With high-profile disputations like those chronicled in the Netflix documentary “The Bleeding Edge” drawing mass attention to medical device regulations, it’s an appropriate time to take a closer look at the standards that regulate medical device clinical trials.

A substantive new white paper titled, “The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future,” by regulatory and compliance expert David R. Dills thoroughly examines the state of device regulations and the regulatory challenges inherent to medical device clinical trials. This first installment of a two-part blog series examines some of the white paper’s regulatory insights, including: the regulations that affect medical device clinical research, development and approval; some differences between device and drug clinical trials and their unique regulatory approval paths; challenges specific to device trials; and the dynamics of regulatory expectations.

Current Clinical Regulations Relating to Medical Devices

Medical devices function physically — unlike drugs, which interact chemically or biologically — and are therefore regulated differently than pharmaceutical or biologic products. Likewise, the clinical trials conducted to determine the safety and effectiveness of medical devices are also distinctive. The regulatory paths for device and drug trials for products to be sold in the U.S. are distinct because medical device development differs from the development of drugs. Not only are regulatory submissions for devices sent to a different branch of the U.S. Food and Drug Administration (FDA) for review than drugs (device submissions go to CBER, the Center for Biologics Evaluation and Research, while drug submissions are reviewed by the Center for Drug Evaluation and Research), they are subject to a different set of regulations than pharmaceuticals as well.

Although the regulations for conducting medical device clinical trials have historically varied widely by region, the primary, globally accepted roadmap for taking a device through the clinical trial progression is now codified in the International Organization for Standardization (ISO) 14155 standard. ISO 14155 provides the necessary guidance for conducting medical device clinical investigations and stipulates that trial sponsors are responsible for implementing a risk management program, classifying adverse events, and monitoring the ongoing safety evaluation of the clinical investigation for the medical devices they are studying. It’s worth noting that the most recent amendment to the standard includes a change to the title itself, “ISO 14155:2011 Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice (GCP).” The inclusion of GCP in the revised title indicates the intersection of medical device investigational exigencies with the International Conference on Harmonisation (ICH) GCP E6 guidelines that outline the expectations and responsibilities of all participants involved in conducting clinical trials.

Comparing the Regulatory Pathways of Devices and Drugs

The regulatory journeys of medical devices and drugs vary in sometimes subtle, sometimes drastic ways.

• Devices don’t need to be researched with the same degree of scrutiny as drugs if they show ample safety and effectiveness in confirmatory studies that support a premarket approval (PMA) application. In fact, clinical trials for medical devices may not even be required, depending on the class (risk stratification) of the device.
• Clinical trials for medical devices focus on prototype development, while drug trials pay more attention to dose responses.
• Because devices are approved through the PMA application process, a single confirmatory study is often sufficient for approval.
• In clinical studies for devices, the requirement for long-term data is generally satisfied by a post-approval study (as opposed to drug studies, where post-marketing studies are typically considered Phase IV of an extensive trialing process).
• Additional clinical trials are not always required when new iterations of medical device designs are devised. Minor modifications to a device may be made for the purpose of enhancing safety, reliability or other grounds for improvement. When refinements are made for such reasons, they may not require prior regulatory approval if other testing (i.e., bench or animal) is sufficient to validate the suitability of the design change.
• When a clinical trial is required for a medical device, it may be possible to derive evidence from sources other than well-controlled clinical studies (e.g., well-documented case histories conducted by qualified experts, clinical studies and objective trials without matched controls, partially controlled studies, etc.).

 Challenges Specific to Medical Device Clinical Trials

When medical device clinical trials are conducted, four major concerns must be addressed that don’t have comparable applications in clinical trials administered for drug products.

