Evidence of clinical performance and safety of medical devices has been at the forefront of recent international regulatory reforms. The European system in particular has gone through several rounds of revision where at each stage the requirements for clinical information have been tightened. The 2007 revision of the Medical Device Directives made clear that clinical evidence was required for all classes of device. The current change from Directives to European Regulations will make direct clinical trials the default for Class III and Active Implant devices and again raise the bar for all other devices.
Two other regulators have been updating their requirements. China’s CFDA recently published Regulation 25 – a detailed update of Chinese Good Clinical Practice requirements which is the final phase of a complete revamp of Chinese clinical evidence regulations . In China the default is now a requirement for direct trials unless either the device is on a specific exemption list or a comparison can be made demonstrating substantial equivalence to a predicate approved in China. In Australia, the TGA has released a long awaited consultation draft of their Clinical Evidence Guidance.
Amongst all of this evolution and strengthening of the rules, there are emerging common practices which need to be understood to manage clinical evidence and device evaluations for those tackling international markets.
Direct Clinical Trials – the Gold Standard for High Risk Devices
First, for high risk devices (especially class III and active Implants) the default expectation of most regulators is now direct clinical trials. That’s certainly the case in Europe where the expectation is direct trials unless strong justification can be made otherwise. In China the default is now a requirement for direct trials unless either the device is on a specific exemption list or a comparison can be made demonstrating substantial equivalence to a predicate approved in China. TGA’s new draft guidance includes a lengthy section on specific requirements for high risk devices and makes it clear that direct clinical data are preferred – although the agency notably has stopped short of mandating clinical trials for any particular device.
Clinical Evidence Reports must be robust
The very variable quality of clinical evidence and the strengthening of regulations worldwide have led regulators to be far more specific about the approaches to literature or design based reports in lieu of direct clinical trials. In particular:
Literature reviews need to be robust. At a minimum that means :
- Clear search criteria and with written justifications for search terms and selection of databases
- Inclusion and Exclusion criteria for selection of papers form the search returns
- Objectivity – all relevant papers must be considered and reviewed – including those not supportive.
TGA has made it clear for some time that their expectation is that the literature review is not only robust and objective but that it has top be sufficiently well documented that it could be reproduced by the reviewer.
Regulators now expect clinical evidence reports to consider the postmarket history of the new device (if it has prior international approvals) as well as similar devices. Such data can come from the literature, from in-house customer feedback and clinical study reports as well as from public sources such as FDA’s MAUDE database and TGA’s IRIS scheme and the related DAEN databases. One of the considerations of any device design and assessment is a risk analysis where likely failures are documented and assessed in terms of both likelihood and severity. Postmarket data provide a source of semi-quantitative or quantitative data for risk estimation purposes as part of the ISO 14971 risk assessment. Regulators are now expecting to see such analyses with realistic estimates based on postmarket and literature data. In China, CFDA now expects to see a sophisticated review of the literature and other postmarket evidence – including meta analyses.
Predicate Devices 510(k) meets the CE mark meets the China FDA?
Hidden within the very different regulatory processes of Europe and The US FDA there’s always been an area of common ground – that is the direct comparison with similar or “predicate” devices. IN th eUS this has been notionally about demonstrating substantial equivalence, although anyone who’s prepared a 510(k) with consideration of clinical data has actually been dooing pretty much what’s also been expected in a European (or GHTF) style clinical evaluation report.
The China FDA have now taken this to a new level. The Chinese regulations now require a formal predicate equivalence comparison as part of clinical evaluation reports submitted in lieu of Clinical Trials. The CFDA has borrowed the 510(k) equivalence table concept and extended it – requiring more detailed information against a named predicate device. IF the device is high risk Class III, the the CFDA expects clinical equivalence arguments to be based on the primary clinical data of the predicate. Of course no-one is going to release their primary data to a competitor. So in effect this means that CFDA Clinical Evaluation Report submissions for high risk devices really only work in China if the applicant has another similar (e.g. earlier generation) device on which to base a predicate comparison. For lower risk devices CFDA accepts predicate comparisons based on published data – making the clinical evaluation process very similar to what’s involved in 510(k) submissions.
Know the Guidances
The US FDA has for many years published device specific guidance documents which include specific recommendations for clinical trial designs and expectations.
TGA’s draft Clinical Evidence Guidance goes down this path and includes a complete chapter on specific requirements for selected high risk devices including joint prostheses, stents, pulse generators including pacemakers, defibrillators and other nerve simulators, heart valves, and most topically – surgical meshes. China’s CFDA has published a range of guidance documents on similar high risk devices (e.g. on stents and hip joints) which set out quite specific expectations for trial designs and sizes. It’s important to understand early in the development process if there are specific expectations for markets of interest – know the guidances and be prepared to follow them unless you are prepared to…
Talk to the Regulator
Notwithstanding the wealth of regulation and guidance, as technology develops there are always going to be cases of new devices for which current approaches are simply not appropriate. In such circumstances it’s going to be essential to engage with the regulator and be prepared to present a case for a better way of doing things. There are formal process for pre-submission consultations, some of which (e.g. Japan PMDA’s Consultation program) are specifically geared to review of clinical protocols prior to conduct of clinical studies. Well planned pre-submission consultations can result in much greater certainty about what regulators will accept in terms of clinical trial design or other forms of evidence and dramatically ease the path to registration through shorter review times and much lower likelihood of rejection for inadequate clinical evidence.
In summary, for higher risk devices regulators are now much more likely to expect to see direct clinical data. For those seeking to achieve registration using literature based submissions, Clinical Evaluation Reports need to be robust, objective and consider all available information – including postmarket histories, predicate devices and other design and testing information.
Preparing a clinical submission? We can assist with the planning and drafting of Clinical Evaluation Reports for multiple markets including Europe, China and Australia. We can also assist in setting up pre-submission consultations with regulatory agencies. Contact us to discuss how we can support you, email email@example.com or call +61 2 9906 2984.