Regulatory Considerations for Clinical Studies: Clinical Trials for Medical Device Innovators Part II. The second, in a blog series about clinical trials for medical device innovators. Read part I: Designing Clinical Trials, here.
For regulatory purposes, clinical trials are grouped into two basic varieties: significant risk (SR) studies and nonsignificant risk (NSR) studies. The Food and Drug Administration (FDA) prefers that IRBs (Institutional Review Boards) make this determination; however, many IRBs put this back on the FDA to decide. Caution: If your study will involve multiple investigative sites and multiple IRBs, if any one of the IRBs decides it is a SR study, then the whole study will need to be so designated. You may wish to be proactive and write to the chief of the branch of the FDA which will hold authority over your device, describing your study and requesting determination by the FDA regarding the risk status of the study. This decision would then govern how your study is conducted.
All SR studies require an IDE (investigational device exemption). If your device is considered to present SR to patients, you will need to apply for an IDE and obtain FDA approval prior to conducting the study. In contrast, NSR studies only require approval of an IRB. If an IDE is required, an IDE Early Feasibility Study now may offer some leeway with respect to the amount of nonclinical testing required to support the IDE, so it is likely worthwhile to try this route. The alternative is a traditional IDE which often requires all nonclinical testing (bench and animal) to be completed prior to applying for an IDE.
If you conduct a clinical feasibility study and decide that you want to complete development of the device and obtain regulatory approval for it on your own, this may be the perfect time to meet with the appropriate authorities of the FDA to discuss your plans and obtain their advice. Assuming a pivotal clinical study will be necessary to obtain data for approval, early in the planning stage of the study is a good time for a “presubmission” meeting (in this case, probably a “pre-IDE” meeting). Your request for the meeting will include a description of the device, proposed indications for use, overview of product development, planned nonclinical testing, the design for the proposed clinical study, and specific questions for the FDA. The FDA makes available numerous guidance documents on their processes. In this meeting, you can determine what nonclinical testing the FDA will require in order to approve the IDE, the endpoints and follow-up for the clinical study, and agreement that the design of your proposed clinical protocol is likely to prove adequate to yield sufficient analyzable data for determining if the device is approvable. FDA reviewers/scientists generally look for objective, measurable endpoints (e.g., procedural success, long-term success, rates of adverse events). If you are also interested in collecting data to support a coverage decision, third-party payers tend to be interested in more subjective endpoints (e.g., quality of life and effect on patients), which may be difficult to validate. Nevertheless, it is beneficial to work these subjective endpoints into the pivotal study so that the data are available when it is time to discuss cost coverage for your device.
The most important thing you can bring to a pre-IDE meeting is a well-reasoned clinical protocol. Here is where decisions begin to become difficult. What kind of a clinical trial is needed? Your options for the design of a clinical study may be broader than you think. Investing in consultation with an experienced biostatistician may be well worth the time and investment at this point. Selecting the trial design that maximizes the likelihood of obtaining relevant data while minimizing time and expense is both a science and an art; therefore, do your homework and choose a statistician you trust.
Your options for a pivotal clinical trial will depend to some extent on what is already known about your device and the condition it will be used to treat; is it an incremental improvement on a current product, or is it a novel technology? Do you plan to show superiority to the current standard of care with respect to effectiveness, or do you expect to show noninferiority, while perhaps demonstrating an improved safety profile or a less expensive device?
Of course, the gold standard for clinical trials that always comes to mind first is the prospective, blinded, randomized, controlled study. Such studies can be large and expensive, but if recent, well-conducted studies have been published using the standard of care, you may very well be able to use their results to develop a performance goal to which your new device can be compared given sufficient data from an observational study with a single-arm registry and appropriate hypothesis testing. Having an experienced biostatistician is crucial to developing the most efficient study design possible and justifying it to the appropriate regulatory authorities.
Continue to follow our blog to view the upcoming Part III: Managing Clinical Trials.
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