Mahasweta Pal, freelance medical writer on Kolabtree, provides a comprehensive comparison of medical device regulatory compliance in the US (FDA) vs that in Europe (EU MDR).
Decomplicating the EU MDR has been a prime concern for medical device makers and, with higher vigilance and risks associated, medical device consultants have strategic roles to play. As medical device manufacturers brace towards the implementation of the EU MDR directives in the forthcoming months, it becomes extremely imperative to understand what changes the EU MDR brings with it. Meanwhile, the FDA continues its vigilance, the latest being on Essure—a female sterilization device associated with life-threatening complications for women. Not surprisingly, regulatory offices are certainly grappling with a lot of quality management issues. Medical device manufacturers, on the other hand, still have to consider their chances with getting premarket approvals for their products, even as regulatory frameworks become more stringent and markets become riskier. So, here we discuss the differences in the regulatory approval of medical devices, by the FDA and the EU MDR.
Aspects on which the differences exist:
The US regulatory controls are documented in accordance with the Federal Food, Drug, and Cosmetic Act and the regulations in Title 21- Code of Federal Regulations (21 CFR) Parts 1-58, 800-1299. This long, exhaustive regulatory framework is used by medical device companies to attain the FDA market authorization. It is based on the Title 21-CFR Quality System Regulations, which are defined for each device category. According to the FDA regulations, companies follow requisite regulatory steps assessing the overall risk profile for each device and ensuring reasonable safety and effectiveness assurance while adhering to the respective marketing pathways. The marketing pathways include Premarket Notification (510(k)), De Novo Classification Request, Exempt, Premarket Approval (PMA), Product Development Protocol (PDP), Humanitarian Use Exemption (HDE), and Biologics License Application (BLA).
The European counterpart “EU MDR” comprises a 28-page preamble, 10 chapters, and 16 Annexes with multiple chapters per annex. Briefly, the chapters detail the obligations of the economic operators, the revised CE marking process, the identification and traceability of the devices, registration of devices and their economic operators, a summary of safety and clinical performance, and the development and rebuilding of the European data bank on medical devices.
The MDR lists the primary responsibilities and conditions set forth for the Notified Bodies, regarding their role in processing clinical information to validate the intended use of the device, the conformity assessments, and clinical investigations on the device. Lastly, it introduces post-market surveillance and vigilance of marketed devices as a big step, as well as confidentiality and funding obligations, penalties, and the cooperation between member states, Medical Device Coordination groups, data protection, and device registers. Chapter X pertains to Final Provisions, which the EU deems necessary for mitigation of already marketed devices. Compliance with the EU MDR is changing since the classification categories have changed and the Common Specifications have been expanded as compared with the MDD. The MDR replaces the earlier Medical Device Directive (MDD) and the Active Implantable Medical Device Directive (AIMDD), while the in vitro Diagnostic Device Regulation (IVDR) replaces the IVDD.
2. Device Classifications
The first step before starting on the 510(k) submission is identifying the right class for the device using the FDA’s medical device databases. Class I and Class II devices, which have low and moderate risk, are regulated by the 510(k) pathway. This pathway requires product developers to present data demonstrating the functional equivalence of the device with a previously approved device, known as the ‘predicate’. Medical products may be exempted from following the tenets of this regulatory process if they do not exceed the limitations stated under 21CFR 880.9 and those that show higher potential risks of illness or injury due to their application, e.g. implantable devices, fall under Class III and undergo a stricter pathway—Premarket Approval.
Under Premarket Approval (PMA), sponsors present data demonstrating and validating the safety and effectiveness of the data in congruence with stringent evaluations of the benefit versus risk profile. Most importantly, the sponsors have the mandate to demonstrate evidence of the least environmental risk and a relatively higher life-sustaining potential. In recent years, the FDA has classified Class III devices as those “that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury.”
In fact, the FDA has determined that general and special controls alone are insufficient to assure the safety and effectiveness of Class III devices. Therefore, these devices require a PMA application under section 515 of the Food, Drugs, &Cosmetics Act in order to obtain marketing approval. This means that if the device classifications are accurate, a medical device sponsor has crossed halfway into the process.
On the other hand, device classifications based on the EU MDR are as follows: there are 4 categories of devices–non-invasive devices, invasive medical devices, active medical devices, a special category with exceptions (including contraceptive, disinfectant, and radiological diagnostic medical devices). The MDR has additional rules for treatment devices based on nanomaterials. Further, the devices are classified based on the risk, which determines the scale of data and depth of evaluation required for the prospective products.
Keeping aside the separate directive for in vitro diagnostic devices, here are the device classes.
- Class I – Provided non-sterile or do not have a measuring function (low risk)
- Class I – Provided sterile and/or have a measuring function (low/medium risk); the MDR adds to this group, reusable surgical instruments as Class I reusable surgical instruments.
- Class IIa (medium risk)
- Class IIb (medium/high risk)
- Class III (high risk)
Every device class has separate testing requirements, as discussed in different chapters and Annexures of the EU MDR. Devices with preinstalled user handling software would also be audited and validated under Article 6.11, Rule 11 of the MDR. These involve software used in monitoring devices, communication, diagnostics, and treatment. Most software is classified as Class I or IIb, in case serious deterioration of the patient’s condition is associated with its use. Software used for monitoring physiological parameters, where the nature of variations in those parameters can result in an immediate risk to the patient will also be classified as IIb. Whereas, software used in diagnostics or treatment that is associated with the risk of death or irreversible deterioration of a patient’s condition is classified as Class III.
