Risk management of IVDs requires a different approach
Insights from a Let's Talk Risk! conversation with Shree Koushik
Note: this article highlights insights from a conversation with Shree Koushik as part of the Let’s Talk Risk! with Dr. Naveen Agarwal series on LinkedIn. Listen to the full recording of the discussion below.
In-vitro diagnostics (IVDs) devices are used to perform specific tests on blood and tissue samples taken from the human body to detect diseases or other conditions. Imaging devices such as X-ray, Ultrasound or MRI machines are also considered to be diagnostic medical devices. Test results from IVDs or images from diagnostic devices can be used to monitor a person’s overall health and to help cure, treat or prevent diseases1.
Personalized medicine is fast becoming a reality and diagnostic devices are playing a key role. High-speed genomic sequencing is now a reality, which can help in early screening, detection and treatment of certain cancers2. We can now quickly identify mutations of the COVID-19 virus to study their spread, design new IVDs and vaccines3. Rapid advances in artificial intelligence and machine learning (AI/ML) are enabling new diagnostic devices to help diagnose difficult conditions such as autism spectrum disorder (ASD) in very young children4.
It is not an understatement to say that the next generation of diagnostic devices will lead to significant breakthroughs in medicine and human health.
Unlike a typical medical device, IVDs “do not touch” a patient. IVD-related risks to patient safety are considered to be indirect risks5 because the information generated by an IVD is an intermediate step in the sequence of events. In the IVD world, a trained technician will generally run the assay and provide the information to a clinician. In case of an over the counter (OTC) test, such as a rapid COVID-19 test, the end-user directly receives the test results.
What they do with that information is not within the control of the IVD manufacturer. A doctor may receive a positive diagnosis from an IVD but may choose to do nothing about it when deciding the course of treatment for the patient. Someone using an OTC test for COVID-19 may believe they are not infected when they receive a false negative result. These are only a few examples of different scenarios that may eventually lead to harm through an extended sequence of events and hazardous situations over which the IVD manufacturer has not control.
You can work through the risk process for a medical device and mitigate the risks because you know that it “touches the patient” and the end-user will directly use the device. An IVD is different.
Since the risk to patients from an IVD are “indirect”, the focus or risk management activities is mainly on minimizing false positive6 and false negative7 results. However, even the most accurate and stable IVD may lead to unacceptably high rates of false positives or false negative results during actual clinical conditions for an individual patients. This is why risk management of IVDs becomes particularly difficult.
Performance requirements for IVDs in terms of sensitivity8 and specificity9 are generally driven by risk of false positive and false negative results to safety. As an example, a blood test to ensure that a bag of donated blood is not HIV-positive must have very high specificity of more than 99%. This is because, a false negative result on a single bag of donated blood can potentially infect a large number of recipients. On the other hand, a reasonably high sensitivity in the range of 90-95% may be sufficient for a Hepatitis C IVD because it is used on an individual patient in a clinical setting under a doctor's supervision. Therefore, we have to understand the consequences of false positive and false negative results in different clinical situations to establish the performance requirements for an IVD.
You have to make sure that your IVD meets the user needs and risk is integrated in the process through Design Inputs.
In the United States, the FDA reviews the performance characteristics data from both lab and clinical testing before an IVD is cleared or approved after careful consideration of the benefit-risk. A clear understanding of the user needs and integration of risk with design inputs should be documented in sufficient detail to help facilitate a favorable regulatory decision.
But how do you identify and estimate the risks to patients in different hazardous situations and link them to design inputs? As noted above, this exercise is very challenging for IVDs because of the indirect link to risks.
Here are a few ideas and best practices that emerged from our discussion:
Focus on user needs and secure management buy-in: unfortunately, there is a gap in the IVD industry in analysis of user needs and adequate identification of design inputs, including those related to patient safety. Most small IVD manufacturers, and startups lack management buy-in to invest in resources to adequately define user needs. As a result, work on risk management is lacking. It helps to build management support using a storytelling approach to risk, highlighting the impact of inadequate risk management on future revenues, not just the regulatory approval process.
Use guidance provided in Annex H of ISO/TR 24971: Annex H in ISO/TR 24971 provides “22 pages of goodness” to risk practitioners in the IVD industry. Extensive guidance is available for risk analysis for activities including identification of the intended use, reasonably foreseeable misuse, characteristics related to safety, hazards , harms and estimation of the probability of occurrence of harm using a revised P1, P2 approach. Guidance is also provided for risk control, benefit-risk analysis, disclosure of residual risks and production and post-production activities. Using this guidance, a risk management procedure and supporting templates can be established to create a risk management file for an IVD.
Leverage publicly available data on adverse events: FDA’s MAUDE10 and TPLC11 databases are good resources to learn about publicly reported adverse events related to device issues, related patient injuries and recalls. If you have an IVD similar to a currently marketed product, this information can be very helpful in understanding potential malfunctions and how they might be linked to patient harms. These can be useful inputs to the risk process.
Benchmark similar IVDs: Based on the underlying technology or method of detection, it may be a good idea to benchmark other similar IVDs approved or cleared for a different intended use. As an example, lateral flow assays and ELISA are routinely used in many different applications. If your IVD is based on these methods, it is useful to study other similar devices to identify various risk inputs and performance expectations. A good place to start is to first find the FDA product classification and related information using the FDA 510(k) database.
About Shree Koushik
Shree Koushik has over 25 years of research experience in biochemistry and molecular biology. As a consultant in the medical device industry over the last 10 years, he has successfully helped multiple clients receive FDA approvals for medical devices, combination products, software and IVDs in the microbiology, immunology, personalized medicine, cardiovascular, general surgery and dental specialties. He has also conducted numerous Quality Systems audits, developed Quality Management Systems and represented companies in their response to FDA inspections. Currently, he serves as the managing partner of BRDA consulting offering customer-centric solutions in regulatory affairs, quality assurance and business development.
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.
American Cancer Society: Precision medicine in cancer care
ISO/TR 24971:2020, Annex H: “These risks are indirect, often characterized by extended sequence of events that involve “competent intermediaries” such as trained users who use IVD medical devices to perform IVD examinations and clinicians who rely on the examination results.”
A false positive result means that the IVD results is positive when in fact it should be negative. As an example, an OTC COVID-19 showing a positive result when the individual in fact is not infected with the SARS-CoV2 virus.
A false negative result means that the IVD result is negative when in fact it should be positive.
Sensitivity: a performance characteristic of an IVD which indicates the fraction of true positive results from samples that are known to be positive. As an example, 90% sensitivity means that the IVD correctly shows a positive result in 90% of samples which are known to be positive. Sensitivity can be further defined as analytical sensitivity or diagnostic sensitivity.
Specificity: a performance characteristic of an IVD which indicates the fraction of true negative results from samples that are known to be negative. As an example, 95% sensitivity means that the IVD correctly shows a negative result in 95% of samples which are known to be negative. Sensitivity can be further defined as analytical sensitivity or diagnostic sensitivity.
MAUDE: Manufacturer and user facility device experience is a searchable database for medical device reports submitted to the FDA by device manufacturers.
TPLC: Total product life cycle is a searchable database that includes premarket and post-market data about medical devices, including device related issues, patient injuries, premarket approvals, premarket notifications and device recalls.
This synopsis is a masterful review of IVD regulatory and risk requirements.