FDA issues draft guidance on how and when to use adaptive designs in medical device clinical trials
As acceptance of adaptive designs for clinical trials continues to grow, the FDA has taken the next step, issuing a draft guidance on planning and implementing adaptive designs for medical device trials.
Adaptive Designs for Medical Device Clinical Studies provides a detailed look at when adaptive designs make sense, the types of adaptive designs and how data should be analyzed, plus challenges and regulatory considerations. It reflects the FDA’s current views on the concept.
An adaptive design for a medical device trial allows for prospectively planned modifications based on accumulating study data without undermining the trial’s integrity and validity. The draft states that when implemented, “adaptive design can reduce resource requirements and/or increase the chance of study success.”
The 40-page guidance provides examples of both adaptive and non-adaptive study designs. It explains how to decide if a trial could benefit from adaptive designs, with several examples of the advantages of prospectively planned adaptive studies. It also warns an unplanned modification to a device clinical trial may weaken its scientific validity, jeopardizing approval or endorsement of the FDA.
According to the guidance, adaptive design must follow two important rules: “(1) control of the chance of erroneous conclusions (positive and negative) and (2) minimization of operational bias. These principles are crucial to assure that a clinical study produces valid scientific evidence.”
The guidance follows approval of about 120 adaptive device trials between 2007 and 2012 by the Center for Drug and Radiology Health. Since then, adaptive designs have not been used as commonly.
“Historically, two hurdles exist for device companies in the potential use of adaptive study designs,” said Eric Distad, director, medical devices and diagnostics at Novella Clinical, a Quintiles company. “The first is a lack of understanding or clarity as to what the FDA may require. The guidance document should provide some additional level of understanding and comfort with adaptive design and, therefore, may lead to more use of adaptive approaches. The second challenge still stands: device studies tend to have smaller enrollment targets and (typically) shorter enrollment periods and, therefore, a decreased window to implement the reviews required for an adaptive design.”
He said the FDA’s guidance will provide a pathway and some clarity for companies wishing to explore adaptive designs.
Sponsors are encouraged to discuss planning adaptive designs with the appropriate FDA review division in advance. The agency said it has established mechanisms, such as pre-submission meetings, to conduct such interactions in a timely and efficient manner.
“Not every study fits adaptive design, such as quick-enrolling brief trials, while longer, multi-arm, multi-stage trials are more suitable—you have enough time to pause and collect data and make adaption based on the data as needed,” said Vicki Anastasi, vice president and global head, medical device and diagnostic research at Icon. “Overall, there is nothing surprising in this guidance document, which makes the FDA seem more receptive and encouraging for the medical device industry.”
She said using adaptive designs for FDA reviews in biopharmaceuticals has had ups and downs, which have prompted device companies to wait until their use was more stable.
“We now are poised to see adaptive designs in medical devices take off, as the FDA has made clear its pre-submission meetings and acceptance of planned modifications as part of the overall trial,” said Anastasi. Icon’s Aptiv Solutions provides software and services for adaptive trials.
The FDA says adaptive trials can be more efficient, saving time, money and resources when compared to unchanged (fixed) designs. For example, a trial with two or more investigational arms could plan to drop one of them based on accumulating data.
The advanced design also can improve the chance of trial success by using patient sample size reassessments, which could lead to an adjustment in sample size if the treatment effect is smaller than anticipated. This can result in converting an underpowered study—likely to fail—into a well-designed study more likely to succeed, according to the draft guidance.
“Adaptive designs can enhance patient protection by increasing the probability that a patient is allocated to the treatment most likely to result in a better outcome for that patient,” the draft states. “From an ethical standpoint, adaptive designs may optimize the treatment of subjects enrolled in a study and safeguard their welfare from ineffective or unsafe treatments and interventions at the earliest possible stage.”
The FDA also warned about the limitations of adaptive designs, notably that pre-planned study design modifications can require more effort at the design stage, are more complicated and can be difficult to plan, cost more and be logistically difficult to carry out.
Distad of Novella disagrees. “With the appropriate resources (e.g., a strong biostatistician with adaptive design experience), I have not seen a significant increase in the planning phase of a trial,” he said. “Ideally, using adaptive design will decrease sample size. In the case that it increases sample size, implementing that change may allow a successful study where a static design may have led to a failed study.”
Whether the guidance will spur more adaptive device trials is unknown, but Anastasi said it marks a major change.
“The device industry is poised to take off, and the guidance is a tool they can use,” she said.
The guidance applies to premarket medical device submissions, including premarket approval applications, premarket notification, 510(k) submissions, de novo submissions, humanitarian device exemption applications and investigational device exemption submissions.
Comments on the draft are due by Aug. 17. Submit electronic comments to www.regulations.gov or written comments to the Division of Dockets Management (HFA- 305), FDA, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Identify comments with Docket No. FDA-2015-D-1439.
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