3. Clinical Testing Processes
Considering that most devices fall under the 510(k) process, it is observed that clinical testing takes about 6 to 15 months, based on the type of device and its outcome measures included during the trial period. After accurately assigning the device classification, a medical device maker may proceed to undergo the exhaustive, multi-dimensional 510(k) submission, which includes all these evaluations before preparing 510(k) submissions:
- Preliminary safety testing
- Risk estimation
- Hazards identification
- Hazards management planning
- Risk mitigation strategy planning
- Risk control analysis
- Risk control effectiveness verification
- Overall residual risk analysis
- Risk vs. benefit analysis
- Final risk management review
If the device class is not absolutely finalized, an application to the FDA through the 510(g) protocol. The first four processes involve smaller study sizes and from the fifth step, it involves clinical trials of varying study sizes. Therefore, the overall average timespan of the device approval process can range anywhere between 7 months (for less invasive devices that have less than one-year follow-up clinical trial timepoints) to 14 months (for devices targeting complex diseases involving at least one-year follow-up regimes during clinical trials).
Meanwhile, under the EU MDR, Class I devices will be evaluated based on Annex IV and V of the EU MDR, and are exempted from conformity assessment by the NB for CE marking. Whereas, some Class I devices with medium risk and Class IIa devices may need to undergo Conformity Assessments based on Annex XI of the MDR (Part A). Class IIb and Class III devices need to have strong technical documentation of device type examinations, Conformity Verification, Product Verification, and extensive risk evaluation during the Conformity Assessments with the Notified Bodies, based on articles of Annex II, X, XI (Part A and B). If the Class IIb and III devices are implantable devices, the MDR designates them for further testing under the special provisions. Devices containing bioresorbable biomaterials undergo specific assessments by expert panels after the NBs provide their report.
With the MDR, compliance documentation will include reports on “Common Specifications” and “Harmonized Standards”, which means that medical device makers shall provide data to establish that the device is in conformity with the basic safety and performance requisites including a risk management system that ensures an acceptable risk-benefit ratio, electrical safety, mechanical security, software lifecycle processes i.e. verification and validation, and usable medical devices, specifically after minimizing risks due to lack of usability. The Technical Documentation protocol also includes reporting the need for future improvements in active implantation devices.
A note on MDR Documentation and CERs
The MDR specifies in detail the different aspects of documentation required by a sponsor starting from technical documents of preclinical and general safety testing, performance evaluation, conformity assessment documentation, CE marking conformity, EU Declaration of conformity, and the Information to be submitted regarding medical devices and their economic operators, registration documents, technical files, and the documentation necessary to be presented in the Clinical Evaluation Report (CER). The EU MDR specifies that reports on preliminary classification criteria, conformity assessment on type examination, procedures for custom-made devices, technical documentation regarding the quality management system, and correlation tables are presented.
There are elaborate requirements listed for Notified Bodies regarding how they will receive the clinical information during different phases. The MDR expects to include the data on medical devices that had no intended medical use before but are being listed in the MDR to be of medical use. Lastly, the MDR mandates manufacturers to undergo final audits of Technical Documentation, based on Annex IX. Since the role of the NB has been expanded, the last two years were assigned for Notified Bodies to be re-designated or re-qualified according to the new regulations.
Also read: How to hire a CER Writer for your medical device
Future implications for EU MDR
Noteworthily, among the drastic changes in the EU MDR, we have to remember that the MDD was a directive, which countries had to integrate into their national legislative policies. However, the MDR is a regulation that member states have to directly apply without any successive integration process into their national law. As with the earlier MDD, Conformity Assessments remain the major regulatory hurdles that manufacturers have to prepare for. The Conformity Assessments will be evaluated by the Notified Bodies, which are agencies designated by the member states of the EU, as was being followed under the MDD. According to the MDR, the functional significance of the Notified Bodies will be drastically revamped and in the future, it is predicted that fewer Notified Bodies will be retained, while the rest may lose their license.
Some agencies such as the BSI UK were assigned as Notified Bodies under the MDR recently. Going forward, the scope of BSI UK’s new MDR designation ranges from medical devices incorporating medicinal substances or nanomaterial to class III custom-made implantable devices. However, the future implications of NB designations and/or qualifications need to be watched closely, as post-BREXIT the NBs designated in the UK will no longer be part of the list of all NBs in the EU.
Overall, the EU MDR is a leap over the previously inadequate MDD. Moreover, since, active implantable devices–which were associated with quality and safety breaches in the past few years–will be undergoing higher levels of evaluation, the implementation of the MDR is anticipated to be binding. Effectively, the European Union may reach the par with the FDA in terms of 360° surveillance of clinical information of CE marked products immediately, as well as those of the past. However, the differences that may still come about will be understood more clearly in the future, when research pertaining to the gap analysis is undertaken by regulatory bodies.
Medical device regulatory compliance is a complex process, involving processes that need constant monitoring and maintenance. The EU MDR has made it even harder to bring a product into the Europe market. Working with an expert consultant helps save time and energy, while ensuring your medical device can be brought to (and stays in) the market successfully.