The Evolution of Medical Device Clinical Trials: Adapting to Regulatory Changes

Groundbreaking technologies are altering the very definition of what is considered a medical device, and these dynamic changes necessitate the evolution of medical device clinical trials. Wearables, Software as a Medical Device (SaMD) products, and other innovations are transforming the regulatory landscape. At this rapidly accelerating pace, conducting clinical investigations for a new device in accordance with the latest regulatory requirements and industry standards is a challenge. It often seems that the speed of innovation is far outpacing regulators’ ability to provide up-to-date clinical guidance, which creates ambiguity. To minimize uncertainty and start getting a feel for the current regulatory climate, it’s helpful to first examine some of the characteristics that distinguish medical device clinical trials from other clinical investigations.

The Unique Regulatory Pathways of Medical Devices

Because medical devices are inventions that function physically, they are subject to unique regulations that are different from those that apply to pharmaceutical products, which are typically discoveries that function biologically or chemically. That being the case, the regulatory journey of a medical device will vary — sometimes subtly and sometimes drastically — from that of a drug. Consider the following five ways clinical trials for medical devices differ from those conducted for drug products:

1. So long as the device shows ample safety and effectiveness in confirmatory studies that support a premarket approval (PMA) application, it shouldn’t require the same high degree of research scrutiny that drug trials demand. Moreover, medical device clinical trials may not even be required in some cases, depending on the device’s class (i.e., risk stratification).
2. Since medical devices are approved through the PMA application process, a single confirmatory study is often sufficient for approval.
3. Clinical investigations of medical devices typically focus on prototype development, in contrast with drug trials which place greater emphasis on dose responses.
4. A post-approval study generally satisfies a medical device clinical trial’s requirements for long-term data. In drug studies, conversely, post-market studies are the fourth phase of an extensive investigative process.
5. Minor modifications to a device are frequently made to enhance safety or reliability, or for other improvement reasons. When new iterations of a medical device’s designs are devised, it’s rare for regulatory bodies to mandate additional clinical trials. Minor alterations aren’t likely to require prior regulatory approval if other testing (i.e., animal or bench) sufficiently validates the suitability of the design changes. In some clinical trials for medical devices, evidence can be derived from sources other than well-controlled clinical studies (e.g., if there are existing well-documented case histories conducted by qualified experts, if a partially controlled study already met the requirements, etc.).

For a deeper look into the significant differences between drug and medical device clinical trials, check out the article “How to Conduct a Well-Controlled Clinical Trial.”

Current Regulations Applicable to Medical Device Clinical Trials

Two main regulations apply to the conduct of medical device clinical trials. Devices sold or manufactured in the U.S. are regulated by the U.S. Food and Drug Administration (FDA). Global standards are set by the International Organization for Standardization (ISO).

U.S. Regulations – Title 21 of the Code of Federal Regulations

The FDA regulations for clinical devices are outlined in Title 21 of the Code of Federal Regulations, aka 21 CFR. These regulations and requirements must be adhered to while conducting clinical trials for medical devices, and they are commonly referred to as Good Clinical Practices (GCP):

• GCP guidelines include requirements for Investigational Device Exemptions (IDE), a designation that allows a device to be used in studies for the purpose of collecting safety and effectiveness data.
• Before a study is launched, all clinical investigations of medical devices must have an approved IDE.
• The regulation specific to IDE, 21 CFR Part 812, outlines the procedures for conducting clinical trials for medical devices and includes specifications for application, labeling, records, reports, and responsibilities of sponsors and investigators.

Global Standards – ISO 14155

The global standard that addresses GCP for medical device clinical trials is ISO 14155. It sets forth guiding principles for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness and safety of medical devices. The ISO 14155 standard has many overlaps with FDA regulations and specifies the requirements that are generally applicable to the four core facets of medical device clinical trials:

1. Protecting the rights, safety, and well-being of human subjects.
2. Ensuring the scientific conduct of the clinical investigation and the credibility of the clinical investigation results.
3. Defining sponsor and clinical investigator responsibilities.
4. Providing assistance to sponsors, investigators, ethics committees, regulatory authorities, and other bodies involved in the conformity assessment of medical devices. ⁽¹⁾

Updates to ISO 14155 were issued in 2020 to refine the standard’s focus on clinical evidence, data reliability, and increasing safety, among other reasons. In addition, the new version is more closely aligned with other widely recognized clinical directives such as the ICH E6(R2) GCP guideline, the European Medical Device Regulation (EU MDR), and the Declaration of Helsinki.

Whereas the previous version of ISO 14155 placed greater emphasis on identifying risk of failures rather than proactive measures, the 2020 updates add new directives that promote a risk-based approach to clinical investigations. The standard now calls for the development of a risk management plan that should be incorporated into the study protocol before the study begins and followed throughout the product life cycle. The updated standard also points to a need for more effective corrective action / preventive action (CAPA) management in cases of significant noncompliance and for device deficiencies that occur during the course of clinical investigation of medical devices. ⁽²⁾

Learn More About Clinical Investigation of Medical Devices

The information presented in this article is only a broad overview of the dynamic and complex world of medical device clinical trials. For a more comprehensive exploration of clinical trials for medical devices, download the white paper “The Evolution of Medical Device Clinical Trials: Their Background and a Look Toward the Future.”

References:

1. “ISO 14155:2020(en): Clinical investigation of medical devices for human subjects – Good clinical practice,” International Organization for Standardization website, 2020.
2. “An ISO 14155:2020 Primer – Good Clinical Practice for Medical Device Trials,” by Sandra Sather and Jennifer Lawyer, Clinical Leader, Feb. 2, 2021.