Achieving Excellence in Medical Device Benefit-Risk Assessments

A Roadmap to Faster Approvals and Reduced Compliance Oversight

medical device risk

Medical devices save lives, but they are not without risk. Whether it is a disposable soft contact lens used on a daily basis, or an intraocular lens surgically implanted to treat cataract, use of medical devices can potentially result in serious injury or even death. There are thousands of medical devices on the market, but there are also reports of millions of injuries and thousands of deaths associated with these devices in the last 10 years.

In the United States, the Food and Drug Administration (FDA) is responsible for ensuring that all medical devices are safe and effective for their intended use. FDA evaluates whether a device is safe and effective by weighing any probable health benefit against probable risk of injury or illness, including serious injury or death. If the medical benefits are reasonably expected to outweigh the anticipated risks at the time, marketing of the device is allowed.

The decision to allow marketing of a medical product based on this benefit-risk assessment is not easy. Although the FDA reviews a lot of data when evaluating a device submission, the final decision is essentially a judgment call. Unlike the drug approval process, medical device submissions are not always required to submit data from clinical trials, especially for a majority of devices going through the 510(k) process. Even for high-risk devices going through the Premarket approval (PMA), clinical trial data is not sufficient to ensure applicability across a broad range of real-world use scenarios.

The FDA makes regulatory decisions based on benefit-risk evaluation at the intersection of science, medicine, policy, and judgment, in accordance with applicable legal and regulatory standards.

In short, there are a lot of unknown-unknowns, and any assessment of benefit-risk carries a significant amount of uncertainty. That is why post-market surveillance of medical devices is critical to continuously monitor the benefit-risk balance, and in many cases, the FDA requires post-approval studies as a condition to approving high risk devices.

What can medical device manufacturers do to reduce the amount of uncertainty in benefit-risk evaluations?

This question is relevant not only for approval of new devices, but also for products already approved. When there are recurrent malfunctions of devices in the market, and reports of serious injuries, the benefit-risk balance is negatively impacted. FDA expects appropriate, timely remedial action in these situations, but may also choose to exercise its broad enforcement authority in different ways to ensure continued public safety. A poor safety record makes you a target of elevated FDA scrutiny and erodes your credibility with FDA in developing safe and effective new products.

There are three ways to achieve success in establishing and maintaining a favorable benefit-risk balance.

Effective implementation of ISO 14971

FDA recognizes ISO 14971, the International Standard for risk management of medical devices, and conformity with the requirements of this standard is a good starting point.

Conformity to requirements, however, does not necessarily mean effectiveness. In order to be effective, the system needs to enable risk management decisions that are consistent, grounded in objective facts, and continuously lead to reduction in uncertainty through a documented history of risk estimation, risk evaluation, risk acceptability and risk control. Good documentation of these decisions helps to streamline the premarket review for both FDA and manufacturers.

In light of regulatory changes such as the EU-MDR, and a rapidly evolving value-based reimbursement environment in the United States, competence in risk management is no longer a nice-to-have for the medical device industry. From this perspective, both regulatory and market forces are driving the need to achieve excellence in risk management.

It may take a significant amount of time, even several years, to achieve a high level of competence and effectiveness in risk management. However, it can be a source of sustainable competitive advantage resulting in shorter development cycle, faster regulatory decisions and superior post-market safety performance.

Structured framework for benefit-risk assessments

Implementation of ISO 14971 requires an assessment of benefit-risk at each individual risk level, and at the overall device risk level after implementing risk controls. However, the standard offers only a high-level guidance for benefit estimation and criteria for benefit-risk judgments. As a result, benefit-risk assessments in most cases tend to be subjective, qualitative, and expert judgment-based and generally lack consistency across diverse product lines.

FDA began developing a more systematic approach to benefit-risk assessments in 2009 as part of the human drug review process. A qualitative framework was developed, piloted and subsequently improved before fully integrating within the decision-making processes of both Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). On the medical device side, Center for Devices and Radiological Health (CDRH) and CBER jointly issued a guidance for premarket approvals and De Novo classifications first in 2012, and later revised it in 2016. The qualitative framework for benefit-risk assessments of devices differs from that of drugs due to the diversity and risk-profiles of medical devices; however, it still provides a systematic approach to consider different factors in assessing, comparing and summarizing the benefits and risks of devices.

FDA does not mandate use of the benefit-risk framework, but this approach can offer a clear advantage to the industry. Most recently, FDA has issued a draft guidance for consideration of uncertainty in making benefit-risk determinations. References to these, and other relevant guidances are provided at the end of this article.

FDA is now moving to more quantitative approaches, primarily on the drug evaluation side. A recent webinar by CBER provides examples of analytical methods such as Value Tree analysis, Influence Diagram, Effects Tables, Forest Plots, Sensitivity Analysis, and comparing different options using a Multi-Criterial Decision Analysis (MCDA) model. A public workshop held in September 2017 also provided a comprehensive review of emerging quantitative methods that could be applied to benefit-risk assessments. It is possible that such methods will become more relevant, and even expected, for medical device benefit-risk assessments.

Culture of Quality and focus on Patient Safety

There are clear signs that FDA is beginning to emphasize a culture of Quality, not just Compliance, in considering both enforcement and regulatory decisions.

In late 2017, the CDRH announced a voluntary Case for Quality (CfQ) pilot program with the intent of encouraging the medical device industry to focus on design and manufacturing practices that have the greatest impact on product quality and patient safety. The idea is that if manufacturers can demonstrate a level of maturity in their operations to consistently achieve better quality outcomes, then the industry as a whole can provide a higher level of assurance of safety and effectiveness. In launching this program, FDA appears to have realized that exclusive focus on Compliance over the years has not resulted in significant improvements in quality and safety.  

A recent review of the program outcomes shows that participating organizations have achieved a significant reduction in defects and non-conformances, and increase in customer satisfaction as a result of maturity appraisals. Unlike an FDA inspection, the CfQ maturity appraisal identifies opportunities for improvement, reduced regulatory burden, increased innovation and faster time to market. In return, the FDA is increasingly choosing to forego routine inspections, pre-approval inspections and accelerate review of change notices.

On the regulatory decision-making side, there are indications that FDA is shaping its policy to adopt a product life-cycle approach, which relies on organizational excellence as a starting point. FDA has launched a software pre-cert pilot program which aims to provide a streamlined regulatory pathway for SaMD (software as a medical device) products based on an excellence appraisal.

The (software pre-cert) program goal is to provide efficient regulatory oversight of software-based medical devices from manufacturers who have demonstrated a robust culture of quality and organizational excellence (CQOE) and are committed to monitoring real-world performance.

A culture of Quality and focus on patient safety helps bring a level of credibility and lowers the uncertainty in benefit-risk assessments for regulatory decisions. When an organization is able to demonstrate excellence, it can simultaneously benefit from accelerated approvals and reduced regulatory compliance oversight.

In conclusion, effective risk management, structured benefit-risk framework, culture of Quality and focus on Patient Safety offer a promising road map to medical device manufacturers in achieving a sustainable competitive advantage.



FDA Guidance – Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications , August 2016

FDA Guidance – Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions, September 2018

FDA Guidance – Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics, September 2018

FDA Guidance – Patient Preference Information – Voluntary Submission, Review in Premarket Approval Applications, Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision Summaries and Device Labeling, August 2016

Public Workshop II: Benefit-Risk Assessments in Drug Regulatory Decision-Making, September 2017

Case for Quality Pilot Program, December 2017

Case for Quality Progress Report, Q4 2018

FDA’s Software Pre-Cert Program, 2019 Plan