Harmonization in Plain Sight. Are FDA and CE Substantially Equivalent?
Medical device harmonization continues to struggle, with substantial differences between FDA and Europe continuing to be an obstacle. However, current changes in Europe and proposed changes in the US may change all that. “Substantially different” is starting to look like “substantially equivalent”.
The biggest obstacle to global harmonization of medical devices regulation has been the fundamental difference in approach of the USA, and in particular, its 510(k) program compared to the “Conformity Assessment” approach embodied in European and other “GHTF-aligned” jurisdictions.
In the US, the 510(k) process is based on substantial equivalence to an existing cleared device with the assumption that clinical performance follows technological and procedural equivalence. In Europe (and in Canada, Australia, Japan and elsewhere) the assessment is a first principles review of design verification testing plus clinical evidence, which may or may not include actual clinical trials depending on device risk class. Recent changes in Europe have effectively mandated clinical trials for all new Class III and implantable devices.
A recent FDA announcement foreshadowed a modernization of the 510(k) program. The agency envisages encouraging manufacturers to use only recent (modern) predicates in 510(k) filings, and also to make much greater reliance on up-classifications to PMA and of the de novo 510(k) process. And it’s these changes which provide the pathway to migrate FDA’s regulatory regime to one which will, to all intents and purposes, be equivalent to the European pathway.
That leaves auditing, where FDA uses 21 CFR 820 Quality Systems Regulations (QSR) and the rest of the world uses ISO 13485. But FDA has announced the intention to migrate to ISO 13485, and the MDSAP program is gaining traction as a regulatory audit program endorsed by most of the major international regulators. The one that hasn’t signed up to MDSAP is Europe – but that’s more a function of the IMDRF membership being between Competent Authorities – the European Notified Bodies are not IMDRF members. And Europe is also distracted right now with Notified body redesignation. Nonetheless, the actual European audits are almost identical in scope to the MDSAP model and most MDSAP auditors are also Notified Bodies – so efficiently combining Europe into an MDSAP program is certainly possible.
A key part of a 510(k) filing is the equivalence table comparing the new device to the predicate. So, let’s do a thought experiment, and prepare an equivalence table between FDA de novo and PMA processes and the European Conformity Assessment processes embodied in the new MDR.
| FDA | European MDR | Comments | |
| All Devices | |||
| Testing | Device testing against FDA consensus standards | Device testing against harmonized standards | Standards are mostly the same (although FDA may qualify the detail and also recognizes a wider range of both US and foreign national standards) |
| Registration | Registration and Listing with FDA | Registration and listing on EUDAMED | Equivalent requirements |
| GMP | Uses 21 CFR 820 (QSR) but will migrate to ISO 13485 in 2019. | Uses ISO 13485:2016 | Requirements equivalent – although there are substantial differences in audit practice which are expected to reduce. |
| Required for all Class II, III and for some Class I devices | Required for Class I(s)/(m), IIa and above (Class I exempt) | Same except for some very low risk devices | |
| Class I devices | |||
| Evidence | Must meet general controls for labelling and manufacture as well as postmarket complaints and | Must comply with General Safety and Performance Requirements | Some differences: US enforces GMP for some devices, Europe has the same Essential Requirements for design and manufacturer, but these requirements are rarely policed. Both are light touch regulation for low-risk products. |
| Review | No premarket regulatory review | No premarket regulatory review | Same |
| Class II (a/b) | 510(k) or De Novo | Conformity Assessment | |
| Design | 21 CFR 820.30 Design Controls | ISO 13485:2016 Clause 7.5 Design Controls | ISO/QSR Design controls are equivalent and FDA will move to ISO 13485. |
| Labelling | Review of Labelling/IFU and claims
| Review of Labelling/IFU and claims against General Safety and Performance Requirements
| Both require intended use and indications to be supported by device testing and clinical evidence. |
| Clinical Evidence | Mainly relies on substantial equivalence arguments.
| MEDDEV 2.7/1 v4 requires lower risk devices supported by clinical literature and substantial equivalence comparison to predicate devices. | Requirements substantially aligned but the definitions of predicates still differ (i.e. FDA cleared device vs. device which has substantial clinical data and history of safe use). |
| Review of direct clinical data in ~15% of traditional 510(k) and most de novo filings | Higher risk devices and new technologies must include direct clinical trial data | ||
| Class III | PMA review
| Conformity Assessment & Design Dossier Review | |
| Testing | Exhaustive review of design verification testing | Exhaustive review of design verification testing | Same |
| Clinical Evidence | Must be supported by primary clinical trial data | Must be supported by primary clinical trial data | Same |
Really not so different, right?
Well not quite. There remains the thorny problem of non-equivalence of classifications. Many Class III devices in Europe are Class II in the US where they can meet the lower requirements for 510(k) submissions.
But this evolving equivalence is being recognized internationally, where Australia’s TGA announced in August 2018 that they would accept FDA regulatory approvals as evidence for Australian registration of medical devices. TGA is also wise to the differences in classification – they will only accept PMA approvals to support Australian Class III devices.
The perceived barrier to harmonization is that the US doesn’t do conformity assessment. Yet the de novo process particularly, as well as PMA for Class III devices look very similar to MDR conformity assessment reviews. And the insistence on clinical trials for Class III devices in the MDR brings those reviews closer to a US PMA.
Really harmonization is right there in plain sight.
And maybe that’s the future, FDA’s 510(k) modernization program could be the first step in transitioning away from the “traditional” 510(k) model and adopting conformity assessment in all but name.
Now, all we need is for IMDRF to find a way to align device classifications between its members.
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