Medical devices encompass a wide array of products with myriad uses. A medical device can be any product used to cure, prevent, diagnose, or treat illness, provided that its principal intended purposes are not achieved primarily by chemical or metabolic action, as would be the case with a pharmaceutical. Devices range in complexity from simple tongue depressors to heart pacemakers and sophisticated imaging systems. There are more than 100,000 products in over 1,700 categories, and they cover a wide spectrum of risk. The U.S. medical device industry grew from 5,900 firms in 1980 to 16,900 firms in 1995. U.S. consumption of medical devices exceeded $40 billion in 1994. The 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic (FFD&C) Act gave FDA expanded responsibility for regulating medical devices in the United States. FDA’s regulatory responsibilities have three components: (1) approving new medical devices’ entry into the market; (2) monitoring device manufacturers’ compliance with FDA laws and regulations, including the good manufacturing practices (GMP) regulation to ensure continued quality control; and (3) operating a postmarketing surveillance (PMS) system to gather information about problems that could necessitate withdrawing a device from the market or taking other actions. The Office of Device Evaluation within FDA’s Center for Devices and Radiological Health is responsible for the evaluation of medical device applications. During fiscal year 1994, the Office of Device Evaluation received 16,905 submissions for review, of which it classified 10,293 as major submissions. The 1976 amendments established a three-part classification system for devices, based on the device’s level of risk and the extent of control necessary to ensure the safety and effectiveness of the device. Most medical devices are Class I or Class II (low and medium risk) and reach the market through FDA’s premarket notification—or 510(k)—process.Under its 510(k) authority, FDA may grant clearance for the marketing of devices if it determines that they are substantially equivalent to certain devices already on the market—called predicate devices. Once FDA has made that determination, a manufacturer can begin to market the new device. High-risk, or Class III, devices enter the market through the premarket approval (PMA) process. A PMA review is more stringent and typically longer than a 510(k) review. If a manufacturer needs to test a new device in human subjects before applying for marketing approval or clearance, and if the device presents a significant health risk to subjects, the manufacturer applies to FDA for an Investigational Device Exemption (IDE) to allow use of the device in clinical studies. See appendix II for a more detailed discussion of FDA’s review processes. The U.S. medical device industry values FDA’s “stamp of approval” but has leveled several criticisms against FDA. The industry contends that FDA takes too long to review applications and that review time increased drastically in the early 1990s. Manufacturers maintain that FDA’s review process is unpredictable and burdensome, particularly with regard to the amount and types of data they must submit. Additionally, the industry has stated that FDA is not always reasonable when it requires randomized human clinical trials to demonstrate that a device is safe and effective. In 1990, the EU began to adopt a series of three directives to regulate the safety and marketing of medical devices throughout the EU. The directives specify roles in the device regulatory system for the European Commission; the governments of member states; and review and approval organizations called notified bodies, which are often private entities. When this system is fully in place in several years, every medical device marketed in the EU will have to carry a “CE” mark, indicating that it meets common standards of performance and safety, known as essential requirements. Devices carrying the CE mark can be marketed throughout the EU. The first EU directive, for active implantable devices, covers powered devices that remain in the human body, such as heart pacemakers. It first took effect on January 1, 1993. During a 2-year transitional period, member states could continue to implement their national laws governing these devices, and manufacturers had the choice of either seeking approval to market a device in individual countries under each country’s laws or following the procedures that would allow the device to carry the CE mark and be marketed throughout the EU. As of January 1, 1995, all active implantable devices were subject to the new EU system alone. The second directive, known as the Medical Devices Directive (MDD), covers most other medical devices, ranging from bandages to hip prostheses. The MDD took effect on January 1, 1995, and its transitional period will last until June 13, 1998. The third directive, covering in vitro diagnostic medical devices, such as blood grouping reagents and pregnancy test kits, is under development and will not take effect until at least 1998. The U.S. and EU medical device regulatory systems share the goal of protecting public health, but the EU system has the additional goal of facilitating EU-wide trade. Another distinction between the two systems pertains to the criteria for reviewing devices. Devices marketed in the EU are reviewed for safety and performing as the manufacturer intended; devices marketed in the United States are reviewed for safety and effectiveness. Effectiveness includes the additional standard of providing benefit to patients. One goal of the EU medical device review system is to lower trade barriers and achieve a single market throughout the EU by harmonizing member states’ regulatory controls. At the EU level, the Directorate General for Industry is responsible for implementing the medical device directives. The directives specify that a member state may not create obstacles to the marketing of a CE-marked device within its territory. The other goal of the EU system is to protect public health. Medical devices that circulate in the EU must meet the medical device directives’ essential requirements, the first one being that devices will not compromise the health and safety of patients. The responsibility for enforcing the national regulations that implement the directives in the member states lies with each country’s Department of Health. Before the inception of the EU system, the level of regulation in member states varied widely, and in some countries most medical devices were not regulated at all. Therefore, although the system was created within the context of encouraging trade, in many European countries the directives will increase the level of medical device safety regulation. The U.S. medical device regulatory system exists within a public health context. FDA’s mandate is to ensure that devices that reach the public are safe and effective. The agency has limited statutory responsibility to promote trade. Devices marketed in the EU under the new regulatory system must conform to the essential requirements contained in the applicable medical device directive. Because the directives cover a wide range of products, the essential requirements provide broad targets for manufacturers to meet. The essential requirements are divided into two sections. First, the general requirements state that devices must be designed and manufactured in a way that will not compromise patient health and safety and that devices must perform as the manufacturer intended. Second, the design and construction requirements cover topics such as chemical, physical, and biological properties; labeling; radiation safety; and accuracy of measuring functions. The EU system relies greatly on recognized performance standards, which can be