Public health scandals create outcries that often result in government legislative crackdowns. Such a case occurred in the wake of the Poly Implant Prothèse (PIP) breast implant scandal of 2010, in which a French manufacturer substituted unapproved industrial-grade silicone oil for approved medical-grade silicone.1 Almost 400,000 women received the PIP implants. Many of the implants made with industrial-grade silicone ruptured, causing serious illness and, in some cases, death.
In order to prevent similar catastrophes in the future, the European Commission in September 2012 proposed the addition of new medical device regulations to its existing medical devices directive (MDD).2 In April 2014, the European Parliament adopted a legislative resolution on the European Commission's amendment to update the existing directives.3
Some industry experts worry that these regulations will increase costs and impede the early access to new devices that patients in Europe currently enjoy relative to other parts of the world. Many manufacturers have not yet begun complying with the regulations; however, surprise audits are already occurring (see Unannounced Audits), and manufacturers that continue to wait will risk finding themselves unable to bring new products to market or to maintain certification on existing devices. On the other hand, manufacturers that find efficient ways to comply with emerging regulations will enjoy the benefits of public confidence, increased transparency, and abundant clinical data demonstrating the safety and efficacy of their products.
REGULATIONS IN PLACE
The new EU medical devices guidance documents (MEDDEVs)4 should be understood as supporting and clarifying existing directives. Therefore, according to a representative from Swiss Medic, the competent authority for medication and medical device manufacturers in Switzerland, notified bodies and competent authorities (for definition of these and other regulatory terms, see EU Regulatory Glossary) should already be working within the MEDDEVs.
The frequency of unannounced audits of device manufacturers in the European Union is increasing, according to comments made by European Commission staff in June 2014 after the Employment, Social Policy, and Consumer Affairs Council discussed a working document on the implementation of the new regulations so far.5
By April 2014, more than 40 notified bodies had finalized or were finalizing procedures, and most were launching trials or had carried out audits of device manufacturers, the report stated.
AT A GLANCE
• Stricter requirements are now in place for premarket and continuous postmarket assessments of all devices, including previously approved ones. Such initiatives include mandating manufacturers to conduct extensive clinical trials both before and after their medical devices hit the market, analyze safety and efficacy data from those trials, and make the data available to the public.
• Many manufacturers have not yet begun complying with the regulations; however, surprise audits are already occurring.
• One of the most important aspects of the new regulations is an expanded list of regulated devices, which now includes products such as IOLs, noncorrective contact lenses, aesthetic implants, software used in devices, and possibly certain standalone software.
COMMON QUESTIONS
Who must comply? One of the most important aspects of the new regulations is an expanded list of regulated devices, which now includes products such as IOLs, noncorrective contact lenses, aesthetic implants, software used in devices, and possibly certain standalone software. Under the new regulations, devices currently on the market may be reclassified as to their risk.6 In addition to manufacturers, importers and distributors must also comply with the regulations.
EU Regulatory Glossary
Competent Authority An organization that has the legally delegated or invested authority, capacity, or power to perform a designated function; in the case of the medical device industry, the national authority over medical devices (eg, in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency) is the competent authority.
Conformity Assessment Procedures followed by manufacturers to demonstrate that its devices meet the essential requirements of the MDD.
Medical Devices Directive This directive, instituted in 1993 and most recently revised in 2007, was intended to harmonize standards for medical devices in the European Union.
Notified Body An organization accredited by the national authority of an EU member state to carry out conformity assessment procedures.
What do the regulations entail? Stricter requirements for premarket and continuous postmarket assessments of all devices—including previously approved ones—are key parts of the new regulations. Manufacturers must now conduct extensive clinical trials both before and after their medical devices hit the market, analyze safety and efficacy data from those trials, and make the data available to the public. They must continually assess the risks, hazards, and performance of their devices, which includes sending analyzed data to relevant member states. The PIP scandal made it clear that regulators need an efficient way to identify unsafe devices on the market and quickly remove them.
According to Mark S. Talary, PhD, a senior research and development consultant at IROC Science, in the past, proof of safety and efficacy could consist of existing data from previously published studies. Now, however, manufacturers must show clinical data on their own devices. “In order to maintain certification, they will have to adhere to a formal process for following the product after it is on the market and providing ongoing safety and efficacy data to the notified bodies and competent authorities,” Dr. Talary said.
