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Is it now easier in the United States than in Europe?

By Mark S. Talary, PhD, and Yijun Huang, PhD

Bringing an Ophthalmic Device to Market

European doctors and their patients have frequently had access to new technologies before their American counterparts. In large part, this has been due to what

was perceived as a saner and simpler regulatory process in the European Union than in the United States. But the EU regulatory process is changing, and this may have long-term repercussions for EU surgeons, patients, and investors.

Ignorance of regulatory pathways can scuttle the best-made plans for bringing innovative technologies to market. Technical excellence alone is insufficient to meet the challenge of launching a medical device; companies also need first-class regulatory and quality-control expertise. Although that is true around the globe, it has often been said that the regulatory process is more rational in the European Union than in the United States. But is this true?

Companies have generally found the process of launching new medical devices in the United States more challenging than in the European Union. However, that may be chang-ing because of tightened EU regulations for the approval and certification of medical devices with the European Union’s new Medical Devices Directive (MDD).

CHANGING LANDSCAPEHistorically, medical device companies have criticized the

US Food and Drug Administration (FDA) for stifling inno-vation through inconsistent regulation and slow approval processes. Challenges in the US regulatory environment have sometimes prompted investors to shift funds overseas—often to Europe, where the regulatory process has been less bureaucratic, more efficient, and more predictable.

The FDA has required device makers to provide evi-dence of both the safety and efficacy of a device, whereas the CE Mark has required only proof of safety and proof

Although this column usually deals with medicolegal and regulatory issues pertaining to the United States, it may be useful to consider a global view of issues affecting ophthalmology. The following article highlights some important regulatory changes that will affect products coming to market in Europe. It is often true that the innovation cycle in the United States is arduous and fraught with risk; however, as the authors point out, the process of moving an idea from bench to bedside on the other side of the pond is equally challenging.

THE ROAD AHEAD

1. There are significant inconsistencies in policies among the three directorates-general that oversee the device approval process: the directorates of Communications Networks, Content, and Technology; of Health and Consumers; and of Justice. These inconsistencies are leading to conflicting policies that have a negative impact on innovation.

2. Leaving the classification of each medical device to each member state impedes the goal of EU harmonization.

3. Recent discussions on whether software applications should be considered parts of medical devices, and regu-lated as such, further breaks apart what should ideally be a unified decision-making process for notified bodies.

4. Although the European Union continues to make innovation-friendly statements, inconsistencies in cur-rent policy make the job of navigating the EU regulatory process an impediment to medical device innovation.

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that the device performs in a manner consistent with the manufacturer’s intended use.

Despite any criticisms, the FDA process is not without an upside for industry. Once a device receives FDA clearance, companies can start marketing their product across the entire country. Furthermore, reimbursement in the United States, such as through Medicare, is more consistent than in the European Union, where each member state may require its own form of proof of efficacy before granting reimbursement. Even with a CE Mark, companies have no guarantee that use of a given device will be reimbursable in any given country.

THE FDA ROUTEIn order to have a medical device approved in the

United States, the device must first be classified. Class 1 includes low-risk products such as bandages and sunglasses. Class 2 includes products involving medium risk, such as bone-fixing screws. Class 3 includes high-risk products, such as pacemakers (Table 1).

Information on the FDA website (www.fda.gov/ medicaldevices) can help companies determine how a new product is likely to be classified. After identifying similar prod-ucts listed on the site, a company can determine whether its product is likely to fall into an exemption category that will allow use of a 510(k) approval process (ie, showing equivalence to a product or products already on the market) or whether the product will require full-blown premarket approval (PMA).

The US regulatory process depends heavily on whether predicate devices have already been registered in the United States. A predicate device is a legally marketed device deemed substantially equivalent to the device under investigation. Substantial equivalence is determined on the basis of intended use, design, energy used or delivered, materials, performance, safety, effectiveness, labeling, biocompatibility, standards, and other applicable measures. Where no predicate device exists, companies must use code section 513(g) for a de novo pro-cess, which causes costs to escalate rapidly in terms of both time and money.

TABLE 1. FDA DEVICE CLASSIFICATIONS1

Class I Class II Class III

Risk Low Medium High

Approval None needed; register device and company on FDA website

FDA clearance required, typically 510(k) premarket notification submission

FDA approval required, typically via PMA process

Submission process Register product using FDA.gov Prepare 510(k) application; where not exempt, provide clinical or product testing

Develop clinical trial protocol, get approval by FDA, prepare and submit PMA to FDA

Approval time 1 month 3-6 months 18-30 months

Registration requirements

Proof of payment, correct FDA product code

Proof of payment, 510(k) number issued by FDA

Proof of payment, PMA number issued by FDA

Cost (US$) < 5000 15 000-30 000 > 30 000

Abbreviations: FDA, US Food and Drug Administration; PMA, premarket approval1. US FDA Registration Process for Medical Devices. Emergo. www.emergogroup.com/resources/usa-process-chart. Accessed March 6, 2015.

TABLE 2. ANNEX I OF THE MEDICAL DEVICES DIRECTIVE1

Risk Usage Class Device Types

Low Transient Class I Sterile use (eg, plaster)

Low Transient Class I Nonsterile use (eg, stethoscope)

Medium Short-term Class IIa Sterile use (eg, lancets)

Medium to high and often long-term

Long-term Class IIb Implantable devices (eg, intraocular lenses)

High, including all active implantable devices

Long-term Class III High-risk active implantable devices (eg, replacement heart valves)

1. Europe CE Approval Process for Medical Devices. Emergo. www.emergogroup.com/resources/europe-process-chart. Accessed March 6, 2015.