international, European, or national. Demonstrating that a device meets such standards is voluntary, but this is an acceptable—and often convenient—way to demonstrate that a device complies with the essential requirements. In reviewing medical device applications FDA uses the two criteria mandated by law—safety and effectiveness. For devices entering the market through the 510(k) route, the manufacturer must demonstrate comparative safety and effectiveness, that is, the new device is as safe and effective as the legally marketed predicate device. In evaluating the safety and effectiveness of a Class III device through the PMA route, FDA must determine that the application demonstrates a reasonable assurance that the device is safe and effective. To satisfy the effectiveness requirement, a device must provide beneficial therapeutic results in a significant portion of the target patient population. The U.S. criterion of effectiveness encompasses more than the European criterion of performing as the manufacturer intended; it requires the device to benefit certain patients. For example, to market an excimer laser in the United States, the manufacturer must demonstrate not only that the laser can cut tissue from the patient’s cornea, but also that the laser procedure lessens or eliminates the patient’s nearsightedness. In the EU, if the manufacturer specified that the purpose of the device was to eliminate a patient’s nearsightedness, it would have to demonstrate the validity of that claim. However, if the claim was restricted to the device’s ability to remove tissue in a particular way, judgment of the appropriate use of the device would be left to clinicians. In evaluating effectiveness, FDA generally reviews an individual device on its own merits. In certain situations, however, reviewers consider whether a new device is potentially less effective than available alternative therapies. FDA’s position is that the agency evaluates comparative effectiveness only when a less effective device could present a danger to the public, that is, when a device is designed to treat a disease that (1) is either life-threatening or capable of causing irreversible morbidity, or (2) is a contagious illness that poses serious consequences to the health of others. The EU gives major regulatory responsibilities to public and private bodies; in contrast FDA has sole responsibility in the United States. Both systems link the level of medical device review to the degree of control needed to ensure device safety. However, the two systems use different procedures to reach approval or clearance decisions. Governmental and private organizations both perform major functions in the EU system for regulating medical devices. Each member state designates a competent authority, usually in the Department of Health, which is responsible for implementing and enforcing the medical device directives in that country. The competent authority ensures that the directives are incorporated into national law, approves clinical investigations of devices, and operates the country’s reporting system for adverse incidents. Additionally, the medical device directives contain a safeguard clause. This clause gives the competent authority the power to withdraw an unsafe device from the market; the competent authority can be overruled by the European Commission after consultation among all of the parties concerned. (See app. III for a more detailed discussion of the safeguard clause.) The competent authority also serves as the country’s liaison with the European Commission and other member states. One of the most important responsibilities of the competent authority is to designate and certify the notified bodies located in that country. NBs are the organizations that perform conformity assessments on medical devices of medium or high risk that require the intervention of an independent organization prior to CE marking. The NBs determine whether a device conforms to the essential requirements in the relevant medical device directive. If the device is judged to be in conformance, the manufacturer may then place the CE mark on the product and market it throughout the European Union. NBs may be governmental or private entities, but most are private. In making their NB designations, competent authorities consider whether organizations meet the criteria for NBs contained in the medical device directives. These criteria include standards of competence, impartiality, and confidentiality. Competent authorities may periodically audit NBs and can withdraw NB status from an organization that does not continue to meet the criteria. The competent authority certifies that an NB is qualified to evaluate certain types of devices and to perform specific conformity assessment procedures. Some NBs have a limited certification; for example, they can evaluate only active medical devices or can perform only certain types of quality assurance reviews. Others are qualified to evaluate almost the full range of devices. If an NB is not competent to perform an assessment procedure that a device requires, it can subcontract with another NB or with another organization, such as a testing laboratory, to perform that part of the assessment. A manufacturer may select an NB located in any member state to assess its device. This is a contractual relationship, with the manufacturer paying a fee for the NB’s services. As of October 1995, there were 40 NBs throughout the EU. Germany and the UK had the largest number, 16 and 8, respectively. Representatives of European industry groups and public and private officials in the UK and Germany told us that manufacturers consider several factors when selecting an NB. These include the NB’s expertise and experience with specific devices and assessment procedures, language, cost, and whether the manufacturer has worked with the NB previously. In the United States, regulatory responsibilities rest with one government body—FDA. Currently, however, FDA is creating a pilot program to test the use of private third parties to review low- to moderate-risk devices requiring 510(k) clearance. The agency will individually review and accept third-party review organizations interested in participating in the pilot. After completing a device review, the third party will make a clearance recommendation to FDA. In contrast with the role of European NBs, the private reviewers participating in FDA’s pilot program will not have authority to make clearance decisions. FDA will retain that authority and will base its decision on the third party’s documented review. Manufacturers’ participation in the pilot will be voluntary; they may continue to opt for FDA review. Applicants that must submit clinical data on their devices will not be able to select third-party review; FDA has prepared a preliminary list of devices that may be included in the pilot. FDA expects that applicants that do participate will pay a fee directly to the third party to conduct the review. The pilot is scheduled to begin in mid-1996 and will operate for 2 years; during the second year FDA plans to evaluate the feasibility of using third parties to conduct timely and high-quality reviews of devices. Like the United States, the EU has a risk-based device classification system. The EU has four categories, however, instead of three. The manufacturer determines the appropriate class for a new device, based on classification rules in the directives. The manufacturer may also consult with the NB reviewing the device. In the United States, the manufacturer makes a claim regarding which class a device belongs in when it submits an application for FDA review. FDA, however, has final authority over the classification decision. (See app. III for a more detailed discussion of the EU classification system and