Previously approved products are also subject to these new regulations and can be pulled from the market for failure to comply. “Medical devices must be regularly recertified to maintain their CE Mark, which means all devices will be audited in light of the new regulations,” Dr. Talary explained.
The regulations also require that any new application for the conformity of a high-risk device received by a notified body must be referred to an expert committee.2 Then, if a valid scientific health question is raised, the committee can request that the notified body submit its assessment on the device for comments before any certification can be given.
Additionally, notified bodies now have greater powers and responsibilities, including the power to perform random unannounced factory audits; to require sample data for high-risk devices, such as IOLs, during inspections; to conduct physical or laboratory tests on devices at any time, before or after devices enter the market; and to demand more documentation and audits from companies before making an assessment.2
Clearer rights and responsibilities for manufacturers, authorized representatives, importers, and distributors have been or will be established as well. Each of these stakeholders must designate a person responsible for regulatory compliance who has the expertise to ensure that batch conformity and reporting obligations are fulfilled and that technical documents and declarations of conformity are created and updated. For example, a distributor of medical devices must assure itself of product conformity and be able to prove it on demand before distributing products in EU member states.
REGULATORY CHANGES To ENHANCE SAFETY
Investigations of high-risk medical devices. Before the dissemination of the new regulations, authorities were not obligated to carry out investigations of high-risk medical devices, even when well-designed studies identified problems with their safety or efficacy. Take intracranial stents, for example. In 2011, a randomized controlled trial showed that intracranial stents (implanted in cerebral vessels in combination with angioplasty to prevent strokes) did not in fact lower the risk of strokes in patients with symptomatic intracranial arterial stenosis.7 On the contrary, the number of strokes almost doubled, from 12.8% to 20% in the first year of the trial compared with medical management. In Germany, more than 3,500 patients were treated with stenting since it was approved.8 Meanwhile, the clinical trial of intracranial stenting stopped enrollment after 451 patients, due to a nearly threefold increased rate of early strokes in patients who received stents. In the current environment, such trial results will trigger EU authorities to launch investigations to ensure patient safety.
Unannounced Audits
(Taken directly from the European Commission website1)
1. Notified bodies should carry out unannounced audits at least once every third year. Notified bodies should increase the frequency of unannounced audits if the devices bear a high risk, if the devices of the type in question are frequently noncompliant or if specific information provides reasons to suspect non-conformities of the devices or of their manufacturer. The timing of the unannounced audits should be unpredictable. As a general principle, an unannounced audit should not take less than 1 day and should be executed by at least two auditors.
2. Notified bodies may, instead of or in addition to visiting the manufacturer, visit one of the premises of the manufacturer's critical subcontractors or crucial suppliers if this is likely to ensure more efficient control. This applies in particular if the main part of the design development, manufacturing, testing or another crucial process is located with the subcontractor or supplier.
3. Within the context of such unannounced audits, the notified bodies should check a recently produced adequate sample, preferably a device taken from the ongoing manufacturing process, for its conformity with the technical documentation and with legal requirements. The check of the conformity of the device should include the verification of the traceability of all critical components and materials and of the manufacturer's traceability system. The check should encompass a file review and, if necessary in order to establish the conformity, a test of the device.
To prepare the test, notified bodies should request from the manufacturer all the relevant technical documentation including previous test protocols and results. The test should be undertaken in accordance with the testing procedure defined by the manufacturer in the technical documentation that has to be validated by the notified body. The test may also be performed by the manufacturer, its critical subcontractor, or crucial supplier under observation of the notified body.
4. Notified bodies in charge of product assessment2 should, in addition to the steps foreseen in Sections 1, 2 and 3, sample devices belonging to at least three different device types and, where the manufacturer produces more than 99 device types, devices belonging to at least every hundredth type at the end of the production chain or in the manufacturer's warehouse with a view of testing the conformity of the device types. Variants containing a technical difference that might affect safety or performance of the device should be counted as a separate device type. Dimensional size variants should not be regarded as different types unless specific risks are linked to the dimension. These samples should be tested by the notified bodies or by qualified personnel under their observation on their own premises, or on the manufacturer's premises, or on the premises of the manufacturer's critical subcontractor or crucial supplier or in external laboratories. Sampling criteria and testing procedures should be defined in advance. In particular, if a sampling in the manufacturer's premises is not possible, notified bodies should take samples from the market, if necessary with support by the competent authorities, or should perform testing on a device installed at a customer location. To prepare the test, notified bodies should request from the manufacturer relevant technical documentation including final batch testing reports, previous test protocols and results.
