clinical trial efficiency, while using scientifically sound methods to determine the optimal design for the question and population of interest. To date, CID has primarily been used in exploratory studies. FDA’s goal is to extend their use to trials intended to provide substantial evidence of effectiveness to support regulatory approval of new therapies.
In what areas do you see the most potential benefit with using CID?
CID has the most potential benefit in areas where traditional clinical trial approaches may not be feasible, including areas where the population size is small or limited, or where there is an unmet medical need. For example, CID has particular promise in rare diseases and in pediatric indications. The CID pilot program will aim for diversity in the applications selected, both in terms of design approaches and in the therapeutic areas where these clinical trial approaches are intended to be used. A goal of the pilot program will be to apply what we learn to other therapeutic areas. For example, we have seen a high degree of innovation in oncology trials that may potentially be applied more broadly.
How has CID been used to support the approval of any currently marketed products?
The relative lack of examples of CID being used to support regulatory approvals is one of the motivations behind the pilot program. CID was used in the Partnership for Research on Ebola Virus in Liberia II (PREVAIL II) trial to test potential Ebola therapies under a single protocol, but this trial was stopped as the Ebola outbreak waned, and no drugs were approved using data from this trial.
What are the challenges in using CID to support regulatory decision-making?
It is scientifically challenging to design and analyze these complex trials, but FDA is committed to providing clear and transparent feedback to sponsors on these designs, and to increasing communication and educational efforts both within and outside of the agency. FDA is aware that industry has hesitated to propose designs with innovative features due to a misperception about the agency’s willingness to accept such designs. FDA is interested in the advancement of innovative design and analysis approaches in areas where such approaches will provide benefit. The pilot is designed to facilitate and advance their use in clinical trials intended to provide substantial evidence of effectiveness.
What activities are planned to support the goal of advancing the use of CID?
FDA convened a public workshop in March 2018 to discuss various complex adaptive, Bayesian, and other novel clinical trial designs. The workshop, titled Promoting the Use of Complex Innovative Designs in Clinical Trials, aimed to facilitate information-sharing about the use of CID, and obtain input from stakeholders about the CID pilot program.
In addition, FDA is conducting a pilot meeting program and will publish draft guidance and develop or revise relevant Manuals of Policies and Procedures (MAPPs), Standard Operating Procedures and Policies (SOPPs), and/or review templates. The draft guidances – required under section 3021 of the 21st Century Cures Act and in PDUFA VI– will address several areas related to CID, including the use of complex adaptive clinical trial designs, best practices for conducting simulations, the submission of resulting information, the types of quantitative information that should be submitted for review, and recommended analysis methodologies.
To facilitate the appropriate use of CID methods, FDA will also develop staff capacity to support the computationally intensive review work necessary to evaluate such designs and analyses.
Under the CID pilot meeting program, sponsors will have the opportunity to submit meeting requests on a rolling basis, and FDA will select up to two requests per quarter over a five-year period. Sponsors who are selected will participate in an initial and follow-up meeting with regulatory staff to discuss how the proposed CID approach may be used in their drug development program. The statistical staff in CDER or CBER will lead the meetings, and the meetings will include additional relevant expertise from across the agency. FDA may then use elements of the clinical trial design as a case study for continuing education and information-sharing.
What information from the CID pilot program will be shared publicly and why?
All drug development programs included in the pilot program must hold an investigational new drug application (IND) for that program or have engaged with FDA on their product through a pre-IND, with the expectation that study results will be used as evidence of the effectiveness of the therapy in a regulatory submission. By participating in the CID pilot program, sponsors will agree that FDA can publicly present certain design and analysis elements, including designs for drugs that have not yet been approved, so that all stakeholders can benefit from the knowledge gained.
Information on design and analysis will be shared on the CID web page to improve understanding of the advantages of the innovative features of these studies. Other information will be posted on the CID web page as it becomes available.