app. II for a more detailed discussion of the FDA classification system.) Just as every device released in the United States must demonstrate safety and effectiveness, every device in the EU, no matter what its class, must comply with the essential requirements. In both systems, the purpose of classifying devices is to dictate the level of control the system exerts to ensure that devices comply with the respective requirements. The EU directives set out a complex array of assessment procedures that manufacturers must follow to demonstrate that a device conforms to the essential requirements. A device’s class determines the type of conformity assessment review the device must undergo, but the manufacturer is usually permitted to choose an assessment route from at least two options—often involving two general approaches. One approach is a review of the full quality assurance (QA) system that governs every phase of the manufacture of a device, from design through shipping. Officials of a German NB told us that one goal of a full QA review is to ensure that the manufacturer has written quality control procedures for every one of these phases and that these procedures are followed. NB reviewers conduct on-site inspections as part of this process. The other approach consists of two components. The first is a procedure called a type examination, in which the NB physically tests a prototype of the device to determine if it meets certain standards. The type examination component is paired with a limited QA review focused only on the production phase of manufacture. This review is intended to ensure the consistency of product quality. We refer to this overall approach as the type examination route. Appendix III contains a more detailed description of the different routes of conformity assessment and the assessment requirements for different device classes. The EU system includes both of these device approval routes as a compromise between member states that tended to rely on one approach or the other. For example, in the UK a voluntary oversight system had emphasized full QA system review, while the type examination approach had prevailed in Germany’s regulatory system. Both the EU and U.S. systems minimize oversight for the devices considered least risky. For EU Class I devices that do not involve a measuring function or sterile products, manufacturers may simply furnish a declaration that the device conforms to the essential requirements and maintain technical documentation that would permit review of the device. There is no NB review, but the manufacturer must register such devices with the competent authority in the country of the manufacturer’s place of business. In the United States, FDA exempts selected low-risk devices from premarket notification requirements. Manufacturers must still register their devices with FDA and must comply with GMP rules. Most new U.S. devices fall into Class I or Class II and are evaluated for substantial equivalence to devices already on the market. FDA determines whether a device has the same intended use and same technological characteristics as a predicate device by reviewing a 510(k) application submission. If a new device has the same intended use and technological characteristics, FDA deems it substantially equivalent to a predicate device and allows the device to be marketed. Also, if a device has new technological characteristics and FDA determines that they do not raise different questions of safety or effectiveness, FDA will find the device to be substantially equivalent. If the device has new technological characteristics and raises different questions of safety and effectiveness, the device will be found not substantially equivalent. The manufacturer can then seek approval for it through the premarket approval process. FDA requires a PMA review for most Class III devices. This is a more rigorous review because of the device’s inherent high risk or lack of established safety and effectiveness information. A multidisciplinary staff at FDA evaluates the PMA application. Nonclinical studies that the team reviews may include microbiological, toxicological, immunological, biocompatibility, engineering (for example, stress, wear, fatigue), and other laboratory or animal tests as appropriate. The team also reviews the results of any clinical investigations involving human subjects. Generally, FDA evaluates a manufacturer’s tests and does not perform its own tests on products. For a small portion of PMA reviews, FDA reviewers seek advice from an advisory panel of clinical scientists in specific medical specialties and representatives of industry and consumer groups. U.S. device manufacturers have expressed concern that FDA asks them to submit an excessive amount of data during the 510(k) review process. The director of FDA’s Office of Device Evaluation told us that FDA requires only what is necessary to establish that a device is as safe and effective as its predicate. She also told us that FDA has chosen to interpret the 510(k) requirements so that more devices can go through that review process rather than the longer PMA process. As a result, the agency needs enough data to demonstrate that those 510(k) devices meet the standard of substantial equivalence and do not raise new concerns regarding safety and effectiveness. When an NB certifies a manufacturer’s full QA system, the manufacturer may be able to attach the CE mark to several related products. The philosophy behind this approach is that if a company has a good design and manufacturing system, the devices it produces will be safe and perform as the manufacturer claims. Therefore, the full QA assessment route does not require the NB to conduct individual reviews of related devices that are produced under the same QA system, although the NB can do so when the situation warrants it. The certification covers the related devices, allowing the manufacturer to market all of them without going through an additional conformity assessment. Representatives of a British industry group told us that the QA approach makes it possible to continually monitor a company without testing individual items that may not be representative of the overall quality of production. Officials who work in the EU system told us that they expect manufacturers to choose the full QA route to conformity assessment more frequently than the type examination route. This route can be particularly advantageous for larger companies. The officials believe the type examination route is more likely to appeal to smaller companies that do not produce many product lines or a company that wants to get a particular device to market before it has time to put a full QA system in place. The kinds of standards manufacturers must meet during European QA reviews are similar to the GMP requirements in the U.S. system. (See app. II for additional information about GMP requirements.) However, in contrast to the ability of a full QA review to stand alone as a conformity assessment route for some devices in the EU, FDA never bases a 510(k) clearance or PMA approval decision solely on a GMP inspection. Some U.S. medical device manufacturers have raised concerns that FDA sometimes asks that a new medical device be tested in a clinical trial when the manufacturers believe that approach is inappropriate and unwarranted. They have also asserted that clinical trials can be performed more quickly in Europe. European officials told us that prior to the issuance of the EU medical device directives, Europe had very few requirements for clinical investigations. Under the new system, manufacturers may be required to provide clinical evidence that a device meets the essential requirements for safety; this evidence may come from either published scientific literature on similar devices