Clinical Trials for Medical Device Innovators Part II: Regulatory Considerations for Clinical Studies

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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, measureable 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.

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Continue to follow our blog to view the upcoming Part III: Managing Clinical Trials.

Clinical Trials for Medical Device Innovators Part I: Introduction and Designing Clinical Trials

The first, in a blog series about clinical trials for medical device innovators.

In 2017, Cook was approached to co-author the recently published book, “Medical Innovation Concept to Commercialization.”  William D. Voorhees III, Ph.D., Vice President and Chief Science Officer and Theodore Heise, Ph.D., RAC, Vice President Regulatory and Clinical Services, both of MED Institute, collaborated to write the chapter, “Clinical Trials for Medical Device Innovators.” Overall, the purpose of this book is to provide physician-inventors and entrepreneurs with a practical, step by step approach to move a novel concept from the back of a napkin to a tangible, commercially successful product.

Cook News August 2018 MED InstituteWilliam D. Voorhees III, left, and Theodore Heise, holding a copy of “Medical Innovation Concept to Commercialization”.

Dr. Voorhees earned his A.B. in Biology from Hamilton College and a Ph.D. from the Department of Veterinary Physiology & Pharmacology at Purdue University.  As a faculty member of the Hillenbrand Biomedical Engineering Center at Purdue, Bill conducted a wide variety of original research in applied physiology including CPR, transchest cardiac pacing, electroventilation, hyperthermia therapy for solid tumors, hypothermia to protect the myocardium during myocardial infarction, and respiratory function monitoring.  He has authored over 70 refereed scientific articles resulting from this research.  He also served as liaison with the R&D Department of Methodist Hospital of Indiana in Indianapolis.  Bill has been with MED Institute for 28 years, joining the newly formed Clinical Trials/New Product Approvals Group in September 1990.  He was named Vice President/Chief Science Officer in September 2001.  Bill also serves as the Director of Regulatory Affairs and Director of Scientific Communications.  He takes seriously his commitment to patients to ensure the quality and scientific integrity of the research conducted by MED Institute.

Dr. Heise has 25 years’ experience in regulatory affairs, currently serving as Vice President of Regulatory and Clinical Services at MED Institute.  In this capacity, Ted leads the company in designing scientifically robust regulatory and clinical study strategies for its clients: entrepreneurs, consultants and physicians bringing novel medical products through the complex steps of the development process. Graduating with a BS in chemistry from the University of Nebraska at Omaha, Ted went on to earn a Ph.D. in analytical chemistry from Iowa State University.   He has been a member of the Regulatory Affairs Professionals Society since 1993, and the American Chemical Society since 1988. Ted is a U.S. delegate to the technical committee for international consensus standards that governs biocompatibility testing and clinical investigations of medical devices, and serves as convener of its working group on chemical characterization. Ted is also active in developing processes to generate real world evidence for medical devices, representing Cook Medical on the corporate stakeholder board for the SVS/Vascular Quality Initiative and participating in projects within MDEpiNet and Harmonization by Doing.

In their chapter from the book, “Medical Innovation Concept to Commercialization,” presented here as a series of 5 blog posts, Bill and Ted share the wisdom they have gained from their 20 plus-year adventure designing, conducting, and analyzing clinical trials on novel medical devices.

Designing Clinical Trials

Perhaps the most exciting and rewarding time in the development of a new medical device is the first time one sees it work successfully in a patient, but the ensuing clinical trial can be the most exhausting, frustrating, expensive, and time-consuming part of the entire enterprise. So before rushing headlong into the unknown, consider the following: “Is it necessary for me to conduct a clinical trial of my new device?” The answer is “It depends.”

It depends on what you are trying to accomplish. Maybe you just want to show that your device works (i.e., the Proof of Concept). Perhaps you have reached a point at which no more can be learned without testing in humans, for example, pain relief cannot be studied on the bench at all and rarely well in animals. Your goal may be to demonstrate product effectiveness to investors and to raise additional funds. Maybe all you want is enough clinical data to improve your chances of selling the rights to the intellectual property. Perhaps you just want to enhance market awareness and exposure to the device (such as having a few key opinion leaders use it and write a paper), or maybe you want to take it all the way to regulatory approval with proof of safety and effectiveness, which is collected typically in what is called a pivotal study. Even if you want to own the regulatory approval of your device, keep in mind that a clinical study may not be needed if you can show that all relevant risks can be mitigated by bench and/or animal testing or with appropriate labeling. This is why a rigorous risk-analysis is imperative to your plan for development of the device.

Assume you have developed your device to the point that you have made prototypes that you have bench-tested adequately to satisfy yourself that they function as expected and they appear safe to use in humans. The “Grandmother Test” is a good benchmark; would you let your grandmother be treated with this device? Even if the answer is “Yes,” you probably need a clinical feasibility study first. Conducting a clinical feasibility study may also be a good first step when only formal testing in humans can provide the evidence that the device offers the expected benefit (Proof of Concept) or is required for making any final changes in design (e.g., to apply to specific human anatomy). Such data can simply be gathered no other way than to test in humans. Even if you know you will need a pivotal study for regulatory approval, it is likely that you will need initial information about how large a therapeutic effect the device will have before you can design a larger pivotal study to compare its results with state-of-the-art therapy (often a currently marketed device) in a statistically rigorous clinical study. A feasibility clinical study can be used to provide this crucial information.

If your interest lies only in developing the new device to the point that the concept (intellectual property) can be sold to another company to finalize its development and take it to commercialization, then conducting a clinical feasibility study may be adequate to provide the information that the company planning to purchase your device will need to decide to close the deal.

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Continue to follow our blog to view the upcoming Part II: Regulatory Considerations for Clinical Studies.