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European Pharmaceutical Contractor

Spot the Difference

While the quality standards for Europe and the US are closely aligned, regulatory differences continue to complicate the development of medical devices programmes located on both sides of the Atlantic.

A medical device is usually understood as a therapeutic or diagnostic principle for use in human beings, which fulfils its purpose by physical rather than biological action. As opposed to pharmaceuticals, the standards, data requirements and procedures for marketing authorisation of medical devices vary greatly between different legislations, despite the fact that a Global Harmonization Task Force has been active for almost 20 years (1,2).

Clinical data are a requirement for market authorisation of a medical device regardless of the jurisdiction. In terms of terminology, the US regulations describe clinical trials for both medicines and medical devices as ‘clinical studies’. European terminology differentiates between ‘clinical studies’ for medicinal products and ‘clinical investigations’ for medical devices, which is also the terminology used in the international norm ISO 14155 (2011). In this article we will use the two terms interchangeably. Note that in the context of medical device regulations the term ‘Europe’ encompasses all 27 European Union countries plus Switzerland, Liechtenstein, Iceland, Norway and Turkey.

Principle Regulatory Differences between the US and Europe

In Europe, market access is achieved through a process of selfcertification by the medical device manufacturer – a process which is carried out in cooperation with notified bodies and under supervision of competent authorities. The notified bodies assess the conformity to essential requirements relevant to EU directives and to applicable standards. The notified bodies not only assess the quality system and documentation, but also offer assistance in the development process.

In contrast, the US regulations foresee for most types of devices a more or less extensive process of authorisation by the regulatory authority. One of the most common processes – the so-called 510(k) procedure – is a premarket submission made to the US Food and Drug Administration (FDA) to demonstrate that the device to be marketed is at least as safe and effective as a legally marketed device (3,4). The different medical device classification systems used in Europe and the US make matters further intransparent (2). Although both systems are risk-based, the applied logic is different. This is especially relevant in the context of clinical investigations as the risk class is one of the critical factors for deciding whether a clinical investigation will be required at all. The situation may arise that for marketing authorisation of one and the same device, a clinical investigation may be required in one but not in the other legislation.

Recent Developments

As is described elsewhere in this journal, significant changes have recently occurred in Europe with respect to clinical evaluation and investigation. Briefly, the newly amended European Directives on Active Implantable Medical Devices and Medical Devices introduced stringent rules for clinical data evaluation and investigation, and the new ISO Norm 14155 (2011) set a new standard for the conduct of clinical investigations (5,6). The new standard gives detailed guidance on how to conduct clinical investigations and is the declared good clinical practice standard for medical devices.

The FDA have been reviewing the procedures for medical device market authorisation and are pondering additional risk classes. Also, they consider adopting the norm ISO 14155 (2011) as the good clinical practice standard for medical device studies.

Clinical Evaluation

In the context of a development programme, the manufacturer in Europe is required to evaluate whether a clinical investigation is needed to support the claims for safety and performance of the respective medical device. This is done in the process of clinical evaluation, which may either be a critical evaluation of the relevant literature, a critical evaluation of the results of all clinical investigations, or a combination thereof (14). Clinical investigations are called for if the available literature data are not considered sufficient to support the claims for safety and performance of the respective medical device, regardless of its class. For implantable devices and devices in class III, a clinical investigation is usually required (6). A clinical evaluation is not a one-time event, but a continuous process during the entire life cycle of a product (15). The clinical evaluation report is an integrated part of the technical file or design dossier, respectively, of the product.

No structured clinical evaluation is foreseen by the US legislation, and the general rule effective in Europe that all devices must undergo a clinical evaluation does not apply. Nevertheless, some level of clinical information must be provided with a 510(k) notification, namely data gained from clinical experience in humans with the predicate device. Clinical studies are required for some devices under Special Controls (class II), even when following the 510(k) route, and for most class III devices which require premarket approval. Authorised devices may need to be clinically evaluated when they are being modified or applied with a new intended use. Which route to market application has been followed for a particular device is published by the FDA in the medical device classification database, where substantially equivalent devices are also specified (16). Nevertheless, it is highly recommended to seek the FDA’s advice prior to starting clinical development in order to ascertain that the chosen route to marketing authorisation and the clinical data sets to be obtained are in accordance with FDA’s expectations. During the pre-investigational device exemption (IDE) process, FDA input for the clinical study protocol can be obtained.

