A new, detailed template for protocol development is available to sponsors of medical device trials that rely on real-world evidence (RWE).

The 38-page template sets out a 12-part framework for building a protocol and provides a set of guiding principles for medical device trial designers, including setting study objectives, identifying the target population and describing trial procedures, the monitoring plan and statistical analysis of results.

The template was developed by the National Evaluation System for Health Technology Coordinating Center (NESTcc), a consortium of device manufacturers, health systems, academic institutions and the FDA.

In the section on Study Specific Objectives, NESTcc recommends explaining how the specific objectives were chosen in line with the SMART principle (specific, measurable, attainable, relevant and time-framed). It also wants to know how statistical significance will be defined and whether the product being assessed is a device system or a specific component.

The general principles to follow in the section on Target Population, Patient Selection and Source for Patient Recruitment include the use of objective criteria for defining inclusion and exclusion features. It also asks devicemakers to provide a high-level description of steps taken to assess data quality as described in the NESTcc Data Quality Framework, which was released last week and focuses primarily on the use of EHR data in the clinical care setting.

In the section on Outcomes, NESTcc says that sponsors of medical device trials must provide clear definitions of primary and secondary endpoints and method of outcomes assessment. Sponsors must also list specific procedure outcomes, such as procedure time, physiological and biological data captured as part of the procedure, and procedure-specific data. On device outcomes, sponsors must clearly identify which features of the device will be measured. On control outcomes in observational studies, sponsors need to describe why the outcome is highly unlikely to be causally related to the device or comparator. And the outcome schedule must include timing of patient evaluation, a rationale for both short-term and late outcomes, and pre-specification of a list of potential adverse effects.

NESTcc recommends in the section on Patient Exposure to the Device that exposure definitions should be as specific and detailed as possible. General principles to follow include describing the units for exposure measurement, the precision with which exposure will be measured, the approach to confirming exposure to the device, and the training and experience of the device operator/surgical team.

In the section on Study Design, NESTcc says fundamental features required include the number and type of comparison groups, blinding and outcomes. General principles include justifying the choice of design as precisely as possible; defining the primary study objective; and if a randomized trial, a description and justification of the treatment allocation.

On the subject of blinding, NESTcc says that to the extent possible, whether a randomized or observational study, proper blinding/masking is encouraged. The Study Design section has guidance on the units of randomization, observation and analysis.

NESTcc also addresses the issue of mechanism of treatment assignment. NESTcc says in randomized trials, the treatment assignment mechanism is described as known because the investigators have control of the process. In observational studies, the treatment assignment mechanism is characterized as unknown and must be estimated.

In the section on Study Procedures, NESTcc says a clear description of how the study will be conducted should be included in the protocol. Information regarding how patients are approached and consented, how randomization will be conducted, how data will be collected, definitions of protocol deviations and how those will be treated, what constitutes subject withdrawal or discontinuation, and what stopping rules will be used, if applicable, should also be included.

On the subject of Required Sample Size, NESTcc recommends indicating the type of study design, the approach to evaluation and justifying additional features of the trial that impact sample size, such as the adjustment for multiplicity or clustering, the approach to controlling for confounding variables, prevalence/incidence rates and accounting for missing data.

NESTcc says that trials should be registered on the clinicaltrials.gov website prior to enrolling the first patient, with no exceptions. Observational trials could also be registered at the NESTcc website or at the Center for Open Science, https://bit.ly/3avUVIj.

The consortium’s recommendations also emphasize the importance of data safety monitoring boards/committees. Finally, NESTcc includes the general principles to follow on the Statistical Analysis Plan that includes the treatment of missing data, specifying the use of statistical software and providing a plan for adjustment for multiplicity of all endpoints. In conclusion, the framework points out that additional considerations will be required when assessing imaging modalities and diagnostics.

To read the framework, click here: https://bit.ly/32SoS2V.