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European doctors and their patients have frequently had access to new technolo-gies 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 that may have long-term repercussions for European 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 chal-lenge 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 changing because of tightened EU regulations for the approval and certification of medical devices with the EU’s new Medical Devices Directive (MDD).

CHANGING LANDSCAPEHistorically, medical device companies have criticized the

FDA for stifling innovation through inconsistent regulation and a slow approval process. Challenges in the US regula-tory environment have sometimes prompted investors to shift their funds overseas—often to Europe, where the reg-ulatory process has been less bureaucratic, more efficient, and more predictable.

The FDA has required device makers to provide evidence of both the safety and efficacy of a device, whereas the CE Mark has required only proof of safety and proof that the device performs in a manner consistent with the manufac-turer’s intended use.

Despite any criticisms, the FDA process is not without an upside for industry. Once a device has received FDA clear-ance, 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

Is it now easier in the United States?

BY MARK S. TALARY, PhD; AND YIJUN HUANG, PhD

BRINGING AN OPHTHALMIC DEVICE TO MARKET

THE ROAD AHEAD1. There are significant inconsistencies in policies among the three directorates-generals 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 regulated 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 current policy make the job of navigating the EU regulatory process an impediment to medical device innovation.

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screws. Class 3 includes high-risk products, such as pacemak-ers (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 products 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 inves-tigation. 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 process, which causes costs to escalate rapidly in terms of both time and money.

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 sub-stituted industrial grade silicone oil for medical grade.1 Considerable harm was done to patients when some of the implants ruptured—and harm was done as well 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

TABLE 1. FDA DEVICE CLASSIFICATIONS1

Classification 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$) < 5,000 15,000–30,000 > 30,000

PMA = premarket approval1. US FDA Registration Process for Medical Devices. Emergo website. www.emergogroup.com/resources/usa-process-chart. Accessed January 22, 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 higher and often longer term

Long-term Class IIb Implantable devices: eg, IOLs

Highest, 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 website. www.emergogroup.com/resources/europe-process-chart. Accessed January 22, 2015.

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

The first step in developing a medical device for release in the EU 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 guarantee, 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 member state, the manufacturer must implement a qual-ity system and prepare a technical file and design dossier (Table 3). The notified body will then audit the manufac-turer’s quality system and technical file. After the device passes the audit, the manufacturer 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 application 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 demon-strate that this continuous improvement process is being undertaken.

TABLE 3. QUALITY SYSTEM BY CE CLASS1

Classification 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 (€) < 4,000 < 12,000 12,000–24,000 < 40,000 > 40,000

MDD = Medical Devices Directive; QMS = quality management system; N/A = not applicable1. Europe CE Approval Process for Medical Devices. Emergo website. www.emergogroup.com/resources/europe-process-chart. Accessed January 22, 2015.

• Whether in the United States or the European Union, bringing ophthalmic products to market requires expertise to navigate challenging regulatory pathways.

• Increasingly, issues of device quality and patient risk have become important in EU medical device regulation.

• Companies that neglect issues of quality control and risk reduction during the early stages of product development in the European Union may pay a price as they reach the later approval stages, when they first come into contact with regulatory authorities.

• Changes in EU regulatory directives and the slow legislative process are confusing the regulatory pathway and making the release of innovative products a growing challenge.

AT A GLANCE

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CONCLUSIONA combination of changes in EU regulatory directives and

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

Yijun Huang, PhDn Cofounder and Chief Technology Officer, EyeKor, Madison,

Wisconsinn yhuang@eyekor.comn Financial disclosure: Owner, Shareholder (EyeKor)

Mark S. Talary, PhDn Chief Technology Officer, IROC Science, Zurich, Switzerlandn mark.talary@irocscience.comn Financial disclosure: Salaried by company (IROC Science)

Competent Authorities Charged by the EU mem-ber 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 respon-sible for market surveillance, field safety corrective 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 company without a physical presence in the European Union. Authorized representatives act as points of contact between manufacturers 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 January 22, 2015.

GLOSSARY OF KEY CE MARK STAKEHOLDERS1