Medical Device Link.

REGULATORY OUTLOOK

Since the European single market activities of the late 1980s, three main medical device directives have passed into law in the countries that make up the European Union (EU). These New Approach directives regulate how devices may be placed on the market and identify postmarketing vigilance requirements. These three directives are as follows:

• Active Implantable Medical Devices Directive (AIMDD), 90/385/EEC.¹
• Medical Devices Directive (MDD), 93/42/EEC.²
• In Vitro Diagnostic Medical Devices Directive (IVDD), 98/79/EC.³

The two-digit numbers at the beginning of the directives indicate the year in which the text was published in the Official Journal of the European Communities (OJ); it can be concluded that there was a span of eight years between the first and the third. During this period, a number of the generic elements of the directives changed, so it was logical that at some stage in the directives' lives, their requirements should be aligned.

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The opportunity for alignment came with the review time scale included in the MDD, article 11, paragraph 4. It required the European Commission to review the operation of specific aspects of the directive five years from the date of entering into force. These aspects included four areas: adverse incident reporting, clinical investigations for Class I and Class IIa devices, design dossier examination by notified bodies, and combination products.

The MDD took effect June 15, 1998, and the review of its operation began in 2003, with the European Commission and member national competent authorities (NCAs) taking the opportunity to review all three directives at the same time.

This review resulted in a revising directive, 2007/47/EC, which was published in the OJ on September 21, 2007. ⁴ This directive makes no changes to the IVDD, but in many respects it brings the other two directives broadly into line with the IVDD.

This article will not cover the details of the four-year revision process, with its many disagreements and eventual compromises between the European Commission, European Parliament, and European Council. Suffice it to say that some areas, such as the reuse of single-use devices, are still not covered by the directives. In addition, to avoid repetition, only changes to the MDD will be covered in any detail. In general, the same changes apply to the AIMDD.

Table I. (click to enlarge) Major areas of the MDD amended by the revising directive 2007/47/EC.

Unfortunately, consolidated versions of the revised directives were not available at the time of writing, although these were promised by the European Commission before the end of 2007. Until they are available, interested parties will have to read the 35 pages and 141 amendments of the revising directive together with the current consolidated versions of the directives to understand all that has changed. The most significant amendment topics for manufacturers are indicated in Table I. These are explained in more detail below.

Definitions

The revising directive clarifies what constitutes software within the scope of the MDD. Software that is intended to be used specifically for diagnostic or therapeutic purposes will be subject to the directive's requirements. Recital (6) of 2007/47/EC amplifies this by stating that software for general purposes when used in a healthcare setting is not a medical device. The classification definitions in Annex IX have also been amended to include software as an active medical device.

Clinical data is defined as “the safety and/or performance information that is generated from the use of a device.” Such data may be sourced from clinical investigations of either the device itself or equivalent devices, published scientific data on equivalent devices, or from published or unpublished reports on other clinical experience of either the device or equivalent devices.

Device subcategory and generic device group are defined in the context of the extent of documentation that notified bodies (NBs) must, in the future, examine during quality management system audits. The definitions are virtually indistinguishable from each other (device subcategory means “a set of devices having common areas of intended use or common technology;” generic device group means “a set of devices having the same or similar intended uses or commonality of technology”). However, device subcategory applies specifically to Class IIa devices, whereas generic device group applies specifically to Class IIb devices. The quality system annexes have been amended to require NBs to assess the technical documentation for at least one representative sample for each device subcategory or generic device group to determine compliance with the directive.

Single-use device is defined as a device intended to be used once only for a single patient. The definition has been included because of concerns that regulation of the reuse of single-use devices within Europe is not universal and, in some cases, is contradictory. During development of the revising directive, arguments were presented for both control under the revised directive and for an outright Europe-wide ban. The European Commission has always presented the view that the directives apply only up to the point of putting a device into service, as defined. The control of reprocessed devices, unless marketed as fully refurbished under the refurbisher's name, is outside of the directives' scope and should, therefore, be left to the NCAs to decide. The European Parliament did not agree, however, and has required the Commission to develop proposals for the regulation of reprocessed single-use devices by September 2010. The Commission has already started this process by posting a public consultation questionnaire regarding reuse on its Web site, which received approximately 75 replies.

