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Safe Medical Devices for Children (2006)

Chapter: 3 Regulatory Framework for Postmarket Surveillance of Medical Devices

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Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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3
Regulatory Framework for Postmarket Surveillance of Medical Devices

“As I see it, what the Senator from New York is doing in this particular case is the same thing as if the Congress of the United States should attempt to say by law that calling a sheep’s tail a leg would make it a leg … if he desires to legislate against these mechanical devices he ought to do it in the open instead of by indirection and attempting to define as a drug something which palpably is not a drug.”

Senator Bennett Champ Clark (79 Cong. Rec. 4841, April 2, 1935)

The extension of U.S. Food and Drug Administration (FDA) oversight to devices has been uneven and sometimes has relied on stretching the definition of drugs.1 Until 1976 when Congress added the Medical Device Amendments (P.L. 94–295) to the Federal Food, Drug, and Cosmetic Act (P.L. 75–717), federal officials had limited explicit authority to regulate the safety or effectiveness of medical devices. In this legislation, Congress provided for additional regulatory scrutiny of medical devices while creating a regulatory framework that recognized certain differences between drugs and devices, particularly the substantial variability in the risk posed by different types of devices.

Virtually the entire regulatory framework for medical devices is general, that is, it applies to devices whether their primary or exclusive use is with adults or children. One exception is that when medical devices are tested with children in studies that will be submitted to FDA, they are usually subject to regulations for the protection of human research subjects that provide special, additional protections for child subjects. Also, in meeting its regulatory responsibilities, FDA may take special notice of children, for example, by limiting the labeled indications for the use of a device to

1  

As described in Chapter 1, the Supreme Court in 1969 sustained FDA’s categorization of a laboratory screening device (an antibiotic sensitivity disk) as a drug subject to premarket review (United States v. Bacto-Unidisk, 1969).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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adults or directing that pediatric questions be examined in studies following the approval of a device.

This chapter provides a descriptive foundation for the later discussion of the adequacy of FDA’s program of postmarket surveillance to protect children. The chapter begins with a brief overview of organizational responsibilities for medical device regulation. It then reviews the premarket regulatory responsibilities of FDA as context for the following description of the agency’s responsibilities for postmarket surveillance of medical devices.2 The last section describes some agency programs and activities, for example, inspections of manufacturers that cover both premarket and postmarket arenas.

ORGANIZATION OF FDA FOR MEDICAL DEVICE REGULATION

Within the Food and Drug Administration, primary responsibility for regulating medical devices (and radiation-emitting electronic products) resides with the Center for Devices and Radiological Health (CDRH). The Center for Biologics Evaluation and Research (CBER) is responsible for regulating medical devices related to blood and cellular products (e.g., kits to test blood for HIV). For combination products that involve a drug and a device or a biological product and a device, the primary regulatory responsibility is assigned to CDRH if the main mode of action of the product is not biological or chemical and does not depend on being metabolized.

Within CDR, the Office of Device Evaluation is responsible for the clearance or approval of medical devices that require premarket review. (The Office of In Vitro Diagnostic Device Evaluation and Safety handles reagents and in vitro diagnostic products.) Another unit, the Office of Science and Engineering Laboratories, contributes to the development of standards and methods for product assessments, performs laboratory evaluations and analyses, and conducts research and testing relevant to medical devices or radiation-emitting electronic products. This unit provides technical support for the development of the device-specific guidance documents as discussed later in this chapter. Although other offices have roles related to postmarket surveillance, the key unit is the Office of Surveillance and Biometrics (OSB). It has three divisions, the Division of Biostatistics, the Division of Postmarket Surveillance, and the Division of Surveillance Systems.

Within OSB, the Division of Postmarket Surveillance oversees the adverse event reporting program, which includes the analysis and investiga-

2  

As noted in Chapter 1, in referring to premarket and postmarket rather than premarketing and postmarketing activities, this report follows the legislative language that provided for this study and the usual (but not invariable) practice of FDA in describing activities that occur prior to or following the entry of a medical product into the market.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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tion of reports. It also conducts epidemiologic research on the safety and use of medical devices and supports the development of epidemiologic methods for medical device research. As described in Chapter 5, the division has recently assumed responsibility for monitoring postmarket studies required at the time a device is approved for marketing. The Division of Biostatistics provides statistical support for both premarket and postmarket programs and also conducts and collaborates in original research on the health effects of device use. The Division of Surveillance Systems takes the lead in planning, developing, implementing, and maintaining OSB databases and information systems.

Additional support in evaluating device problem reports may be provided by the Division of Device User Programs and Systems Analysis (which is part of CDHR’s Office of Communication, Education, and Radiation Programs and which includes FDA’s human factors program). The Office of Science and Engineering Laboratories provides technical assistance for premarket as well as postmarket programs.