or data from a clinical trial on the device under consideration. Implementation of the EU medical device directives may result in clinical trials being required more frequently than they had been in the past. Officials from a German NB discussed with us circumstances under which they would be likely to need data from a clinical trial to evaluate a new device under the EU directives. If the device uses an accepted technology to treat a medical indication for which use of that technology is also accepted, a clinical trial would not be necessary. If both the technology and the application are novel, however, they said they would require a clinical trial. In situations where there is a mix of novel and approved device technology and medical indication, they would need to make a judgment call. They said that regardless of whether a clinical trial is necessary, clinical data, based on either previous clinical trials, scientific literature, or field experience, would have to be provided. Although it is unclear how frequently European reviewers will ask manufacturers to perform clinical trials, FDA officials believe that clinical trials are often needed to establish the safety and effectiveness of devices undergoing PMA review. According to FDA, fewer than 10 percent of the medical device products FDA reviews under the 510(k) process require clinical trials. When FDA does require a clinical trial during a 510(k) review, the agency is looking for clinical confirmation that a device is as safe and effective as the legally marketed predicate device. NBs carry out a regulatory function within the EU’s medical device system, but the manufacturers whose devices they review are also their clients. This raises questions about the independence of the NBs. Additionally, NB employees are subject to less comprehensive conflict-of-interest rules than are FDA device reviewers. Unlike FDA, an NB is in the complicated position of both performing a public health function—and in that capacity having to answer to a governmental competent authority—and having a client relationship with the manufacturer that has hired it to review a device. NBs have a duty to ensure that medical devices that carry the CE mark conform to the EU medical device directives’ essential requirements regarding safety and performance. At the same time, however, they are in competition with each other to secure the business of manufacturers seeking assessment services. The businesses of some NBs include consulting work as well as product reviews, which can further complicate their independence. The director of the UK competent authority told us that if an organization has a consulting arm, his agency checks to see if the consulting function is kept separate from the conformity assessment function. Only then can it be designated as an NB. An EU official told us that he believes the European Commission needs to address this problem of potential conflict of interest for NBs. The EU medical device directives require the staff of NBs to be free of all pressures and inducements, particularly financial, that might influence their judgment or the results of their reviews, especially from anyone with an interest in the outcome of the review. To meet this requirement, NBs and their personnel must comply with European standards governing potential conflicts of interest. These standards are very general. Essentially, they (1) prohibit anyone involved in product testing or accreditation from having a commercial, financial, or other interest that could affect their judgment; and (2) attempt to shield laboratory and certification personnel from control by anyone with a direct financial interest in the outcomes of testing and accreditation. Key terms in the standards, such as control, direct, commercial interest, and financial interest, are not defined. Officials of NBs we visited told us that their employees are bound by international standards and that they must disclose potential conflicts of interest in connection with their assignments. One official told us that as an internal control, the staff who conduct the periodic follow-up surveillance reviews of manufacturers after the initial certification of a product or QA system are different from those who conducted the initial review. FDA employees are subject to a more comprehensive set of rules than are NB personnel. FDA rules include a substantial list of general rules that encompass all the goals and prohibitions included in the EU rules. In addition, they include supplemental guidance on specific matters that could present conflicts of interest, for example, outside employment, stock ownership, gifts, entertainment, filing responsibilities, and political activity. The EU rules are silent on how the general rules might apply in these situations. The EU medical device system is new and not yet fully operational. Although FDA’s system has been in place for almost 2 decades, the agency’s process is in flux as managers try to respond to criticism by experimenting with streamlined procedures. It is too early to evaluate the impact of those efforts on the length of FDA’s review process. At this time there are no data on the experience of the EU device review system that permit meaningful comparison with FDA. In contrast to FDA’s almost 20 years of experience in carrying out the U.S. device review program, implementation of the EU system is quite new. The only medical device directive that is fully in effect is the one for active implantable devices. The transition period for the directive that covers most devices began just 1 year ago. The system is not yet fully in operation. For example, each competent authority is supposed to establish a system for manufacturers to report adverse incidents with devices; eventually all of these national systems will be electronically linked. The UK already had an extensive voluntary system in place that it can build on, but most countries have barely begun to develop their systems. A UK official told us it will probably be a few years before an EU-wide system is in place. In the meantime officials are communicating by fax and letter when they identify problems. It is too early to know how some aspects of the EU system will translate from the directives into a practical working system. For example, the various competent authorities are bound by the same criteria when designating NBs, and the various NBs—both within and across individual member states—are all supposed to use the same criteria to perform conformity assessments. At present there is no way to measure whether that consistency is occurring in practice. European officials told us that experience levels among the competent authorities and NBs vary. For example, in countries that previously had a regulatory program in place, such as the UK and Germany, the competent authorities already had experience carrying out some of the functions the EU system requires of them. Similarly, some NBs have long histories of evaluating medical devices or QA systems, while others have considerably less experience. Even well-established NBs may have greater experience with particular conformity assessment routes or device categories. For example, NBs in the UK tend to have extensive experience performing full QA system reviews and some German NBs have extensive experience with product testing. Medical device manufacturers in the United States have charged that FDA takes too long to approve new medical devices and have asserted that the review process in Europe is faster. In response to criticism about the length of its device review process, FDA is attempting to better manage and streamline its system by experimenting with different review procedures. Agency officials believe these initiatives have reduced review time, but it is too early