By Sean Fenske, Editor-in-Chief
 
Regulatory authorities and standards organizations are reassessing the guidelines and requirements involving the testing of medical devices. Specifically, biocompatibility testing is coming under question; that is, what companies should have to provide to ensure their devices that contact human tissue are safe to do so.
 
Creating possibly even more concern is the fact that not all the changes are aligned across all regions of the world. What’s acceptable in one area may not be appropriate for another location. As such, device submissions have become increasingly complex as medical device manufacturers attempt to provide all the testing required for any area they wish to gain market entry.
 
Fortunately, Jeni Lauer, Ph.D., biocompatibility expert at Nelson Labs, has responded to a number of questions to help clarify the confusion that remains. In the following Q&A, she speaks to the changes taking place in the U.S. and in the EU. She also delves into the specifics around reprocessed devices and what’s causing the most uncertainty.
 
Sean Fenske: Can you please explain what biocompatibility testing is and why it’s important?
 
Dr. Jeni Lauer: Biocompatibility tests attempt to demonstrate patient safety by identifying potential concerns such as allergic reactions and irritation responses, or to determine if a device will induce a fever or cause unacceptable levels of blood clotting reactions. More importantly, they can also provide insight into toxicity and carcinogenicity for devices intended to be used for long durations. They do not delve into whether a device functions properly; rather, the attention is on the materials and processes used to manufacture the device. The focus of the studies is on the patient’s potential tissue or systemic responses to contact with the device.
 
Sean Fenske: Why are changes for this type of testing taking place? What’s driving the change?
 
Dr. Jeni Lauer: We see constant evolution and change in the industry, caused primarily by updated regulations [such as the shift from the EU’s MDD (Medical Devices Directive) to MDR (Medical Device Regulation)], and by updated guidance provided by the ISO 10993 standards. For implantable devices, such as orthopedic implants, these changes are generally positive, in my opinion. For example, I’ve seen several instances of implantable devices used in patients for many years without any testing to demonstrate safety with respect to long-term toxicity or carcinogenicity. In the transition to MDR compliance, companies are expected to ensure these devices are fully assessed for safety. Of course, this comes at a cost, but from a patient safety perspective, this is an improvement.
 
Sean Fenske: What requirements have changed from the FDA? Are they being stricter with regard to testing plans they will accept (or have accepted)?
 
Dr. Jeni Lauer: Interestingly, we’re seeing the FDA take a very pragmatic approach to testing for orthopedic implants, especially with legacy devices that have been in use for years but now require resubmissions. Many of the relevant biological endpoints outlined in the ISO 10993 standards are effectively evaluated through prior clinical use. For example, it would be wasteful to subject a legacy device to an animal test for detecting a fever, an allergic response, or an irritation response because it’s been used repeatedly in humans and these responses have not been noted. What we are not usually able to assess from patient use is long-term impacts due to comorbidities, or different environmental and genetic factors. Thus, the FDA is focusing on the demonstration of safety for long-term toxicity, genotoxicity, and carcinogenicity. Evaluation for these concerns can be accomplished through analytical chemistry tests followed by toxicological review. This ensures a high level of scrutiny is applied to each device, but it’s performed in a thoughtful, pragmatic way. This provides confidence in patient safety for things that can’t be predicted from prior clinical use. This testing and assessment come at a financial cost; however, it is significantly reduced compared to repeating all possible testing.
 
Sean Fenske: What’s happening with regard to biocompatibility testing in the EU? Is there a universal consensus of what’s required among notified bodies?
 
Dr. Jeni Lauer: The deadlines for MDR compliance have been pushed out a bit to allow companies to catch up on testing and documentation. This means we don’t have as much feedback from EU and UK notified bodies as we do from the U.S. FDA. We’re seeing the reviewers from the UK somewhat like the FDA. Generally, they require analytical chemistry testing and evaluation of long-term toxicity, genotoxicity, and carcinogenicity for devices in long-term patient contact, but they’re willing to accept well-written justifications to leverage prior clinical use to evaluate relevant biological endpoints and minimize duplicative animal testing. The EU is not a monolith, and we’re seeing variability between countries and reviewing agencies. In general, the EU is more conservative and less pragmatic, though. I’m currently working through responses with an EU notified body where the reviewer has suggested animal testing for implantation may be required because the shape of the implant has changed since the initial animal testing was performed. However, the modified shape has been in clinical use for many years. In my opinion, repeating in vivo testing is wasteful because the updated shape of implant has been in clinical use for nearly a decade. The ISO standard covering animal testing would call this testing unnecessary and duplicative.
 
