MDD Regulations: What I Wish I Had Known

Having worked in medical device research and development for over 20 years, I have contributed to many regulatory submissions for both the U.S. and European Union (EU) markets. However, now, as an EU Notified Body technical reviewer, I’ve found that there are many things I wish I had known previously to make the process more efficient.

Today’s market and regulatory environment is dramatically changing on a global scale, and success requires intense technical and regulatory preparation, knowledgeable business partners and the willingness and ability to adapt to change. Fewer people are being asked to do more in less time, especially in the startup environment, and regulatory expertise is often specific to local regulations or is contracted outside the manufacturer.

Obtaining CE marking that allows market access to the 30 countries of the European Economic Area (EEA) can be a daunting task for a non-EU medical device manufacturer. However, guidance is available as long as a few basic aspects are understood.

Unlike the U.S., where FDA is responsible for granting device clearance or approval and postmarket enforcement, multiple institutions share this responsibility in Europe. Each of the 27 EU countries or member states (MS) transposes the Medical Device Directive 93/42/EEC (MDD) into law, and interpretations vary slightly. The EU Commission, which sits in Brussels, ensures that each of the national laws align with the MDD.

Each MS also has its own regulating body or Competent Authority (CA) that, among other functions, is responsible for approving clinical investigation plans, reviewing and approving risk analyses for devices containing animal tissue, monitoring vigilance activities and conducting postmarket enforcement. These bodies also designate and oversee other institutions such as Notified Bodies (NB) that are responsible for device and quality system certification. In addition, a European Community Representative (EC Rep) must be used by non-EU manufacturers to represent them in the EC to monitor postmarket vigilance. They also are responsible for registering EU class I devices with the CA.

A myth commonly held by U.S. manufacturers, and one that was recently presented by a manufacturer at a U.S. regulatory conference, is that regulatory clearance in the U.S. is a gateway to CE marking in the EU. While many requirements overlap, previous regulatory clearance plays no part in a certification decision. Medical devices in the EU are governed by the MDD and it is to this that all certifications are judged.

Recent changes to the MDD to incorporate the 2007/47/EC directive requirements (M5 version) went into effect on March 21, 2010. All new and existing devices must now comply with this version of the MDD, as the grace period for compliance is over. Amid its many requirements, the MDD defines device classifications (Annex IX), possible routes to certification (Annexes II – VII) and specific requirements known as Essential Requirements (ERs) found in Annex I to which conformance must be demonstrated for certification.

Classification of EU devices is generally based on the device risk level and consideration of where and how long the devices are to be used. One point often missed is that if several rules apply to the device, the strictest rules resulting in the higher classification prevail.

It is generally known that ISO Certification is required to sell medical devices in the EU, but misunderstanding persists on the differences between ISO 9001 (Quality Management Systems – Requirements), ISO 13485 (Medical Devices – Quality Management System – Requirements for Regulatory Purposes) and the CE certificates from Annex II – Annex VI. As the legal manufacturer, there is a decision on which route of conformity to choose for each classification of device.

For the lowest risk devices, self certification under Annex VII, for which no physical certificate is issued by the NB, is acceptable. For medium and moderate risk devices, certification for the quality system is acceptable. For the highest risk devices, certifications for the product and quality system are necessary.

A product specific certificate on its own is not enough. The scope of a quality system certificate is very important and should be considered carefully. It is imperative that the manufacturer ensure that the new product falls under the scope of the Annex II – Annex VI certificate before any new product is placed on the market in the EU. If unsure, this should be discussed with the NB, as scope extension may be necessary prior to adding the new devices.

Many legal manufacturers purchase aspects of the device technology or utilize subcontractors for significant portions of the design, testing or manufacturing.

Since the legal manufacturer is ultimately responsible for the device being placed on the market, it is critical that sufficient detail about the subcontractor’s work is known in order to address the ERs.

Regardless of whether the contributing party has obtained regulatory clearance, it is still the responsibility of the legal manufacturer to ensure compliance with the MDD. In addition, if a significant subcontractor does not hold an ISO 13485 Certificate from an EU/EEA NB, then an audit of that subcontractor may be required prior to Annex II – Annex VI certification. An ISO 9001 Certificate may not be sufficient.