to evaluate their impact. FDA’s management actions include the May 1994 implementation of a three-tier system of review to improve management of its workload and better link the rigor of review with a device’s level of risk. In addition, since December 1994, FDA has exempted close to 300 additional medical devices from premarket notification requirements and moved other devices into lower classification categories in an effort to concentrate on riskier products and reduce the regulatory burden on manufacturers. FDA is also experimenting with an expedited review process for life-sustaining and life-saving devices under which selected applications move to the front of the review queue. At least 40 devices had been reviewed under this process as of July 1995. Additionally, FDA is refusing to accept deficient or poorly prepared applications until manufacturers provide the information needed for review. We recently analyzed patterns in review time for FDA device applications submitted from October 1988 to May 1995. Review times for 510(k) applications and PMA supplements submitted in 1994 were still higher than they were in 1990 but had decreased from 1993 levels. The trend for original PMAs was less clear, in part because FDA has not yet completed the review of a large portion of those applications. The EU does not have data on the length of its review process that can be compared with the data available about FDA’s experience. The EU system has been in effect for only a short time. Anecdotal information suggests review time may be shorter in the EU, but differences between the systems make it difficult to find comparable benchmarks. For example, NBs may have extensive interaction with manufacturers before the review process formally begins, and they sometimes perform preliminary reviews before beginning the official conformity assessment. This could make it difficult to identify the date on which the NB’s review begins. For similar reasons of lack of comparable data, it is also difficult to compare FDA’s record with the experience of individual European countries prior to initiation of the EU-wide system. The EU system for regulating medical devices is not only new—it is not yet fully in place. Therefore, it is too early to evaluate its success in ensuring the safety of medical devices and bringing them to market in an efficient manner. Because the major actors in the EU system have not had sufficient time to establish a record on how they will carry out their duties, it will be some time before information is available to answer the following questions: How strictly will competent authorities oversee NBs, for example, will competent authorities rescind certifications of NBs if warranted? Will the performance of all competent authorities and NBs be of equal quality, and therefore, will public health authorities and consumers be able to have the same level of confidence in devices no matter where they are reviewed? Will the full QA system and type examination conformity assessment routes both prove to be appropriate ways to regulate devices? Will NBs maintain the necessary degree of independence from manufacturers who are their clients? How will NBs implement requirements for clinical evidence on new devices? Will an adequate postmarket surveillance system be developed? U.S. government officials who want to consider integrating features of the EU approach into the U.S. device review system will be better able to assess the value of the EU system after it accumulates several years of experience. The U.S. medical device industry has advocated giving private third parties a role in the review of medical devices, and FDA is exploring this possibility in a pilot project. Ensuring that private reviewers have the necessary independence, requisite expertise, and sufficient resources would enhance the confidence of the Congress and the American public in the integrity of the device review process. The importance of this assurance would increase if private review organizations were given the added authority of clearing new devices for marketing. FDA and European officials reviewed a draft of this report. FDA’s written comments are reproduced in appendix IV. FDA generally found the report to be accurate and complete and made a number of technical comments clarifying aspects of the agency’s review processes. We incorporated these as appropriate, basing the changes in some instances on further discussions with FDA officials. We also incorporated technical clarifications on the EU system received from European officials. In its comments, FDA stated that the EU system does not evaluate individual devices, but instead evaluates a manufacturer’s quality assurance system. As we noted in the draft report, in some situations the EU system does evaluate individual devices, such as when a manufacturer chooses the type examination route of conformity assessment or when a Class III device’s design dossier is reviewed. We will distribute this report to the Secretary of Health and Human Services, the Commissioner of the Food and Drug Administration, and other interested parties. This report was prepared under the direction of Mark V. Nadel, Associate Director for National and Public Health Issues. If you or your staff have any questions, please call me at (202) 512-7119 or Bruce D. Layton, Assistant Director, at (202) 512-6837. Other major contributors to this report include Helene F. Toiv, Claude B. Hayeck, Mary W. Freeman, Michele Grgich, and Liv Gorla. For our review of the European Union’s medical device approval process, we conducted field work in Germany and the United Kingdom. These countries were ahead of most other member states in adopting the EU regulatory system into their national laws and had greater experience with implementing the new system. Additionally, over half of the notified bodies, which review and approve medical devices under the EU system, were located in these two countries. In Germany and the UK we interviewed government health officials responsible for medical device regulation; officials from two NBs, TÜV Product Service and the British Standards Institution; and representatives of medical device industry groups. We also interviewed EU officials and a representative of an EU-wide industry association. We reviewed EU documents governing the EU regulatory process. Several officials we interviewed reviewed a draft of this report. We reviewed Food and Drug Administration documents and policies as well as laws and regulations governing FDA. In addition, we interviewed officials from FDA’s Center for Devices and Radiological Health. We talked with representatives of the U.S. medical device industry, including the Health Industry Manufacturers Association, the National Electrical Manufacturers Association, and the Medical Device Manufacturers Association, as well as representatives of individual device companies. We also reviewed position papers of several industry groups. We interviewed representatives of organizations with expertise on product review and certification, including officials from the U.S. Department of Commerce; Underwriters Laboratories Inc.; the American National Standards Institute; and the Emergency Care Research Institute. We conducted our review from March through December 1995 in accordance with generally accepted government auditing standards. This appendix provides additional information about several features of the U.S. system for regulating medical devices and FDA review procedures. The process of bringing a new medical device to market takes one of two routes—premarket notification or premarket approval. Most new devices are variations of already marketed devices, are classified as low to moderate risk, and reach the market through FDA’s premarket notification—or 