Moving Forward with Medical Device Adaptive Trials Post-FDA Draft Guidance


By Vicki Anastasi, Reinhard Eisebitt, and Ira Spector 

The FDA CDRH recently released the draft guidance “Adaptive Designs for Medical Device Clinical Studies” to encourage their use, when appropriate, to “improve efficiency and increase the likelihood of study success when conducted in a pre-specified, thoughtful, scientifically valid manner.” 

A gap now exists between device and diagnostic developers’ low utilisation of adaptive designs and the agency’s published encouragement of adaptive designs in guidance and during talks at recent industry meetings. The gap stems in part due to internal deficits with expertise and infrastructure at many companies. These challenges, however, can be readily overcome by developers interested in exploring adaptive designs’ relevancy and benefit for a future PMA or 510(k). This blog outlines the utility of adaptive designs for device development and key resources for those seeking to adopt adaptive designs in their company’s development program(s).

When properly designed and executed, adaptive designs can enhance strategic decision-making in clinical development programmes and provide operational efficiencies that may reduce trial cost and duration. Additionally, the FDA’s draft guidance notes that adaptive designs “can enhance patient protection by increasing the probability that a patient is allocated to the treatment most likely to result in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.” From an ethical standpoint, adaptive designs may optimise the number of subjects enroled in a study and even terminate a trial early to safeguard patients’ welfare from ineffective or unsafe treatments and interventions.

From a commercial point of view, adaptive trials can mitigate risks in development programmes to minimise financial losses from non-performing products and prevent effective devices from being undermined by sub-optimal trial designs. Adaptive designs increase the quality of clinical evidence collected to support regulatory, reimbursement, and market access, thereby enabling more informed decision-making for the best possible path to commercialisation. Along with risk-based monitoring and a robust assessment of health economic drivers, adaptive designs should be part of every manufacturer’s strategy to stay competitive.

Getting acquainted with adaptive design

Many in the medical device field have heard about adaptive designs, but questions remain about which studies are relevant for their products. 

The guidance discusses what the FDA will and will not accept in an adaptive clinical trial design for manufacturers seeking a 510(k) or PMA, provides examples of adaptive clinical trial designs, as well as discusses the benefits associated with adopting this strategy for medical device research.

To provide a concise recap of the guidance, we’ve answered the four most common questions from recent inquiries to ICON’s Medical Device & Diagnostics Research Group.  

1. Is adaptive design appropriate for every medical device study?

Use of an adaptive design is best suited for studies that can allow sufficient time during a trial to conduct interim data analysis and decision-making in a blinded manner. In particular, cardiovascular, orthopedic/spine, and IVD studies offer robust opportunities to realise the benefits of an adaptive design. When executed properly, adaptive trials collect data in the most efficient way possible.

Even for studies that will not employ an adaptive design, the initial planning and simulations involved in adaptive design, such as conducting upfront feasibility analysis, are beneficial to the design of any study. 

2. What are the most useful types of adaptive design for device studies?

While there are many types of adaptive design — the FDA draft guidance alone listed 11 examples — device studies commonly use these four: 

  • Group sequential designs: stopping early for futility or success
  • Sample size re-estimation designs: enroling and dropping patients to save an underpowered or overpowered trial. These designs are sometimes referred to as "right-sizing” a trial
  • Seamless designs: combining pilot and pivotal studies to shorten white space, i.e., time delays, between studies
  • Population (or adaptive) enrichment designs: focusing a trial on a pre-specified responding treatment arm 
3. What criteria must an adaptive design protocol meet?

It’s important to remember that adaptive designs are not a "try and see what happens" approach to clinical trials. Adaptive trials must adhere to stringent criteria in their design and execution. Protocols must be approved by the FDA via a Pre-Submission prior to initiation of the study. Most importantly, any modification made in an interim analysis is planned before the trial begins and implemented without affecting the validity or integrity of the trial.

4. What resources are necessary to implement an adaptive design?

An adaptive design trial does require upfront investment of time in order to perform the simulations necessary to identify the risks that may arise over the course of a trial and develop a design that optimally addresses those risks. This investment is offset by adaptations that, for example, compress study duration through combined pilot and pivotal studies, adjust the sample size to preserve statistical significance, or prevent an overpowered design from continuing to recruit unnecessary subjects.

Proper implementation of adaptive design also requires a specialised team of statisticians, clinical operations experts, and technologies to maintain trial validity and integrity, especially during interim analyses. The team must be knowledgeable in device-specific adaptive trials; one cannot simply copy adaptive designs used in the biopharmaceutical space.

Outsourcing the design and execution of adaptive designs to a CRO is one way to immediately derive the benefits of adaptive designs without having to invest in infrastructure. ICON can provide the key expertise and technological infrastructure needed to design and execute adaptive trials that otherwise must be developed in-house. 

ICON’s ADDPLAN® is a uniquely suited tool for the design and execution of adaptive trials. ADDPLAN is a fully validated, regulatory compliant software for the design, simulation, and analysis of adaptive trials. It is currently licensed by more than 50 pharmaceutical and medical device companies, as well as by the FDA, EMA, and Japan’s PMDA.  

The CDRH, in its draft guidance on adaptive designs for medical device clinical studies, has advised device companies “to have a risk-based monitoring plan in place which focuses on specific aspects of adaptive studies that are of particular importance and may not be present in traditional (non-adaptive) trial designs.” ICON’s ICONIK integrated informatics platform enables risk-based monitoring, utilising an advanced approach called Patient Centric Monitoring. Patient Centric Monitoring is designed to prevent, detect, mitigate and learn from risks and errors in the conduct of clinical trials, whilst maintaining inspection readiness in line with regulatory guidance.

Moving Forward 

Device manufacturers should be encouraged by the FDA’s formal proclamation of support for adaptive designs. While implementing an adaptive design requires careful planning and the right team of experts, doing so is sure to improve the quality of clinical evidence and decision-making at the individual study level and across a company’s entire portfolio. 

More Information: 
0 2008-01-18T13:10:54 Administrator

OTHER ARTICLES CATEGORISED UNDER

  • Medical Device
  • Adaptive Trials