Medical devices are ubiquitous — from thermometers, bandages, and dental floss to blood glucose meters, hearing aids, and complex implantables such as pacemakers. The latest cutting-edge examples even extend to apps on tablets and PCs that physicians use to help monitor and treat patients. To ensure the safety and efficacy of these devices, regulators expect device manufacturers to provide data that accurately reflect the risk profile of the device.¹ As such, the regulatory guidelines for devices are distinct from those governing drugs, particularly in the area of safety.

The Risk-Based Regulatory Framework for Medical Devices in the U.S.

The passage of the Medical Device Amendments to the Food, Drug, and Cosmetic Act in 1976 marked the establishment of a risk-based regulatory framework for evaluating medical devices in the United States.² Within this framework, the marketing requirements for devices vary based on the risk classification of the product and risk is defined as the potential for the device to present harm to the patient. This includes any and all circumstances in which the device could malfunction or be used incorrectly.¹

Low-risk devices — such as prescription eyeglasses, which present a minimal potential for harm to the user and which most consumers can use without instruction — are generally exempt from FDA review, but manufacturers remain subject to certain safety requirements. Manufacturers of moderate-risk devices, such as blood glucose meters, are typically required to demonstrate that their device is substantially equivalent to another device that is already on the market. In the majority of cases, this can be achieved without clinical data.³

However, for higher-risk and innovative moderate-risk devices, the FDA usually requires manufacturers to provide clinical evidence that the benefits of the device outweigh its risks by means of conducting clinical trials.

During the trial, a sponsor must report the results of an evaluation of an unanticipated adverse device effect to FDA and all reviewing IRBs and investigators within specified timelines.⁴ Often, this clinical evidence is critical not only for demonstrating the safety and efficacy of the device, but also for supporting the proper or preferred use of the device in the marketed clinical setting.

Increased Rigor for Medical Device Safety Evaluation in the EU

The safety reporting requirements in clinical trials for devices differ from those for drugs. For drugs, sponsors are only required to report serious adverse events (SAEs) that are unexpected and suspected to be caused by, the drug.⁵ Thus even for clinical studies investigating in vitro devices, a proper system of collecting, analyzing and reporting SAEs has to be set up.

Another difference from drug clinical trials is the necessity to report device deficiencies, which are inadequacies of a medical device related to its identity, quality, durability, reliability, safety or performance, that might have led to SAE if a suitable preventive action had not been taken.⁶ Additional vigilance and appropriate means are required to notice, properly analyze, and report such events.

Sponsors should also keep in mind that, as opposed to drug regulations, the current legislation for devices in the EU is not unified. Every Member State has its own requirements regarding types of events requiring reporting, format of reports or reporting timelines, and sponsors need to be aware of differences in local regulation. These requirements may even be study-specific, as — for example — the nature of reportable SAEs and the reporting frequency can sometimes be agreed to with the Competent Authority if it is justified by the study conduct.

Updated Regulations in the EU

In May 2017, the European Commission adopted new regulations to reflect the substantial technological and scientific progress that has been made in the medical device sector since the EU harmonized its rules on medical device safety and performance in the 1990s. The two new regulations — the Medical Devices Regulation (MDR) and the In-Vitro Diagnostics Regulation (IVDR) — replace the three previous directives on medical devices. The primary elements of the MDR will take effect in 2020, while the initial requirements of the IVDR will enter into full force in 2022. Under the new regulations, both medical devices and in vitro diagnostics are divided into four risk classes, and conformity assessment procedures will vary based on risk. In addition, medium- and high-risk devices will be subject to pre-market authorization by a Notified Body, a significant change from the previous directives.⁷

Of note, under the new EU regulations, medical software and apps are considered medical devices if they record and register data for further medical purposes such as diagnosis, monitoring, or treatment of a medical condition. This includes apps that are used to collect data for clinical trials. Like other medical devices, medical software and apps will be classified based on both purpose and risk assessment.

Navigating the Regulatory Requirement for Medical Devices

Practical limitations related to the device or disease condition often make it difficult, or even unethical, to conduct large, double-blind, randomized medical device trials. As a result, device manufacturers may need to develop alternative, more flexible approaches to clinical trial design and statistical analysis. In some cases, manufacturers may want to consider leveraging alternative data sources, such as patient registries or mathematical modeling techniques, for device validation.

Given the complexity of the regulatory environment, manufacturers may benefit from working with a contract research organization that has deep experience in medical device trials and from working with regulatory authorities to develop a study design and statistical analysis approach that is feasible, tailored to the technology and indication, and created with patient safety in mind.

[1] Faris O, Shuren J. An FDA viewpoint on unique considerations for medical device clinical trials. N Engl J Med 2017;376;1350-1357.

[2] Public Law 94-295. Medical device amendments of 1976. May 28, 1976. Available at https://www.gpo.gov/fdsys/pkg/STATUTE-90/pdf/STATUTE-90-Pg539.pdf.

[3] U.S. Food and Drug Administration. The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] — Guidance for Industry and Food and Drug Administration Staff. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/510k-program-evaluating-substantial-equivalence-premarket-notifications-510k.

[4] 21CFR 812.150

[5] U.S. Food and Drug Administration. Guidance for Investigators, Sponsors and IRBs: Adverse Event Reporting—Improving Human Subject Protection. Available at https://www.fda.gov/media/72267/download.

[6] MEDDEV 2.7/3 revision 3, May 2015. Available at https://ec.europa.eu/growth/sectors/medical-devices/guidance.

[7] European Commission. Fact Sheet: New EU rules to ensure safety of medical devices. April 5, 2017. Available at https://europa.eu/rapid/press-release_MEMO-17-848_en.htm.