Implications of the replacement of in vivo tests with in vitro tests for medical devices (ISO 10993 series)

By Stelia Ntika, PhD medical technology Karolinska Institutet

In April 2022 I did my internship at Swedish Institute for Standards under the supervision of Lars-Magnus Bjursten and Lena Morgan. This internship aimed to assess the ‘push’ to replace animal-based tests with chemical characterisation and in vitro studies to evaluate the biocompatibility of medical devices in the ISO 10993 series (Biological evaluation of medical devices) developed by ISO/TC 194.

Since the 26^th of May 2021, stricter rules on medical devices (MDR: Medical Device Regulation) have been introduced. The new regulation increases transparency by adding the UDI code and the Eudamed database. Moreover, it improves the safety for the patients and the reliability of the medical devices by establishing tighter controls on the evaluation process to also include clinical data. With the introduction of MDR, the requirements for Notified Bodies were increased, leading to a reduction of available Notified Bodies.

As these two activities that impact the regulatory process occur at the same time, it is often difficult to establish the impact of each of them, and they are often interlinked.

As the new regulation has been valid for less than a year and there is a lack of published information, the assessment was based on interviews with different stakeholders, such as manufacturers, evaluators, regulators, consultants, and users.

The aim was to find out how the stakeholders have been affected by the ‘push’ towards more in vitro studies and chemical characterisation and the benefits/downsides of the new regulation from their perspective. In total, 12 people from the stakeholders mentioned above were interviewed.

Although there is a ‘push’ to substitute in vivo testing with in vitro and chemical characterisation there are not many validated in vitro methods that can be used to evaluate the biological safety of medical devices and particularly for implants. Specifically, cytotoxicity, skin irritation, chemical characterization and endotoxin testing can be done in vitro. Presently a new in vitro method is being developed for skin sensitization. However, not all authorities have accepted the in vitro tests, which is becoming a problem.

One of the first questions we asked the stakeholders is the difference in cost with the old evaluation procedure. We concluded that in vitro studies and chemical characterisation are more expensive. The cost increase could happen for different reasons. For example, now there are fewer notified bodies, which creates a backlog taking more time and money to get clearance with the new evaluation procedure. More tests are required and depending on which market the product is destined to, maybe they need to start with in vitro and then do the in vivo test anyways, as FDA, for example, does not accept the in vitro skin irritation test. In addition, now some medical devices need to be re-registered due to higher risk classification, requiring more tests under the new MDR.

Only comparing in vitro vs. in vivo tests, in vitro usually costs 50% more than in vivo.

The second question was focused on the timeline of the biological safety evaluation. We discovered that the process is more extensive now with the new approach. As there are fewer notified bodies, there is a more extended waiting period (8-12 months), and fewer laboratories that perform the in vitro tests. No change was observed in the evaluation process of the devices with higher risk classification. However, there is more emphasis on the risk assessment, and more tests are required for the devices with lower risk classification and as the equivalent material cannot be used anymore this could lead to re-evaluating some material. Herein, it should be noted that the chemical analysis is sometimes misunderstood as it is asked but not needed for low-risk devices.

The third question focused on how difficult it is to get regulatory clearance for the medical device with the new MDR. The stakeholders mentioned that notified bodies have become stricter with more requirements, and finding an available notified body is also more challenging. In addition, the increased administrative burden, the increased requirements, and re-classification may make some products too expensive for the companies to validate under the new MDR. Causing them to be removed from the market. Few conditions have changed for the higher risk classes, and these devices are still the most difficult to get approved.

To the question, if the stakeholders believe that enough is being done to make the risks and the safety of the medical devices acceptable, they replied yes if you follow the standards, but there is space for improvement. Chemical characterisation, and in vitro testing have a higher sensitivity, specificity, and less variability than in vivo tests but often lack validation for medical devices. The new methods are well tested, but there is a need for more evidence for the old techniques and the laboratories doing the evaluations. However, there is an urgency to emphasize benefits vs. risks to create more reliable risk assessments. Some risks may be mitigated by more detailed labels, e.g., listing potential allergens.

The stakeholders believed that the new MDR is an improvement, with a mean score of 4.2 (where 1 is the worst and 5 is the best), from the Medical Device Directive (MDD). However, there are still many things that could be done better. Right now, some of the problems are that the MDR is hard to implement and takes longer for regulatory acceptance. There is, also, a need for more open data research and more notified bodies.

One main limitation of this project is the short time the MDR has been in use. For this reason, no quantitative data were available to compare the new to the old evaluation methods. In addition, there are not many validated in vitro tests and FDA has not accepted part of the standard.

What can be done?

In conclusion, companies need better education and competence to perform risk assessments correctly. It is essential to increase the number of existing notified bodies, balance clinical risks and benefits, and create open databases. The open database would help not to repeat some already performed experiments for equivalent material and lead to less animal testing. Furthermore, it is important to create a regulation for the EU so that small products or devices used for rare diseases are not discontinued due to the new MDR. Finally, sustainability needs to be addressed more in the medical device field.