Focus on intended use in the clinical environment for risk management of IVDs

Insights from a Let's Talk Risk! conversation with Joshua Levin

Note: this article highlights key insights gained from a conversation with Joshua Levin as part of the Let’s Talk Risk! with Dr. Naveen Agarwal series on LinkedIn. Listen to the full recording of the discussion below.

At first glance, risk management of diagnostic devices, including in-vitro devices (IVD), is not overly complex. After all, you mostly have to consider the effects of false negative results, false positive results, and invalid or delayed results.

However, it can be challenging to correctly assign the severity of harm(s) resulting from inaccurate and/or delayed results if we don’t fully understand the clinical context of the intended use of a diagnostic device.

Consider the case of a recent Class I recall¹ of an IVD that detects troponin levels in blood or plasma samples for diagnosing a heart attack. A falsely low or false negative troponin level may cause a delayed or missed diagnosis leading to serious harm or even death, especially in patients who may not show any symptoms of an imminent heart attack.

Therefore, Josh advises practitioners to clearly define severity levels of potential harms directly in the risk management plan. This is especially valuable in a small company environment focused on developing a single device. He recommends a simple, more pragmatic approach to risk management for IVDs, driven by a solid understanding of the clinical context.

Generally speaking, severity level 5 harms (on a 1-5 scale), typically assigned to life-threatening outcomes including death, are uncommon for diagnostic devices because the device does not directly contact the patient. In addition, clinicians are not expected to rely exclusively on the IVD result for diagnosis and treatment plan. However, in situations requiring urgent and timely treatment, such ass in the case of troponin, IVD accuracy and reliability becomes matter of life and death.

That is why the US FDA is very sensitive to the risk of severe due to inaccurate results from an IVD used for directly diagnosing life-critical conditions such as a heart attack. IVDs used similarly for diagnosing other life-critical emergencies also attract a high level of regulatory scrutiny, both during pre-market review and the post-market phase.

As a result, it is important to develop plans for a robust post-market surveillance process for these high-risk IVDs. This is one area where startups do not generally spend a lot of time as they focus intensely on getting to market first. Part of the reason is the perception of a less stringent oversight by FDA in the post-market phase. The revised regulations in the European Union for medical devices and IVDs have significantly more requirements for post-market surveillance and clinical evaluation. FDA, on the other hand, focuses more on complaints handling and adverse events reporting in the post-market phase, and leaves it to the manufacturers to take voluntary actions to minimize patient harm.

In the end, risk management of IVDs in a startup or small company environment is a balancing act. We need to keep it simple, but it helps to build a good understanding of risks in the clinical context based on the intended use of the device.

Here are a few key points that emerged from our discussion:

1. Diagnostic devices are growing fast: driven by the COIVD-19 pandemic, there is a strong demand for in-vitro diagnostics especially for at-home testing. As a result, many small companies are actively developing diagnostic devices, both for in-vitro testing as well as for other applications using artificial intelligence and machine learning. Risk management of diagnostic devices is becoming very important in this rapidly changing environment.

2. Keep it simple but understand the clinical context: risk management of IVDs is not difficult. You need to focus on the impact of inaccurate results (false positive, false negative) and/or invalid or delayed results. Understanding the clinical context of the intended use is very critical. In a startup environment, it may be helpful to assign severity ratings to potential harms directly in the risk management plan. Invest in risk management training for your team to help develop a common understanding of requirements and practical knowledge.

3. Take a systems view and focus on hazard analysis: it helps to keep a system level view in mind when starting your risk analysis. Use a preliminary hazard analysis (PHA) to identify system level hazards, and how they link to potential harms through hazardous situations. Link hazards to failure modes in an FMEA and tie these hazards to requirements for risk control measures. It is useful to appreciate that risk analysis is an ongoing, iterative process that needs to be updated throughout the device lifecycle.

4. Drive the right level of urgency and action during the post-market phase: plan ahead to establish an effective post-market surveillance process. It should not only help you detect emerging safety signals quickly, but also help you to take timely action by separating signal from noise. A combination of appropriate statistical analysis combined with a simple business process of making decisions is useful.

5. Integrate risk management within a working quality management system: it is useful to think about risk management as an integrated part of your quality management system. It should not be considered a separate, stand-alone process. When safety signals are detected from post-market surveillance, the CAPA process should drive a thorough investigation to identify the root cause(s) and appropriate actions.

About Joshua Levin

Joshua Levin is a regulatory consultant, currently advising early-stage and mid-size companies in developing effective regulatory strategies and building efficient quality management systems, With 30 years of experience in the Quality/Regulatory space, including nearly 10 years at the US FDA, Josh has a deep understanding of both technical and regulatory aspects of IVD commercialization.

About Let’s Talk Risk! with Dr. Naveen Agarwal

Let’s Talk Risk! with Dr. Naveen Agarwal is a weekly live audio event on LinkedIn, where we talk about risk management related topics in a casual, informal way. Join us at 11:00 am EST every Friday on LinkedIn.

Disclaimer

Information and insights presented in this article are for educational purposes only. Views expressed by all speakers are their own and do not reflect those of their respective organizations.

1. FDA: Class I recall of Quidel triage cardiac panels for risk of false negative troponin levels