Two additional essential requirements have been included in the revising directive where single-use devices are concerned. However, these state that manufacturers must ensure that the indication of single use is consistent across the community, and that information on factors that could pose a risk if the device were to be reused. The requirements must be included in the instructions for use.

Inclusions and Exclusions

The revising directive confirms which types of devices are included or excluded from the scope of the MDD. Specifically, it addresses devices including or containing pharmaceuticals, human blood derivatives, blood products, tissues or cells of human origin, and tissues or cells of animal origin. It takes into account the expected publication of the Advanced Therapy Medicinal Products (ATMP) regulation before the end of 2007.

Two directives that were previously excluded from consideration by medical device manufacturers must now be taken into account.

The MDD made a demarcation between itself and the Personal Protective Equipment (PPE) Directive (89/686/EEC) by requiring the principal intended purpose of the product to be considered; for instance, whether a manufacturer primarily intends a surgical mask to protect the patient or the clinician. Directive 2007/47/EC amends the MDD by requiring manufacturers to fulfill the relevant basic health and safety requirements of the PPE Directive as well as the MDD requirements if the intended use is within the scope of both directives. Only one CE mark will be required, but if more than one NB has been involved in the assessment process, it is believed that both NB numbers will have to appear with the CE mark. This will hopefully be clarified by future guidance.

In addition, the original MDD allowed medical device manufacturers to consider only the essential requirements of that directive, even if the device included aspects that would otherwise fall within the scope of the Machinery Directive (recently revised and published as 2006/42/EC). The MDD revision, however, requires that: “Where the relevant hazard exists, devices which are also machinery within the meaning of Article 2(a) of Directive 2006/42/EC must also meet the essential health and safety requirements set out in Annex I of that Directive to the extent to which those essential health and safety requirements are more specific than the essential requirements set out in Annex I of this Directive.”

This is a controversial change, introduced by the Parliament without consultation with the medical device industry or support from the Commission. One industry association commented that this was “another example of intransparent policymaking.”

It may be helpful to include here an extract from the definition of machinery from Article 2(a) of Directive 2006/42/EC, to give an idea of the type of medical device that might now be captured by this new requirement:

• An assembly, fitted with or intended to be fitted with a drive system other than directly applied human or animal effort, consisting of linked parts or components, at least one of which moves, and which are joined together for a specific application.
• An assembly of linked parts or components, at least one of which moves and which are joined together, intended for lifting loads and whose only power source is directly applied human effort.

The interpretation by manufacturers, NBs, and NCAs of “more specific than the essential requirements set out in Annex I” will be interesting as time passes. It is hoped new guidance notes to be issued by the Commission before full implementation of the directive will provide clarification.

Custom-Made Devices

There are a number of changes to the requirements for custom-made devices, including the following:

• The custom-made statement required by Annex VIII for Classes IIa, IIb, and III devices must be made available to the particular patient for whom the device has been made.
• The patient may be identified on the statement by means of name, acronym, or numerical code.
• The statement must now include the name and address of the manufacturer.
• In the documentation that must be kept available for inspection by NCAs, the manufacturer must now include names and addresses of the manufacturing site(s).
• If the device is implantable, the documentation must be kept for at least 15 years instead of 5 years.
• Custom-made devices will in the future be subject to the vigilance requirements applicable to devices in serial production.
• Registration of custom-made devices in the European databank (EUDAMED) will no longer be required.

Article 7 Committee and the Comitology Procedure

Comitology, as used within the framework of European legislation, describes a process in which the Commission, when implementing EU law, has to consult special advisory committees. These committees are made up of experts from the EU countries.