510(k)—review process. During the 510(k) review, FDA judges whether a device is substantially equivalent to one already on the market. The premarket approval (PMA) process is reserved for high-risk devices. PMAs and PMA supplements require a more stringent FDA review, which may include the analysis of clinical data to provide a reasonable assurance of safety and effectiveness. In addition, manufacturers must comply with certain postmarket requirements such as reporting of certain device-related adverse events. In fiscal year 1994, FDA’s Office of Device Evaluation received 6,434 510(k) applications and 415 PMAs and PMA supplements. Medical devices are grouped into three classes according to (1) the degree of potential risk and (2) the types of regulatory control needed to reasonably ensure their safety and effectiveness. Class I devices (for example, bedpans and tongue depressors) are those for which general controls provide reasonable assurances of safety and effectiveness. Class II devices (for example, syringes and hearing aids) require special controls in addition to general controls. Class III devices (for example, heart valves and pacemakers) are subject to general controls and must undergo more rigorous scientific review and approval by FDA as well. General controls include registering device manufacturing facilities, providing FDA with regularly updated lists of marketed devices, complying with good manufacturing practices, and maintaining records and filing reports of device-related injuries and malfunctions. The Safe Medical Devices Act of 1990 (SMDA ) revised the requirements for Class II devices, subjecting them to both general and special controls. Special controls include performance standards, postmarketing surveillance, patient registries, and other controls as deemed necessary. Class III devices are subject to the PMA process, which requires the manufacturer to present evidence, often including extensive clinical data, that there is a reasonable assurance that a device is safe and effective before placing it on the market. To help assess the appropriate level of review for devices, the Center for Devices and Radiological Health in May 1994 introduced a three-level “triage” system that, within the existing classification system, assigns priorities for application review based upon the complexity and risk of the device. A tier I review is essentially a labeling review to ensure that the label correctly identifies the intended use of the device. Most Class I devices fall within tier I because a less rigorous scientific evaluation of these low-risk devices does not adversely affect the public health. A tier II review is a scientific and labeling review. This tier encompasses the majority of 510(k)s and select PMA supplements. A tier III review is an intensive scientific and labeling review, using a team review approach for devices utilizing new technology or having new intended uses. FDA convenes an advisory panel when it lacks the expertise to address questions of safety and effectiveness for devices placed in tier III or when it is otherwise appropriate to obtain advice on scientific matters. Most new medical devices incorporate incremental changes to devices already on the market. To clear these devices for marketing, FDA determines whether they are substantially equivalent to (that is, as safe and effective as) legally marketed predicate devices. Substantial equivalence means that a device has (1) the same intended use and same technological characteristics as the marketed device or (2) the same intended use and different technological characteristics—but is as safe and effective as the marketed device and does not raise different questions of safety and effectiveness. FDA initially determines whether a 510(k) submission is sufficiently complete before undertaking a substantive review. During the review, FDA determines the intended use of a device by examining the manufacturer’s proposed label statements, including statements in promotional materials that describe the device and its use. To evaluate technological characteristics, FDA reviews the physical and performance characteristics of the device, such as device design, materials used, and power source. For example, in reviewing a new pacemaker lead made of polyurethane, FDA would assess performance testing information to confirm that the new lead is substantially equivalent to the predicate (or previously approved) lead. This is necessary because differences in chemical formulations of polyurethane or differences in design and assembly can affect safety and effectiveness. In arriving at a determination, FDA reviewers may use voluntary standards and guidance about a particular device. Reviewers also commonly used earlier agency decisions on 510(k)s for similar devices. Another resource is the files of the Center for Devices and Radiological Health, such as establishment inspection and postmarketing surveillance files. These files allow reviewers to examine the reviews of similar device types and to determine what questions, if any, were raised by FDA inspectors about a particular type of device. During the review of a 510(k) application, the reviewer may determine that additional information about the device is necessary to complete the review. This additional information may be descriptive information and/or performance testing information. Descriptive information includes the intended use, physical composition, method of operation, specifications, and performance claims of the device. Performance testing information can be data from bench testing or from animal or clinical testing. Upon completion of the review, the Office of Device Evaluation issues a decision letter, which is then sent to the manufacturer. The letter may contain one of the following: a substantially equivalent decision, a not substantially equivalent decision, a request for additional information, or a determination that the device is exempt from a 510(k) submission. As it does for 510(k)s, FDA first decides whether to accept the PMA or refuse to file it because it does not meet minimum requirements. If FDA accepts the application, a multidisciplinary staff evaluates the filed PMA. The team reviews nonclinical studies such as microbiological, toxicological, immunological, biocompatibility, animal, and engineering tests. The team also reviews the results of clinical investigations involving human subjects. During this stage, FDA prepares a critique of the scientific evidence of the safety and effectiveness of the device. During the review, FDA may, on its own initiative or if requested by the applicant, refer the PMA to an advisory committee representing the appropriate medical field for a “panel” review. FDA will request such a review when it lacks the knowledge or experience to evaluate the safety and effectiveness questions posed by the device or when it is otherwise appropriate to obtain advice on scientific matters. Problems identified in FDA’s critique of the scientific evidence can be discussed further during advisory panel meetings. The committee submits a final report to FDA, but the agency is not bound by the committee’s recommendations. The review team also checks the manufacturer’s compliance with the GMP regulation and makes a judgment about the quality controls used in the manufacture of a device. The purpose of the review is to ensure that the manufacturer is capable of producing devices of high quality. At the end of the approval review stage, FDA may take one of the following actions: Issue an order approving the PMA. Issue an order denying approval. Send the applicant an approvable letter indicating that the FDA intends to approve the device if certain problems (for example, labeling deficiencies) are resolved. Send the applicant a not-approvable