Test or Evaluate? Biocompatibility and Orthopaedic materials
This morning, the US FDA announced with a tweet, the publication of a new guidance on Ultra High Molecular Weight Polyethylene (UHMWPE) in Orthopaedic devices. “Manufacturers should include test data …” to demonstrate material safety, was the helpful advice.
It was perhaps unfortunate wording. I’ll come back to that later.
Really Long term implants
Orthopaedic devices are long term implants, with major joints such as hips and knees now expected to last for decades without wearing out. So the demands on the materials (mainly surgical alloys and extremely durable polymers such as UHMWPE) are extreme. And FDA is right to expect solid data on materials performance and safety for such devices.
The new guidance is a good one and provides lots of helpful advice on all aspects of safety and performance of such materials – including processing, the use of antioxidant additives and their impact on things like wear performance, shelf life and biocompatibility.
To test or Evaluate
And it’s the biocompatibility where it gets really interesting.
Because the guidance doesn’t say you have to test your device for biocompatibility.
Instead the FDA offers a staged approach:
- First look to see if there are other devices which use the identical material in the same way. In which case you can reference those other devices as evidence for biocompatibility. This has always been a preferred approach in orthopaedic implants, where most of the materials are very well defined surgical alloys. It does become more complex with polyethylenes and other polymers, because the formulations may be proprietary, may include additives such as Vitamin E and other antioxidants and may involve more complex processing which can introduce residues. But, if you can point to another device with identical UHWMPE (and that certainly may be the case if a manufacturer uses the material across a range of devices) then there may be no need to do any biocompatibility testing at all.
- If you can’t reference a prior use of the material, do a biocompatibility risk assessment. FDA says you should “explain the relationship between the identified biocompatibility risks, the information available to mitigate the identified risks, and any knowledge gaps that remain.“
- Finally, only do testing where there are remaining gaps in knowledge.
Biocompatibility is Risk Management
This of course is exactly the approach set out in the latest version of the biocompatibility standard ISO 10993-1:2018 Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process.
The FDA Guidance goes on to set out all of the aspects of biocompatibility which matter for orthopaedic implants. This again follows ISO 10993-1. And the latest (2018) version aligns much more closely with FDA’s own Biocompatibility Guidance. It’s important to look at this part very carefully. Because you will need to look for relevant information in relation to each separate endpoint. Your submission will need to include information which demonstrates safety separately in relation to the so-called endpoints of cytotoxicity, irritation, sensitisation, systemic toxicity etc. If any one or more is missing, then you will need to do testing for that item – and do the testing on the finished device.
This guidance from FDA reinforces that biocompatibility is a risk management activity.
- You first identify the hazards (use ISO 10993-1 and figure out which biocompatibility endpoints apply to your device.
- Then you compile the existing information in relation to each of these endpoints. This may be in the form of prior clinical use of the same material, or literature or other sources of relevant information.
- Then evaluate the risks according to the information present.
Only if there is insufficient evidence already available to evaluate risk do you do testing to fill the gaps.
Instead you must evaluate the evidence available and only test where you have to. The 2018 revision of ISO 10993-1 included a small but fundamentally important change to the table of biological endpoints (Table A.1). This table has so long been misused as a checklist. Wherever there was an X, do a test. But now, the X’s are all gone. They have been replaced with an E. E is for Evaluate. ISO 10993-1 is clearly stating: look at all the evidence, evaluate the risks, and then, and only then, consider if additional testing is required to fill gaps in knowledge.
Cover all the bases
The important take away here is that a biocompatibility verification, or a submission to FDA, or to any other regulator, should include a full biocompatibility risk assessment which speaks to every endpoint listed in ISO 10993-1 for your device and in the relevant FDA guidance, (such as the UHMWPE guidance). You don’t necessarily have to test against each endpoint, but you do have to justify, with evidence, that there are sufficient data available to demonstrate safety in each case.
Which is why it was unfortunate that the FDA tweet said “Include Test Data”. That’s the problem with tweets, there’s not enough space for the nuance that the testing may have already been done.
FDA Biocompatibility Guidance (PDF Download)
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