Industry Calls For US FDA Transparency On Use Of Innovative Clinical Trial Designs
Executive Summary
BIO and PhRMA ask agency to provide more guidance on trial implementation, data integrity and novel data sources.
The pharmaceutical industry says the US Food and Drug Administration could further promote the use of innovative clinical trial designs by providing greater transparency on their use and clarity on study conduct and data integrity.
The agency issued a call for suggestions on what it could do to promote effective drug development programs and specifically sought advice on novel trial designs. It noted that these designs are being used in some therapeutic areas, particularly for serious and life-threatening diseases, and asked stakeholders for their views on extending the designs to more therapeutic areas and what guidance they would like to receive from FDA.
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Discussion of the renewal of the prescription drugs user fee program will formally begin with an FDA meeting on 23 July, but industry and the agency have been thinking about what they want for long before that. This story and the two others listed below offer something of an industry wish list based on pre-pandemic comments from sponsors. The coronavirus hasn’t changed these desires, but it has given all stakeholders a taste of extraordinary regulatory flexibility – while also underscoring the need for rigorous science.
In December, FDA issued final guidance on Adaptive Designs for Clinical Trials of Drugs and Biologics that provided more details on Bayesian design features and more flexibility in trial planning. (Also see "Adaptive Clinical Trials: US FDA Offers More Advice On Bayesian Designs" - Pink Sheet, 2 Dec, 2019.)
The Biotechnology Innovation Organization said there are a number of areas where the agency could provide further clarity, such as on study conduct and data integrity. It commented that data integrity during adaptive trials could be compromised if there are not appropriate data monitoring mechanisms in place.
"Additionally, sponsors may need visibility of the data and guidance would be beneficial in understanding how the sponsor and the FDA could work together to control for bias due to potentially unblinded data," the group said.
BIO also called for clarity regarding adequate evidence for decision making, so sponsors know how they can make early decisions on sparse data, particularly in the context of a complex adaptive, master protocol or hybrid protocol with external control. It also asked for additional information regarding adequate interventional and control arms, and adequate safety monitoring and comparisons, including complex adaptive designs in which it could be challenging to assure how to achieve long-term safety.
Data Sources, Statistical Methods
In its comments, the Pharmaceutical Research and Manufacturers of America said that use of innovative designs is generally limited, particularly when conducting confirmatory trials of new medicines.
"The agency should provide additional transparency on how innovative clinical trial designs are used and become accepted practice," PhRMA stated.
The association also recommended that FDA provide additional guidance for clinical trials with complex innovative designs, specifically guidance on novel data sources, simulation and analysis, clinical trial implementation, and novel statistical methods.
"For example, additional guidance on the development and use of natural history study data as an external control group, or the use of synthetic control arms as an alternative, would be helpful," PhRMA said.
In addition to opening a docket for public comments, the agency also held a public meeting in November at which more than two dozen companies and other stakeholders made presentations to review leaders of the Center for Drug Evaluation and Research's Office of New Drugs.
Amgen focused on innovative trial designs in its presentation at FDA's public meeting, advising the agency to more actively share learnings, such as by publishing case examples. (Also see "Innovative Trial Designs Are 'Life And Death Matter' For Pharma, Amgen Tells US FDA" - Pink Sheet, 5 Dec, 2019.)
In other comments, BIO suggested that FDA develop case studies to explain what factors led to the agency's acceptance of certain approaches, such as the use of modeling and adaptive trial designs. "These case studies and discussion could explain why it was acceptable in some circumstances and not in others," BIO said.
The group also asked FDA to consider additional expert input on innovative approaches, particularly around novel endpoints, including novel digital endpoints.