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THE CE ROUTE In the past few years, two issues—device quality and patient

risk—have taken center stage in the EU device approval process. Patient safety became a public concern following several high-profile failures in the medical device industry, including the Poly Implant Prothèse (PIP) breast implant scandal of 2010, in which the manufacturer substituted industrial grade silicone oil for medical grade.1 Considerable harm was done to patients when some of the implants ruptured, and harm was also done to the public’s perception of the EU regulatory process for medical devices.

Now, companies that neglect issues of quality and safety during the early stages of product development in the European Union may pay a heavy price as they reach the later approval stages, when they come into contact with regulatory authorities.

Bringing medical devices to the EU market involves compliance with the basic requirements outlined in the EU’s MDD or Active Implantable Medical Devices Directive (AIMDD), as well as adherence to harmonized standards such as those detailed in quality systems norms.

Although the FDA route has often been criticized for bureaucratic inefficiency, the EU approval process is also bureaucratically complex and involves multiple stakeholders, including the manufacturer of the device and its subcontrac-tors and distributors, authorized representatives, competent

TABLE 3. QUALITY SYSTEM BY CE CLASS1

Class I Class I Class IIa Class IIb Class III

Type Nonsterile Sterile

Implementation N/A Implement company quality system

Documentation Technical file prepared to demonstrate compliance with MDD Design dossier prepared in compliance with MDD

Application N/A Submit QMS and technical file to notified body

Accreditation N/A CE Mark for the device and certificate for the company for a successful audit issued

Registration Register with competent authority No registration for most EU member states

CE Mark Prepare declaration of conformity before affixing the CE Mark

Auditing Self-certified CE Mark Yearly unannounced audits to ensure compliance with EU regulations

Approval time < 1 month 3-4 months 3-5 months 3-6 months 6-9 months

Validity period Does not expire 3 years

Cost (€) < 4000 < 12 000 12 000-24 000 < 40 000 > 40 000

Abbreviations: EU, European Union; MDD, Medical Devices Directive; QMS, quality management system; N/A, not applicable1. Europe CE Approval Process for Medical Devices. Emergo. www.emergogroup.com/resources/europe-process-chart. Accessed March 6, 2015.

Competent Authorities Charged by the EU member states to enforce the MDD at a national level. Each member state will have its own interpretation of the directives, defining how the competent authorities should implement the MDD. Competent authorities are responsible for market surveillance, field safety cor-rective actions (recalls), and accrediting notified bodies.

Notified Bodies Audit manufacturers’ quality systems, test devices for compliance to applicable directives and standards, and assess the conformity of the submitted technical files and design dossiers before a CE certification is approved.

Authorized Representatives Required for any com-pany without a physical presence in the EU. Authorized representatives act as points of contact between manufac-turers and competent authorities.

1. Council Directive 93/42/EEC CONSLEG 1993L0042. European Union website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:20071011:en:PDF. Accessed March 6, 2015.

GLOSSARY OF KEY CE MARK STAKEHOLDERS1

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authorities, and notified bodies (see Glossary of Key CE Mark Stakeholders).

The first step in developing a medical device for release in the European Union is to determine its classification according to Annex I of the MDD, which is based on the intended use, risk of the device class, duration of contact with the patient, degree of invasiveness, and part of the body contacted (Table 2). Unfortunately, this must be done on a country-by-country basis. There is no guaran-tee, for example, that France will classify a device the same way as Denmark; the classification depends on the view of the national competent authority.

Once the classification has been established in a given mem-ber state, the manufacturer must implement a quality system and prepare a technical file and design dossier (Table 3). The notified body will then audit the manufacturer’s quality system and technical file. After the device passes the audit, the manu-facturer must register the device with the competent authority and prepare the declaration of conformity so that the CE Mark can be affixed to the device.

As the product is developed, the company must show evidence of a continuously updated quality system and appli-cation of updates to the quality manual as required. This can be demonstrated through the assignment and training of staff and through conducting periodic gap analyses of the quality

system through internal audits. Documentation of preventive actions helps to demonstrate that this continuous improve-ment process is being undertaken.

CONCLUSIONA combination of changes in EU regulatory directives and

a stagnant EU legislative process related to medical devices is making the release of innovative products a growing challenge in the European Union. Several evident problems are outlined in The Road Ahead on the opening page of this article. A continuation of these problems will threaten the EU’s global competitive edge in technological development. n

1. Pips breast implant scandal: Regulator warned years earlier. May 15, 2012. The Telegraph. http://www.telegraph.co.uk/health/news/9264541/Pips-breast-implant-scandal-Regulator-warned-years-earlier.html. Accessed March 6, 2015.

Yijun Huang, PhD, is cofounder and Chief Technology Officer at EyeKor in Madison, Wisconsin. He is an owner and shareholder at EyeKor. Dr. Huang may be reached at yhuang@eyekor.com.

Mark S. Talary, PhD, is Chief Technology Officer at IROC Science in Zurich, Switzerland. Dr. Talary may be reached at mark.talary@irocscience.com.