letter describing significant deficiencies in the application. Eventual approval is not precluded if the manufacturer provides an adequate response. Almost all PMAs and a small subset of PMA supplements and 510(k)s require clinical trials to obtain answers to questions on safety and effectiveness. A researcher wishing to conduct a study involving human subjects to develop safety and effectiveness data for a medical device can apply to FDA for an IDE. An approved IDE application permits the use in a clinical study of a device that would ordinarily be subject to market clearance procedures. An IDE approval is needed for a significant risk device. For a nonsignificant-risk device (for example, daily wear contact lenses) investigation, the sponsor presents the proposed study to an institutional review board (IRB) along with a report of prior investigations and the investigational plan. If the IRB approves the investigation as a nonsignificant-risk study, the investigation is considered to have an approved IDE and can begin immediately. FDA is not involved in the approval process of the clinical study. If the IRB or FDA determines, however, that the proposed investigation involves a significant-risk device (for example, a heart valve), the sponsor must submit an IDE application to FDA. The application must contain an investigational plan that includes such information as the purpose of the study, a written protocol, a risk analysis and description of patient selection, a description of the device, monitoring procedures, labeling, and consent materials. An IDE application may also include data on the design of the device and data from bench and animal tests. FDA determines whether the study should be approved, considering such factors as whether the benefits of the investigation outweigh the risks and whether the proposed study is scientifically sound. The investigation can begin after the sponsor obtains both FDA and IRB approval for a significant-risk investigation. FDA conducts bioresearch monitoring inspections to help ensure that clinical investigations are conducted in accordance with study protocols and that the rights and safety of study participants are protected. FDA determines compliance with the GMP regulation primarily through factory inspections conducted by its field staff. Section 704(a) of the FFD&C Act gives FDA authority to conduct GMP inspections of medical device manufacturers. During these inspections, FDA investigators examine facilities, records of manufacturing processes, and corrective action programs. The results provide information necessary to evaluate a firm’s compliance with the medical device GMP regulation. FDA may initiate a GMP inspection for any of several reasons. These include routine scheduling, the need to obtain data on an industry new to FDA, investigation of a consumer or trade complaint, a product defect report, an adverse reaction to a device, or a device-related death. FDA also conducts GMP inspections in conjunction with approval of products. One key provision of the Safe Medical Devices Act of 1990 requires that manufacturers conduct postmarketing surveillance, such as studies to gather data on the safety and effectiveness of certain devices. This requirement applies to devices that (1) are permanent implants, the failure of which may cause serious adverse health consequences or death; (2) are intended for use in supporting or sustaining human life; or (3) present a potential serious risk to human health. FDA also has discretion to require postmarketing surveillance for other devices under certain circumstances. This appendix expands on information provided in the report about several features of the EU system for regulating medical devices. The EU Medical Devices Directive, which covers most devices, established a four-part classification system for medical devices. The rules for classification take into account the riskiness of the device, the device’s degree of invasiveness, and the length of time the device is in contact with the body. Class I devices are generally regarded as low risk and include most noninvasive products, certain invasive products, and reusable surgical instruments. Class IIa devices are generally regarded as medium risk and include both invasive and noninvasive products, generally for short-term use. This class includes some wound dressings; certain products that channel and store blood for administration into the body; surgically invasive devices for transient or short-term use; most active therapeutic devices that administer or exchange energy; and active diagnostic devices that supply energy (other than for illumination) absorbed by the body, such as ultrasonic imagers. Class IIb devices are also regarded as medium risk, but this class covers active products therapeutically delivering energy or substances at potentially hazardous levels. Devices placed in this class include blood bags, chemicals that clean or disinfect contact lenses, surgically invasive devices for long-term use, radiological equipment, and condoms and other contraceptive devices (except for intrauterine devices, which are in Class III). Class III devices are generally regarded as high risk and include products that are used to diagnose or monitor or that come in contact with the circulatory or central nervous system, such as vascular grafts. This category also includes devices that incorporate medicinal products, such as bone-cement containing an antibiotic. Under the EU system, the classification of a medical device governs the type of assessment procedure the manufacturer must undertake to demonstrate that the device conforms to the essential requirements in the relevant medical device directive. Generally, when an NB must perform aspects of conformity assessment, the manufacturer may choose the assessment route from two or more options. This type of review examines every aspect of the manufacturer’s quality assurance system, covering every phase of the manufacture of a device, from design through shipping. The phases involved in producing a new device for the market include a feasibility phase; design phase, which results in a written definition of the device; design verification, which involves creating prototypes of the device; mass production; and full market release. At each of these phases the manufacturer must ensure that it has defined the requirements for completing that phase and that the “deliverable” for that phase, such as a product design or a packaged device, is verified by qualified staff. A manufacturer choosing the full QA system route for a Class III device is also required to submit a design dossier for the NB’s review. The dossier may include specifications and performance data of the product as claimed; an explanation of how the product meets the essential requirements for safety; risk analysis, including risk control methods; electrical/mechanical/chemical constructional data, including drawings; design verification documents; and, when relevant, clinical investigation data. After certifying a manufacturer’s QA system, the NB must carry out periodic inspections to ensure that the manufacturer is continuing to implement the QA system. Additionally, the NB may pay unannounced visits to the manufacturer to check that the quality system is working properly. Under the full QA assessment route, the NB does not need to conduct individual reviews of related devices that are produced under the same QA system. If the NB certifies the manufacturer’s QA system, that certification covers the related devices. This practice allows the manufacturer to place a CE mark on and market all of the related devices without going through an additional conformity assessment review. Type examination is a procedure in which the NB ascertains and certifies