Another interesting difference between the U.S. and the EU/UK is the FDA generally does not require analytical chemistry testing for devices used for less than 24 hours. In contrast, the EU and UK reviewers are more inclined to ask for analytical chemistry data from these devices. Devices used for less than 24 hours are evaluated for three to five endpoints (depending on the nature of patient contact), including cytotoxicity, sensitization, and irritation, or these three endpoints plus acute systemic toxicity and material mediated pyrogenicity. Analytical chemistry testing provides widely applicable insight into only one of these endpoints—acute systemic toxicity. That endpoint is more efficiently evaluated through in vivo testing; therefore, rendering the analytical chemistry testing for devices with a limited contact duration somewhat overly burdensome.
 
Sean Fenske: How have reprocessed devices been affected by these changes?
 
Dr. Jeni Lauer: Reprocessed devices present an interesting challenge from a biocompatibility perspective. These are devices that can contact a patient at a hospital after only one reprocessing cycle or after hundreds of reprocessing cycles. The goal here is to assess the device under worst-case conditions for patient exposure, but is that after one cycle, 100 cycles, 200 cycles, or more? One cycle could have more manufacturing residuals and 100 cycles would have more reprocessing residuals. We cannot know the worst-case situation without obtaining data. We also want to be conscious of when we pursue animal testing to assess these risks. We do not necessarily have to perform the full suite of testing under all scenarios.
 
In the past, companies have performed very limited testing after only three to six reprocessing cycles. Recently, I’ve worked on a few assessments for which devices were put through hundreds of reprocessing cycles followed by multiple tests looking for different residues. While some testing may be needed, the general trends I saw in the data were that unacceptable levels of residual chemicals correlated with (and were likely caused by) device damage. This is logical, right? Devices get knocked around during reprocessing and damage to the surface allows for more residues to settle into the cracks and crevices. This type of assessment may be an added expense that doesn’t necessarily increase patient safety unless it is completed in a thoughtful manner. In my opinion, a negative clinical outcome caused by reprocessing is most effectively mitigated by the healthcare reprocessing center staff and the clinicians being vigilant in looking for device damage and discarding anything showing surface wear or damage.
 
Sean Fenske: What aspect is creating the most confusion among medical device manufacturers seeking to adhere to new biocompatibility testing requirements?
 
Dr. Jeni Lauer: There are two main issues. First, the goalposts are constantly moving. At the risk of sounding like an advertisement for consulting services, the best thing medical device companies can do is hire outside support from someone with active industry participation. An approach that worked two years ago may not work today.
 
The second issue creating problems is the reviewers are human with various backgrounds and skillsets. The best way to tackle this issue is to write clear, concise documents. Explain everything as you would to a device novice and ensure you connect all the dots between the device description and data all the way through to the conclusion. A reviewer with less experience will be able to follow everything and a more experienced reviewer will appreciate the effort. Most importantly, both will be more likely to be agreeable.
 
Sean Fenske: Do you have any additional comments you’d like to share based on any of the topics we discussed or something you’d like to tell orthopedic device manufacturers?
 
Dr. Jeni Lauer: I would add that when well-known and regulated materials are used for implants (e.g., ASTM-grade titanium alloys) and they are processed using all relevant standards (e.g., ASTM, ISO), the concern from a biocompatibility perspective is minimized. Understanding this helps to focus on identifying potential hazards and risks of the process and then to use available data to mitigate those risks with a creative, yet scientifically sound, approach. 
 
I’ll also reiterate my advice to seek help with your strategy and documentation. The requirements for training are such that it’s difficult for companies to have the relevant expertise within their staff for major submissions.
 
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