Clinical Investigation

Clinical investigation of medical devices under the US regulations must obey similar rules when compared to pharmaceutical studies. In contrast, the European regulations for medical device studies are different in relevant aspects from the ones for pharmaceutical studies. Table 1 lists some of the most critical issues manufacturers and, if applicable, contract service providers need to be aware of when performing medical device investigations (17).



Conclusion

Major differences in approaches remain between US and EU regulations, and can be broken down into five main areas. First, in terms of device classification, the schemes between the US and Europe with the diverging requirement for clinical studies may result in a clinical investigation being required for a particular device in one legislation, but not in the other.

Secondly, in terms of good clinical practice (GCP), the required GCP standards for performing medical device studies in the US and Europe are very similar, but are not identical. Differences in essential documents and their contents, terminology and applicable laws need to be taken into account.

Thirdly, the objective of a European clinical investigation is to demonstrate safety and performance – such as conformity with claims – of the investigational medical device within the scope of the intended use. In contrast, the US legislation (21 CFR 812) asks for the evaluation of safety and effectiveness, which in addition to conformity with label claims, includes an aspect of clinical benefit or efficacy.

Fourthly, in terms of SAE/ UADE recording and reporting requirements, the European requirements are more demanding. Namely, harm caused not only to study subjects but to also bystanders must be monitored, and all SAE need to be reported to all authorities. In contrast, the US requires all unanticipated adverse device effects to be reported, regardless whether serious or not.

Finally, thinking about the benefit/risk assessment, the European guidelines and standards are very detailed in how to perform a risk analysis.The risks and benefits to be evaluated are largely comparable in both legislations. However, in the US the benefits must outweigh the risks for a clinical study to be justified, whereas in Europe the benefits must merely balance the risks.

The overall quality standard required for medical devise investigations in Europe and the US is virtually identical. Nevertheless, as outlined above, there are important differences between the US and European regulations which must be addressed when designing a combined US-European development programme for a medical device.

References

  1. GHTF created 1992 by European Union, European Free Trade Association, Turkey, Australia, US, Canada, Japan; www.ghtf.org/documents/sg1/sg1n29r162005.pdf
  2. Journal for Clinical Studies 3(2): pp18-23, 2011
  3. www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/
    DeviceApprovalsandClearances/510kClearances/default.htm
  4. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
    PremarketSubmissions/PremarketNotification510k/default.htm
  5. Directive 90/385/EEC, Annex VII
  6. Directive 93/42/EEC, Annex X
  7. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm
  8. www.wma.net/es/30publications/10policies/b3/17c.pdf
  9. www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
    Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf
  10. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
    InvestigationalDeviceExemptionIDE/ucm046722.htm
  11. 21 CRF 812.150 (a)(1)
  12. 21 CFR 812.150 (b)(1)
  13. MEDDEV 2.7/4, MEDDEV. 2.7.1 Rev.3, ISO 14155(2011)
  14. http://ec.europa.eu/consumers/sectors/medicaldevices/files/meddev/2_7_1rev_3_en.pdf
  15. http://ec.europa.eu/consumers/sectors/medicaldevices/files/meddev/2_12_1-rev_6-12-2009_en.pdf
  16. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm
  17. Journal for Clinical Studies 3(3): pp16-22, 2011

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Georg A Mathis is a doctor of Veterinary Medicine with a PhD in pharmacology. He obtained an MBA from the State University of New York at Albany and the GSBA Zurich in Switzerland. After his medical practice, he spent 10 years in medical research. In the past 20 years he has been active in various sectors of the healthcare industry, mostly in executive positions. He was Medical Adviser at Ciba Vision Ophthalmics, Managing Director of Sana Care, a Swiss HMO and CEO of Sucampo Pharma. He is currently Managing Director of Appletree AG, a CRO based in Europe, which is specialised in clinical research in ophthalmology and medical devices.

Annick Toggenburger is a biology graduate with a PhD in Technical Sciences. She has more than 10 years of experience in clinical trials in the medical device area, as well as in the pharmaceutical sector. She joined Appletree AG in 2009 where she continues to manage clinical trials in addition to her role as Medical Writer.

Rolf Marugg has a BSc in Information Sciences. He has been at Appletree since 2009 as Head of Drug Regulatory Affairs and has experience with the Regulatory Authorities and Ethics Committees submission and reporting for studies with drugs and medical devices in UK, Central and Eastern Europe.
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