Under the MDD, Article 7 referred to Council Decision 1999/468/EC, which has been amended by Decision 2006/512/EC. The amendment added a Regulatory Committee with Scrutiny (that is scrutiny by the European Parliament) to the existing provision for a Regulatory Committee. This has resulted in changes to a number of operational aspects of the directive at the Commission level. These changes are in relation to the future amendment of nonessential elements of the directive for which the Article 7 Committee is responsible. The areas affected by this revision that will require proposed amendments to be subject to scrutiny by the Parliament are as follows:

• Article 8­ÃƒÂƒÃ‚ƒÃ‚ƒÃ‚‚—safeguard clause—measures concerning withdrawal from the market of noncompliant devices.
• Article 9—classification—measures relating to adaptation of classification rules.
• Article 11—labeling—information supplied with devices and, in particular, future decisions on electronic labeling.
• Article 14—precautionary principle—particular health protection measures.
• Article 15—clinical investigations—future amendments to Annex X.
• Article 20—confidentiality—public information disclosures, particularly regarding Class IIb and Class III devices.

Although not directly affecting manufacturers, the introduction of this revised comitology procedure is important, because it allows the Commission to make proposals for further amendments to the European Parliament, without having to initiate a further revising directive. This procedure allows the directives to develop alongside future changes in device technology.

Conformity Assessment

Article 11, paragraph 11, previously required a five-year maximum validity of NB certificates issued for compliance with Annexes II (full quality assurance system) and III (EC-type examination). The revising text adds certificates issued against Annexes V (production quality assurance) and VI (product quality assurance) to this five-year maximum validity requirement.

Article 11 has also been extended by the addition of paragraph 14. Paragraph 14 explains that any future decisions relating to acceptable means of delivering the information to be provided by the manufacturer (Annex I, Section 13.1) (for instance, the use of electronic labeling), are implemented in accordance with Article 7, with European Parliament oversight.

Systems and Procedure Packs

The title of Article 12 has been amended to read “Particular procedure for systems and procedure packs and procedure for sterilization” to reflect the fact that the article covers the sterilization of procedure packs, as well as their assembly.

Paragraph 3 of this article, which specifically references sterilization of systems or procedure packs, originally required one of Annex IV, V, or VI to be followed. This has been amended to require either Annex II or Annex V for the aspects of the sterilization itself, so the full quality assurance route is now acceptable for organizations that perform such pack sterilization. This change will be generally welcomed.

Device Registration

Under the earlier wording of Article 14, NCAs were allowed, for Class IIb and Class III devices, to “request to be informed of all data allowing for identification of such devices together with the label and the instructions for use when such devices are put into service within their territory.” With the revision, this has been extended to include Class IIa and active implantable devices.

Device registration is one area of the directives' implementation in which subsidiarity, the ability of member states to make their own decisions on what to include in their national regulations transposing the directives, has already played a major role. Some NCAs require little or no information on devices for which there is NB involvement, whereas others have already implemented, or are now planning, comprehensive registration regimes.

Italy , for instance, has a dedicated online databank. It requires 55 questions to be answered for each device or device family being marketed in Italy , the upload of some elements of the technical file, and the use of an electronic signature SmartCard for validation of the data entry. Once reviewed and approved by the NCA, the manufacturer must also register to be able to sell devices to medical facilities within the Italian national health service. Payment of a €100 “repertorio” fee per device or device family is required.

The French NCA, AFSSAPS, has also launched a more detailed registration scheme, although it is voluntary at the moment. The scheme allows the NCA to sort devices on a hierarchical basis according to their degree of innovation. One of the 30 sections within the questionnaire that must be completed requires manufacturers to identify into which of six innovation levels their devices fall. Levels range from
“no innovation” to “major innovation.” In addition to answering the questions, manufacturers must also supply a photograph of the device, copies of the labeling and instructions for use, the declaration of conformity, a description of the technical operation when applicable, and the sales literature.

The revising directive paves the way for such comprehensive registration schemes to become more commonplace. It allows the nature of such data collection for Class IIb and Class III to be decided by the Article 7 Committee, with oversight from the European Parliament

Authorized Representative

Although the requirement for non-European manufacturers to designate an authorized representative (AR) was written into the IVDD, there was originally no such requirement in the AIMDD or MDD. This requirement has now been rationalized across all three directives. Non-European manufacturers may now have only one AR in the EU per device or device family. The requirement for non-European manufacturers to designate an AR applies equally to all classes of devices, including custom-made devices, systems, and procedure packs. With this change, Article 10, paragraph 3, has been amended so that ARs may now be involved with the NCA in any assessment of adverse incidents, in place of the manufacturer.