NB practices may vary, so the legal manufacturer should discuss this with their NB prior to seeking certification. The manufacturer can verify if the body that issued the ISO 13485 certificate is an NB (or their affiliate) by reviewing the Nando (New Approach Notified and Designated Organizations) Information System data in the European Commission website  .

Article 5 of the MDD states that compliance with applicable ERs can be presumed if conformity with Harmonized Standards can be demonstrated. Knowing what is harmonized, however, is not always straightforward. One key resource is found in the Medical Device information online. This site identifies harmonized standards, whether they supersede another standard, and the date after which the presumption of conformity ceases. However, this site is not updated in real time and there may be standards (or versions) that are harmonized and yet are not listed.

Once the standard is published, however, review of the standard itself should clarify whether it is harmonized. Harmonized standards are considered horizontal if they apply broadly across devices or vertical if they apply only to a subgroup of devices, but all contain an Annex (Z) that describes the scope of ERs for which compliance can be presumed if conformity is met. While conformity with harmonized standards is not required to demonstrate compliance with the ERs, ER compliance justifications must be provided for solutions when relevant harmonized standard sections are not applied in full.

One of the biggest differences between MDD and U.S. FDA regulations is the requirement that, regardless of device classification, conformity with the ERs must include a risk appropriate Clinical Evaluation Report (CER) on the subject device or equivalent devices that is conducted by an individual with appropriate qualifications to evaluate the technology, research methodology and clinical diagnosis/management. For implantable and EU Class III devices, a clinical investigation is also required unless duly justified to rely on existing clinical data.

Many manufacturers mistakenly interpret this requirement to mean that only a literature review and predicate device substantial equivalence (similar to what is required in a US 510[k]) must be demonstrated. Four documents (EN ISO 14155-1, GHTF N2R8, MEDDEV 2.7.1 and MEDDEV 2.12-2) all discuss what is required to fulfill this requirement and detail multiple parameters that are to be included in the CER.

Before any clinical data is even considered as being applicable, equivalence between the subject and comparable devices must be demonstrated based on similarity of clinical, technical and biological parameters with special attention to the performance, principles of operation, and materials. If differences are identified, an assessment must be documented to demonstrate the significance these differences might have on safety and performance.

Assuming equivalence can be demonstrated, the clinical data must also show that the device safety and performance is consistent with state of the art. It is not sufficient to be equivalent to a marginally performing device if state of the art performance is significantly better. For devices containing or utilizing animal tissue (per Directive 2003/32/EC), additional clinical benefit must be demonstrated beyond synthetic or lower risk animal devices as well as demonstrating acceptable risk. Short- or medium-term (relative to intended device lifetime) clinical data may be sufficient to justify not performing a clinical investigation, but may not be sufficient to warrant not performing Postmarket Clinical Follow-up (PMCF).

Annex X of the MDD requires that the clinical evaluation and its documentation must be actively updated with data obtained from the postmarket surveillance (PMS). Hazards identified during PMS must also be actively compared to those identified in the risk management file, which must be updated if new hazards are identified or previous assumptions are found to be no longer valid. The linkage between risk management and PMS is fundamental to continued device certification and is frequently missed.

Even though the CER is a required element for certification, completion is often seen only as a regulatory hurdle and left to the end of the development cycle.

However, if this is done, there is no opportunity for the CER to influence the design of the device, and certification could be delayed in order to address emerging findings from similar devices impacting clinical safety or performance.

Reliance on regulatory generalists or technical specialists to prepare for EU certifications may be costly in time and money if they have not been formally trained in EU Regulations. I know I wish I had known them then. It is critical to invest in business partners who are knowledgeable in these regulations (for instance, consultants, NBs, EC Reps, etc.), who can deliver predictable and timely services to keep the manufacturer informed and aid them in ensuring that the devices meet the ever-changing regulations. The cost of unsafe or underperforming devices is far greater than the benefit of a quick certification.

Watch for more articles from the British Standards Institution in future issues of BONEZONE. Would you like to suggest specific topics for coverage? Please contact Julie Vetalice at 440.543.2101 or julie@orthoworld.com.

Laurel Macomber, M.S., PMP, is a Product Expert at the EU Notified Body, British Standards Institution (BSI), and has over 20 years of experience in medical device R&D, program management and quality systems development for both large and small firms; working on orthopaedic, neurosurgical, cardiovascular and spinal products. Contact Laurel to learn more at 571-294-6538, Laurel.Macomber@BSIGroup.com or online. 

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