5. Notified bodies in charge of verifying the quality system of the manufacturer3 should, in addition to the steps foreseen in Sections 1, 2 and 3, verify whether the manufacturing activity ongoing at the time of the unannounced audit is in line with the manufacturer's documentation relevant for the manufacturing activity and that both are in conformity with legal requirements. In addition, these notified bodies should check in more detail at least two critical processes such as design control, establishment of material specifications, purchasing and control of incoming material or components, assembling, sterilization, batch-release, packaging, or product quality control. Among the suitable critical processes, notified bodies should select one that has a high likelihood of nonconformity and one which is particularly safety relevant.
1. Recommendations. European Commission website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:253:0027:0035:EN:PDF. Accessed January 19, 2015.
2. According to Section 2(a) and Annex I to this recommendation.
3. According to Section 2(b) and Annex II to this recommendation.
Changed documentation requirements. The new regulations outline a scrutiny process that allows authorities to take a second look at a notified body's review of technical documentation prior to CE Mark approval.3 The scrutiny process will require notified bodies to prepare a summary report of the technical review for the medical device coordination group (MDCG) prior to granting the CE Mark to a high-risk device. The MDCG may request additional information and testing results, potentially delaying the submission process by several months and thus reducing the market advantage of launching products in Europe first, as opposed to other markets.
Manufacturers will also be required to update the format of technical files, declarations of conformity, and labeling. Manufacturers will also be required to more clearly disclose any residual risks associated with a device; these are risks that remain after standard risk-control measures stipulated in the MDD have been taken.9 Such risks might relate to the component materials of the device, period and nature of exposure (eg, whether the device is worn outside the body like a Holter heart monitor or implanted like an IOL), and the potential impact of device failure. This additional information must be included as warnings and precautions in the instructions for use and submitted to Eudamed, the European databank for medical devices.10 The purposes of these requirements are to strengthen market surveillance and transparency by providing competent authorities with fast access to information and to contribute to uniform application of the directives.
TIMETABLE FOR COMPLIANCE
Although the European Commission is still fine-tuning the larger legal framework, the new EU MEDDEVs are being enforced by, for example, surprise audits and loss of certification. Companies must implement the necessary systems for compliance as soon as possible to prevent problems and delays. n
1. Pips breast implant scandal: Regulator warned years earlier. May 15, 2012. The Telegraph. http://www.telegraph.co.uk/health/...../Pips-breast-implant-scandal-Regulator-warned-years-earlier.html. Accessed January 5, 2015.
2. Proposal for a regulation of the European Parliament and of the Council on Medical Devices. September 26, 2012. European Commission website. http://ec.europa.eu/health/medical-devices/files/revision_docs/proposal_2012_542_en.pdf. Accessed January 6, 2015.
3. European Parliament legislative resolution of 2 April 2014. European Parlimant website. http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-//EP//TEXT+TA+20140402+ITEMS+DOC+XML+V0//EN&language=EN#sdocta11. Accessed January 6, 2015.
4. Guidance MEDDEVs. European Commission website. http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm. Accessed January 5, 2015.
5. Commission Staff Working Document: Implementation of the joint plan for immediate actions under the existing medical devices legislation. European Commission website. http://ec.europa.eu/health/medical-devices/files/swd_pip_14_en.pdf. Accessed January 5, 2015.
6. Medical Devices: Guidance document - Classification of medical devices. June 2010. European Commission website. ec.europa.eu/health/medical-devices/files/meddev/2_4_1_rev_9_classification_en.pdf. Accessed January 6, 2015.
7. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003.
8. Common paper of the German National Associations of Statutory Health Insurance Funds. www.aok-bv.de/imperia/md/aokbv/politik/versicherte/thesenpapier_gross_0913_engl_1.pdf. Accessed January 6, 2015.
9. Guidelines on medical devices: Guidelines on clinical investigation: A guide for manufacturers and notified bodies. ec.europa.eu/health/medical-devices/files/meddev/2_7_4_en.pdf. Accessed January 6, 2015.
10. European Databank on Medical Devices - EUDAMED. European Commission website. http://ec.europa.eu/health/medical-devices/market-surveillance-vigilance/eudamed/index_en.htm. Accessed January 6, 2015.
Michael Smolinsky, PhD
- Senior Managing Editor at Ethis Communications, New York, New York
- msmolinsky@ethiscommunications.com
- Financial disclosure: None