European Databank (EUDAMED)

A new paragraph 4 has been added to Article 14a. This paragraph is basically an ultimatum to the Commission from the Parliament, because of the Commission's slow progress in setting up an effective European databank. Paragraph 4 requires the Commission to either make the database functional within five years or propose alternatives. The requirement for registration with the databank is not effective until September 2012, but the revising directive requires additional information to be stored in the databank, including AR details and information on clinical investigations. As stated previously, information on custom-made devices will no longer be required.

Clinical Investigation

With the original MDD, there was a perceived a lack of clarity about which classes or types of devices need to have clinical data included in the technical file. In fact, it has always been the case that the technical files for all devices should include a clinical evaluation, but to emphasize this need, Annex X, section 1.1, has been amended to delete the words “in particular in the case of implantable devices and devices in Class III.”

In the case of devices intended for clinical investigations, the manufacturer, or its authorized representative, in accordance with the current MDD, must follow the procedure referred to in Annex VIII and notify the NCAs of the member states in which the investigations are to be conducted. This requirement has been slightly modified, inasmuch that this notification must be done by means of the “Annex VIII Statement” in the future.

The revising directive also requires that if an NCA refuses to approve or halts a clinical investigation, or requires a significant modification or temporary interruption to an investigation, this information must be communicated to the other NCAs and to the Commission. In addition, the manufacturer or its authorized representative must notify the relevant NCAs of the end of a clinical investigation, together with a justification in case the study has been terminated early. If the early termination is because of safety issues, the notification must be sent to all NCAs and to the Commission.

Notified Bodies

The changes made by the revising directive will mean additional work for NBs. They will have to inform their NCAs about all certificates issued, modified, supplemented, suspended, withdrawn, or refused; advise all other NBs about certificates refused, suspended, or withdrawn; and, on request, advise about certificates issued. They will also need to “make available, on request, all additional relevant information.”

The main additional responsibilities will be as a result of changes to the quality system annexes (II, V, and VI). For Class IIa devices, the NB must assess the technical documentation for at least one representative sample for each device subcategory. For Class IIb devices, the NB must provide technical documentation for at least one representative sample for each generic device group to confirm compliance with the directive.

In choosing the representative samples, the NB must take into account the novelty of the technology; similarities in design, technology, manufacturing, and sterilization methods; the device's intended use; and the results of any previous relevant assessments. The NB must also document its rationale for the samples taken and be prepared to justify this to its NCA. The European Notified Bodies Operations Group (NBOG) is set to produce a guidance document on this new aspect of quality system assessments.

As mentioned previously, the need for clinical evaluation of all devices, no matter what class, has been clarified. As a result, NBs will need to spend more time reviewing and assessing the applicability of the manufacturer's clinical data file. This requirement will lead some NBs to become involved with manufacturers at an earlier stage in the development process to review and agree on the clinical evaluation strategy, including whether clinical investigations will be necessary.

Confidentiality

With the wording of the original directive, there was confusion among some NCAs, NBs, and manufacturers over what information can and cannot be shared between NCAs and NBs. The revising directive includes a section identifying what information will not, in the future, be classified as confidential:

• Information on the registration of persons responsible for placing devices on the market in accordance with Article 14.
• Information intended for users sent out by the manufacturer, authorized representative, or distributor in relation to adverse incidents.
• Information contained in certificates issued, modified, supplemented, suspended, or withdrawn.

Annex I

Several amendments have been made to the essential requirements (ERs). The most significant amendments are discussed below.

ER 1 has been extended to require manufacturers to take into account the ergonomic features of the design (to minimize the probability of use error), in addition to the technical knowledge, experience, education, training, and, where applicable, the medical and physical conditions of intended users.

Again reinforcing the need for all devices to undergo clinical evaluation, ER 6a has been added, requiring that demonstration of conformity with the ERs must include a clinical evaluation in accordance with Annex X. As a result, ER 14, which some interpreted to apply primarily to Class III, implantable, and long-term invasive devices, has been deleted.