that a representative sample of the device being reviewed conforms to the essential requirements. The NB reviews documentation on the device that the manufacturer provides and conducts a product test of the device. The NB physically tests a prototype of the device to determine whether it meets certain standards. The documentation reviewed might include documentation of other product tests. Type examination is always linked with a QA review limited to the production phase of manufacture. The QA review is intended to ensure the consistency of product quality. There are three types of limited QA reviews, as follows. In this type of review, the NB must individually test every device produced or test a random sample from every production batch. (This option is also referred to as batch verification.) Few companies choose this approach because it is very expensive. Under this type of review, the NB reviews the manufacturer’s QA system for the production stage of manufacturing devices, including inspection and QA techniques. The NB must carry out periodic inspections after certifying the production QA system and can pay unannounced visits to the manufacturer. Officials who work with the EU system reported to us that this is the type of production phase quality review that manufacturers select most often to complement type examination. The NB reviews and certifies the manufacturer’s system for inspecting and testing final products in an Annex VI review. The NB must carry out periodic inspections and can pay unannounced visits to the manufacturer. Under this procedure, which is available only for devices in Classes I and IIa, a manufacturer furnishes a declaration that a device conforms to the essential requirements and maintains technical documentation that would permit review of the device. The EU’s MDD specifies which conformity assessment routes each class of devices may use to demonstrate conformity with the essential requirements. Figure III.1 illustrates the assessment routes available to each device class. Annex IV Medical Devices Directive (Figure notes on next page) For Class I products that do not involve measuring devices or sterilization, manufacturers may simply furnish the declaration of conformity (Annex VII) and maintain sufficient technical documentation to permit review of the device. There is no NB review, but the manufacturer must register such devices with the competent authority in the country of the manufacturer’s registered place of business. If the device has a measuring function or must be placed on the market in a sterile condition, the manufacturer is also subject to one of the assessment routes covering production quality (Annexes IV, V, or VI). The NB’s review focuses only on the measurement or sterilization aspect of the device. The manufacturer itself may declare conformity with the essential requirements covering the design phase and choose one of the assessment routes covering production quality (Annexes IV, V, or VI). Alternatively, the manufacturer may undergo the full QA system review (Annex II). The manufacturer may choose either the full QA system review (Annex II), or type examination (Annex III) plus one of the production quality reviews (Annexes IV, V, or VI). The requirements are the same as for Class IIb, with two exceptions. If the manufacturer chooses the full QA system review (Annex II), it must also submit a design dossier to the NB. If the manufacturer chooses type examination (Annex III), it must choose either product verification (Annex IV) or production quality assurance (Annex V) for the production phase assessment. Product quality assurance (Annex VI) is not an option for Class III devices. The EU’s medical device directives have a safeguard clause that requires each member state’s competent authority to withdraw from the market CE-marked devices that the competent authority finds may compromise patients’ health or safety. The competent authority must immediately inform the European Commission both that it has taken this action and of its reasons for withdrawing the device. If the Commission agrees that the action was justified, it will inform the other member states that the device has been withdrawn. If the Commission believes the withdrawal was unjustified, it informs the competent authority that made the decision and the device manufacturer of that decision. If a competent authority persists in banning a CE-marked product from its country’s market, despite the European Commission’s decision that the device belongs on the market, the Commission can bring a legal proceeding in the European Court of Justice. European officials view the safeguard clause as a last resort, not something to be invoked routinely. If member states could routinely block the sale of CE-marked devices in their countries, the EU system’s goal of facilitating EU-wide trade would be undermined. Medical Devices: FDA Review Time (GAO/PEMD-96-2, Oct. 30, 1995). FDA Drug Approval: Review Time Has Decreased in Recent Years (GAO/PEMD-96-1, Oct. 20, 1995). Medical Technology: Quality Assurance Systems and Global Markets (GAO/PEMD-93-15, Aug. 18, 1993). Medical Technology: Implementing the Good Manufacturing Practices Regulation (GAO/T-PEMD-92-6, Mar. 25, 1992). Medical Technology: Quality Assurance Needs Stronger Management Emphasis and Higher Priority (GAO/PEMD-92-10, Feb. 13, 1992). Medical Devices: FDA’s 510(k) Operations Could Be Improved (GAO/PEMD-88-14, Aug. 17, 1988). The first copy of each GAO report and testimony is free. Additional copies are $2 each. Orders should be sent to the following address, accompanied by a check or money order made out to the Superintendent of Documents, when necessary. VISA and MasterCard credit cards are accepted, also. Orders for 100 or more copies to be mailed to a single address are discounted 25 percent. U.S. General Accounting Office P.O. Box 6015 Gaithersburg, MD 20884-6015 Room 1100 700 4th St. NW (corner of 4th and G Sts. NW) U.S. General Accounting Office Washington, DC Orders may also be placed by calling (202) 512-6000 or by using fax number (301) 258-4066, or TDD (301) 413-0006. Each day, GAO issues a list of newly available reports and testimony. 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Summary: Pursuant to a congressional request, GAO compared the Food and Drug Administration's (FDA) and the European Union's (EU) systems for reviewing and approving medical devices, focusing on: (1) key differences between the two systems; (2) the outputs of the two systems; and (3) the feasibility of FDA adopting features of the EU system. GAO found that: (1) U.S. and EU medical device regulatory systems share the goal of protecting public health, but the EU system is designed to facilitate EU-wide trade; (2) while EU reviews medical devices for safety and performance, FDA reviews devices for safety, effectiveness, and benefit to patients; (3) while EU gives major medical device regulatory responsibilities to public agencies and private organizations, FDA has sole responsibility over device regulation in the United States; (4) both systems link the level of medical review to device risk, but the two systems use different procedures to reach approval or clearance decisions; (5) questions and concerns have arisen regarding possible conflicts-of-interest in the EU medical device review process because EU notified bodies carry out a regulatory function within the EU medical device system and conflict-of-interest rules for EU reviewers are less comprehensive than in the United States; (6) sufficient data does not exist on the EU medical device review system to permit meaningful comparison with FDA because the EU system is new and not yet fully operational; and (7) it is too early to evaluate the impact of new FDA streamlined review procedures.