With many factors to consider, preparing a global submission may seem daunting, and adhering to the varying testing requirements and interpretations of standards of regional regulatory organizations adds to the chaos. But when you know the different interpretations and preferences for specific tests and standards, it is easier to see the best way to approach submission for your device.
It is crucial to be up to date on the current ISO standards and understand how regulatory bodies are interpreting them. ISO 10993 standards provide a framework for the biological evaluation of medical devices within a risk management process. They are not a rigid set of test methods or evaluation procedures but are a series of standards that provide information to help identify the biological risk associated with a medical device. By bringing risk to the surface, changes to the device can mitigate said risk.
Because interpretations of ISO 10993 standards vary by each region's regulatory body, it can be challenging to determine a regulatory approval strategy. Understanding the various interpretations by regulatory bodies, such as the European Union (Notified Body), United States Food and Drug Administration (U.S. FDA), Ministry of Health, Labour and Welfare of Japan (MHLW) and China's National Medical Products Administration (NMPA) can help guide your submission plans.
European Union: MDR
The newest – and arguably most complex – regulation is the Medical Device Regulation) MDR. The regulatory environment in the EU is changing with the transition from Medical Device Directive (MDD) to MDR. Due to COVID-19, the new date for MDR application is May 26, 2021, and the compliance date, which was not delayed, remains the same (May 26, 2024). You can learn more about MDR here.
The EU accepts ISO standards without exceptions, so if your device is compliant with current versions of ISO 10993 standards, it is likely compliant with MDR or will require minimal additional documentation. However, it is critical to confirm with your testing partner to avoid the removal of any devices from the EU market.
In approaching your submission strategy, be aware that Notified Bodies (N.B.s) prefer a risk-based approach and alternatives to replace in vivo testing, including chemical characterization, previous testing, literature, in vitro tests and safe clinical history. If you absolutely require in vivo testing, there is a preference to only perform it after chemical characterization and in vitro testing.
Any evaluations or tests that follow older versions of the ISO standards require a gap analysis. You will need a risk assessment if any carcinogenic, mutagenic or toxic reproduction substances, phthalates, or endocrine disrupters have concentrations at or above 0.1 percent.
An MDR submission will require you to review test reports for compliance to current standards, prepare gap assessments and justify any deviations.
United States: FDA
Unlike the EU, the U.S. FDA does not recognize all ISO 10993 standards; some standards are only partially recognized. Manufacturers should review the U.S. FDA website to determine if, and to what extent, a standard is recognized. Also, the FDA provides guidance for the manufacturer on the use of ISO 10093-1. Obtain additional guidance by contacting testing partners with experts on their team who are members of ISO committees and have legacy knowledge from experience with previous device submissions. At the end of the day, it comes down to the individual reviewer's discretion on the acceptability of ISO compliance.
A device that contains a novel material (a material not previously used on a medical device and not already evaluated by the U.S. FDA) will require additional in vivo cytogenetic testing as part of a genetic toxicity test battery. In addition, the U.S. FDA has a preference for MEM elution cytotoxicity test.
The best approach is to use the risk assessment and tests performed for EU submission, as well as include a MEM elution cytotoxicity test.
In February 2020, the Japanese MHLW published Notification No.1006-1, which revises a previous notification from 2012. The notification recommends the use of the most current version of ISO 10993 standards and expands the expectations of biological evaluations. Most of the expectations are consistent with ISO standards, such as the requirement of the same endpoints for evaluation, as listed in ISO 10993-1 (2018). Furthermore, all biocompatibility tests must comply with Good Laboratory Practices (GLPs).
MHLW expects detailed information on patient contacting materials that do not meet recognized standards. For those that do not, you will need material composition and physical test information. There is also a data integrity review to confirm the reliability of the data submitted. The MHLW may also ask for raw data for any particular biocompatibility test. If the requested data is not available or deemed insufficient, the submission could be at risk of rejection.
Japan requires two different extraction strategies: one for the evaluation of sensitization and the other for the evaluation of genotoxicity. These extraction strategies attempt to deliver sufficient extractable materials to be representative of the whole device.
Using available information to address the required endpoints sets you up for success when preparing the MHLW application.
The NMPA has significantly expanded in size over the last ten years. Due to this there is the perception that China requires testing and does not accept risk-based evaluations. In reality there are cases in which NMPA has accepted risk-based evaluations and it currently does accept these assessments; however, acceptability is at the reviewer’s discretion. NMPA is making an extensive effort to train their reviewers and to accept more risk-based evaluations.
The NMPA evaluates medical devices with C.E. mark and/or 510(k) clearance using alternative procedures which facilitate the review. However, the NMPA may not accept current versions of ISO standards (currently accepted versions of the standards are posted by the organization on their website and can be translated into English) and may prefer conformance to older versions on the standards. Furthermore, they often request that the biocompatibility evaluations reference the Chinese standards that are equivalent to ISO standards.
By delaying submission until the EU and the U.S. clear the device, you can streamline the submission process for the NMPA since devices previously in the U.S. or EU follow an abbreviated review process. However, to avoid unnecessary delays, it is important to provide a risk assessment referencing the ISO equivalent Chinese standards. Your testing partners can help in providing appropriate information needed for a successful submission to NMPA.
The regulatory environment is consistently changing due to periodic standard revisions and new guidelines from regulatory agencies. While ISO 10993 standards are recognized globally, every region has different interpretations and preferences for what they want to see in the application process. Simply following ISO 10993 standards may not result in the acceptance of your biocompatibility evaluation. Having a thorough understanding of regulatory expectations in the regions where you plan to submit devices for review can guide endpoint selection, test design and more. Preparing sooner than later can help ensure your device's success no matter where in the world you are submitting for review.
To learn more about how to approach each regulatory body, and follow an example of a product through regulatory approvals, check out this webinar, "Biocompatibility Evaluation of Medical Devices for Global Registration."
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