Although the wording of ER 7.4 has been substantially amended and extended, nothing has changed significantly in terms of what a manufacturer has to do if its device incorporates either a medicinal product or a human blood derivative. There is, however, a new requirement for a manufacturer's NB to verify the usefulness of the substance as part of the medical device, taking into account the intended purpose of the device. It also requires NBs to seek a scientific opinion from one of the NCAs or the European Medicines Agency (EMEA) on the quality and safety of the substance, including the clinical benefit and risk profile.

In addition, should changes occur to an ancillary substance incorporated into a device, in particular with regard to its manufacturing process, the manufacturer must inform its NB, which must consult the relevant medicines' competent authority involved in the initial assessment, to confirm that the quality and safety of the ancillary substance are maintained.

ER 7.5 has also been extended to cover the topic of substances that are carcinogenic, mutagenic, or toxic to reproduction (CMR). Specifically, it states that if phthalates that are CMR category 1 or 2 (according to Annex I, Directive 67/548/EEC) are contained in a device, then the labeling must identify it as a device containing phthalates.

Also, if the intended use of the device includes the treatment of children, pregnant women, or nursing mothers, then the manufacturer must provide a “specific justification” for phthalates' use with these patients, together with information on residual risks and precautionary measures in the labeling.

A new ER 12.1a is included, covering devices that incorporate software or that are stand-alone medical software. In such cases, the software must be validated “according to the state of the art taking into account the principles of development life cycle, risk management, validation, and verification”.

ER 13.3 (a) had been amended to make it clear that the name and address of the authorized representative must be included on the label, and ER 13.3 (f) has been replaced by the requirement for single-use devices to be marked, and for such a marking to be consistent across the EU.

ER 13.6 (o) now requires the details of any human blood derivatives in the device to be included in the instructions for use, in addition to the details of any medicinal substances.

Finally in Annex I, a new ER 13.6 (q) has been added to require the instructions for use to include the date of issue or a revision reference.

Annex II

There are six major changes to Annex II.

The declaration of conformity must now be “clearly identified by means of product name, product code, or other unambiguous reference,” and it must also cover “one or more medical devices manufactured,” rather than “a given number.”

A third indent is added to section 3.2 (b), requiring the application from a manufacturer to an NB to identify the specific methods of monitoring the operation of its quality system. In particular, that includes the type and extent of control applied to a third party when the design, manufacture, or final inspection and testing, or elements thereof, is carried out by a third party.

Annex II, section 4.3, has been amended to require the relevant competent authority or EMEA to give its opinion on devices containing medicinal products or human blood derivatives within 210 days.

Section 6.1 has been amended to require technical documentation concerning implantable devices to be kept for a minimum of 15 years after the last product has been manufactured.

Annexes III–VI

Equally, in Annex III, EC-type examination certificates for implantable devices and their additions must be kept for the same period of time.

As mentioned previously, section 7 of Annex II has also been amended to include additional representative sample assessment requirements by the NB for Class IIa and Class IIb devices.

When applicable, the same changes apply to the other quality system annexes, V and VI.

Annex VII

In section 3 of Annex VII, the seventh indent has been replaced by three indents. The seventh indent previously required “the test reports and, where appropriate, clinical data in accordance with Annex X” to be included in the technical documentation. It has been replaced by the following three indents:

• The solutions adopted as referred to Annex I section 1 second paragraph [ergonomic features].
• The preclinical evaluation.
• The clinical evaluation in accordance with Annex X.

Sections 5 and 6.1 have been amended to add Annex II to Annexes IV, V, or VI, thereby allowing manufacturers of Class I sterile or measuring devices to be able to use the full quality assurance route to demonstrate compliance with those particular aspects of the device.

Annex VIII

More detail has been added concerning the documentation to be maintained for a device undergoing clinical investigation. The list in Section 2.2 has five new indents as follows:

• The investigator's brochure.
• The confirmation of insurance of subjects.
• The documents used to obtain informed consent.
• A statement indicating whether the device incorporates, as an integral part, a substance or human blood derivative referred to in section 7.4 of Annex I.
• A statement indicating whether the device is manufactured utilizing tissues of animal origin as referred to in Directive 2003/32/EC.

Changes to the requirements for custom-made devices have been described earlier in this article.

Annex IX

Some minor changes have been made to the classification rules. Those changes include stand-alone software being considered as an active medical device, and the definition of the central circulatory system being extended by the addition of the aorta arcus and the aorta descendens to the bifurcatio aortae.