1. Inherent problems in designing medical device trials: Designing any clinical trial is a complex endeavor, but medical devices bring their own set of challenges to clinical research. In most medical device studies, it’s all but impossible to use placebos or conduct double-blind trials. It would be unethical, for example, to perform a hip replacement procedure on a healthy patient who doesn’t need the surgery or to perform a bogus operation on one who does. There may also be problems with unstandardized methodologies, phase variations in clinical development, and similar issues that wouldn’t have any impact in a drug trial. Additionally, trials for devices are likely to require at least one type of imaging modality that allows the sponsor to view the device to ascertain if it is functioning correctly.
2. Most devices are used by health care professionals, not just end-user patient recipients: Functionally, a medical device typically has two users: the health care professional who deploys it and the patient who receives it. A device’s safety and effectiveness functions facilitate a clinical outcome that is a combination of the professional user’s competency operating in parallel with the patient-device interaction. This is unlike a drug, which has its efficacy and safety determined solely by the product’s effect on the end-user recipient. The dual-user challenge posed by a medical device increases the criticality of sufficient training for the primary user in the implementation of the device as a central component of its clinical performance.
3. Inability to blind the user, which could result in bias issues or other difficulties: If a clinical investigator is jointly responsible for both treatment and the assessment of performance, bias can easily find its way into a clinical study. To avoid such biases during the assessment of a device’s efficacy, blinded evaluators should always be favored over clinical investigators whenever possible.
4. Limitations in comparative trial design: Ethical considerations, among other issues, can preclude comparative clinical trials. To appropriately evaluate outcomes, the use of historical controls or patients as their own controls (both pre- and post-surgery, where applicable) may be required.

One might assume these challenges are exclusively regarded by medical device organizations as excessive constraints on their clinical trials. However, in many instances, they are considered beneficial. These unique circumstances frequently result in a regulatory clearance or approval process for medical devices that is much more flexible in comparison with the drug approval process.

Meeting the Study Design Expectations of Regulatory Agencies

The most extensive directives for designing a study in accordance with regulatory expectations are found in the FDA’s Design Considerations for Pivotal Clinical Investigations for Medical Devices guidance (with the phrase “pivotal clinical investigations” referring to the stages of development in which a device is evaluated for efficacy and safety). While the guidance is not intended to be the all-encompassing final word on study design best practices, it does elaborate on a variety of study design principles that will meet FDA expectations for premarket clinical data requirements. And, despite being geared toward designing clinical investigations in support of PMAs, the guidance provides beneficial information for sponsors who conduct clinical studies to support De Novo (automatic Class III designation) and 510(k) clearance (premarket notification for devices deemed to be “substantially equivalent” to others already on the market) submissions as well.

Each section of the guidance outlines practical issues and potential impediments that are common in clinical study designs and the potential implications for a device’s safety and effectiveness. The guidance delves deeply into each of the following aspects of study design for medical devices:

• The regulatory framework for level of evidence and study design
• Types of medical devices (divided into two broad categories of diagnostic and therapeutic/aesthetic devices)
• The importance of exploratory studies in pivotal study design
• Some principles for the choice of clinical study design (general considerations, guidelines for study objectives, subject/site selection recommendations, etc.)
• Clinical outcome studies (and relevant design factors such as bias sources and bias minimization)
• Diagnostic clinical performance studies and the critical factors that affect their design (specifically, the importance of the device’s intended use, the choice of appropriate study population and mitigation of specific sources of bias)
• Sustaining the quality of clinical studies (with specific techniques and plans provided to help sustain the level of evidence of clinical studies)
• The investigational plan (i.e., the detailed protocol for the design, conduct and analysis of the clinical study)

Adaptive Design

In 2015, the FDA invited sponsors to consider adopting a study design methodology intended to help them increase the chances of study success and minimize resource requirements. This “adaptive design” blueprint outlines appropriate uses of medical device clinical trial designs that allow trials to implement planned changes (based on accrued data) while still maintaining study integrity and validity.

In addition to providing examples that demonstrate how to properly incorporate adaptive designs into trials, the Adaptive Designs for Medical Device Clinical Studies guidance examines some of the scheme’s advantages. Some of those incentives include greater understanding of device benefits and risks, enhanced cost effectiveness and efficiency, and stronger transitions from premarket analysis to postmarket follow-up. The formalization of the guidance in 2016 is the FDA’s indication that adaptive clinical study designs may be a primary means of offsetting some of the challenges associated with meeting rigorous clinical study and data requirements. These painstaking obligations are often some of the most troublesome and costly aspects of registering devices.

To Be Continued …

Keep an eye out for the next part of this series that will explore regulatory data consistency issues in medical device clinical trials, organizational adaptations to the changing clinical landscape, and the latest relevant developments like the FDA’s Early Feasibility Studies (EFS) program.

In the meantime, you can take a closer look at the medical device regulatory environment and ambitious trajectory of device trials by downloading the white paper, “The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future.” 

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James Jardine is a marketing communications specialist at MasterControl Inc. and has covered life sciences and regulatory issues for more than a decade. He has a bachelor’s degree in journalism from the University of Utah. 

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