In addition, the definition of continuous use has been clarified. The revising directive explains that “in calculating the duration referred to in Section 1.1 of Chapter I, continuous use means an uninterrupted actual use of the device for the intended purpose. However, where usage of a device is discontinued in order for the device to be replaced immediately by the same or an identical device, this shall be considered an extension of the continuous use of the device.”

The second paragraph of rule 15 has been extended to place devices intended specifically to be used for disinfecting invasive devices, such as endoscope washer-disinfectors, into Class IIb.

Certain devices have already been reclassified as Class III by Directives 2003/12/EC of February 3, 2003 and 2005/50/EC of August 11, 2005 (effective from September 1, 2003, and September 1, 2007, respectively). These devices include breast implants and hip, knee, and shoulder joint replacements.

Annex X

The clinical evaluation annex of the directive will also be amended by 2007/47/EC to clarify that clinical data are required for all device classes. This evaluation of these data must in the future follow a defined and methodologically sound procedure.

The procedure must be based on at least one the following criteria:

• A critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics, and intended purpose of the device, where there is demonstration of equivalence of the device to the device to which the data relate, and the data adequately demonstrate compliance with the relevant essential requirements.
• A critical evaluation of the results of all clinical investigations made.
• A critical evaluation of the combined clinical data provided in the two criteria listed above.

In the future, the clinical evaluation must also be updated as a result of postmarket surveillance.

In addition, for implantable devices and devices in Class III, clinical investigations have to be performed unless it is duly justified to rely on existing clinical data. For all devices, where demonstration of conformity based on clinical data is not deemed appropriate, an adequate justification for such an exclusion has to be based on risk management, considering the “specifics of the device/body interaction, the clinical performances intended and the claims of the manufacturer.”

Finally, all serious adverse incidents that occur during a clinical investigation must be reported immediately to the NCAs in the member states where the study is taking place.

Transposition and Future Plans

The revising directive requires member states to publish the national laws implementing the revisions by December 21, 2008, with full application of those revised regulations by March 21, 2010.

It would be comforting to think that with these amendments, the European device regulatory picture would be stable for a significant period, but this is unlikely for a number of reasons. First, the European Commission is in the final stages of developing a regulation to implement revisions to the underlying structure of the New Approach directives. The device directives, along with around 20 other sectoral directives, are part of this structure. High on the priority list for these amendments are improvements in the consistency and quality of work performed by conformity assessment bodies, as well as improved market surveillance. Finalization of the regulation is expected during the first half of 2008, following which a review of how the changes affect the device directives will have to be completed.

In addition, in 2005, the medical device unit within the Commission was charged to begin a review in 2008 of the MDD and AIMDD, together with the directive on human blood and blood derivatives, 2000/70/EC. This review is aimed at simplifying the regulations to make the market more accessible, especially to small companies. The potential result may be that these directives are combined into a single piece of legislation.

With the soon-to-be-implemented regulation on advanced therapy medicinal products (ATMP), the Commission must consider whether the full set of medical device directives and regulations should be combined into a single legislative package. But, given the ever-changing technological and political environments, it is probable that further changes to the regulatory requirements would be made at the same time. There is also the question of how to address medical products that currently fall outside of current and planned legislation. These include products that could be considered medical devices except that they contain human stem cells or contain or are made from viable tissues or cells of animal origin. Currently, these types of products are covered only by a variety of national regulations.

Conclusion

Although the exact nature of future legislation for medical devices in Europe is difficult to predict, it is safe to say that further changes are likely. The only wish from industry is that the inclusion of a hint of harmonization in 2007/47/EC will pave the way for greater international cooperation and harmonization, rather than the development of more regional requirements. Tucked away in a new article (Article 20a) in the MDD, it says: “Without prejudice to the provisions of this Directive, cooperation may be part of initiatives developed at an international level.” The Commission had already organized and chaired a workshop on the need for harmonized requirements at the 11th Conference of the Global Harmonization Task Force (GHTF) in Washington , DC in October 2007. This new article may be a sign that, after 15 years, the importance of GHTF for the future of the global medical device industry is, at long last, being taken seriously.

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