In addition to its central offices in Maryland, FDA has more than 160 field offices, laboratories, and other sites throughout the country. These sites house most of the agency’s Office of Regulatory Affairs employees who are responsible for various enforcement activities (e.g., seizures of adulterated foods or medical products) and for inspections of medical product, food, and cosmetic manufacturers (FDA, 2003g). Table 3.1 shows CDRH budget authority and total funding levels for FY 1994 to FY 2004.

TABLE 3.1 Budget Authority and Total Program Level Funding History for Center for Devices and Radiological Health FY 1994–2005 (in millions)

Year

Budget Authority (Center and Field)

Total Program Level (Budget Authority plus User Fees)

1994

$159

$159

1995

157

170

1996

144

152

1997

147

160

1998

144

156

1999

147

159

2000

158

170

2001

173

186

2002

180

194

2003

193

217

2004

191

222

NOTE: Program level funding includes user fees from inspections of mammography facilities and, beginning FY 2003, fees provided for under the Medical Device User Fee and Modernization Act of 2002.

SOURCE: FDA Congressional Justification submissions (data compiled by CDRH staff).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

The fiscal year 2004 budget for OSB postmarket surveillance activities was approximately $15 million, approximately half of which covered costs for about 70 full-time equivalent staff positions, including approximately 50 positions devoted to postmarket surveillance specifically (personal communication, Thomas P. Gross, M.D., Director, Division of Postmarket Surveillance, CDRH, October 1, 2004, and April 6, 2005). About one-third of the budget involved the MedSun program, which is described later in this chapter. The budget includes no funds for the analysis of outside data sources, such as Medicare databases or professional society registries.

BASICS OF PREMARKET REGULATION OF MEDICAL DEVICES

The premarket regulatory processes of FDA include evaluations, decisions, and other actions that occur prior to the marketing of a medical product. In some cases, requirements are established before or at the time of marketing approval for actions that will take place after marketing, for example, when further clinical studies are specified as a condition of FDA’s approval of a device.

When Clearance or Approval of a Device Is Required

According to FDA, approximately 20,000 American and foreign firms produce about 80,000 brands and models of medical devices for the U.S. market (FDA, 2002b). Before they can be marketed in the United States, roughly 55 to 60 percent of medical devices require FDA clearance or approval.

The requirements that must be met for a device to be legally marketed in the United States depend in considerable measure on its risk classification. The Medical Device Amendments of 1976 provided that devices be classified—in ascending order of risk—as Class I, II, or III devices (21 USC 360c). FDA completed the basic process of classifying existing devices into the three groups by 1988 (Merrill, 1994). In 2004, the three classes accounted for about 43 percent, 44 percent, and 13 percent of classified devices, respectively (personal communication, Donna-Bea Tillman, Ph.D., Deputy Director, Office of Device Evaluation, CDRH, January 18, 2005; see also FDA, 2004n).3Table 3.2 provides examples of common pediatric-use devices in the three classes.

3  

The 13 percent figure includes Class III devices that require premarket approval.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

TABLE 3.2 Examples of FDA Class I, II, and III Devices

Device Class

Examples

I

Bassinets

Nursing bottle nipples

Infant caps

Mechanical toothbrushes

Circumcision trays

Mechanical wheelchairs

II

Neonatal incubators

Dialysis catheters

Circumcision clamps

Powered wheelchairs

Apnea monitors

Transcutaneous electrical nerve stimulators

Ventriculoperitoneal shunts

III

Implantable insulin pumps

Implantable cardiac pacemakers

Ventricular assist devices

Cochlear implants

Deep brain stimulators

Class I Devices

Class I devices are considered to present relatively low risk to patients. As specified in statute (21 USC 360c(a)(1)(A)), this class covers

  • devices for which certain “general” controls (e.g., standards for good manufacturing practices) provide reasonable assurance of the safety and effectiveness of the device or

  • devices that are not intended or represented (“purported”) to support or sustain life or play an important role in preventing impairment or that are not expected to pose an unreasonable risk of illness or injury.

General controls apply to Class II and Class III as well as Class I devices. These controls are discussed further below.

Nearly all Class I devices and some Class II devices may be marketed without FDA clearance or approval. Examples of Class I devices that are not exempt from review under the notification procedures outlined below are dental mercury, mechanical wheelchairs, and surgeon’s gloves (FDA, 2005e,f,g). If a device that is normally exempt from FDA premarket clearance is to be marketed for a new intended use or involves a new fundamental technology, it would require a premarket clearance.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×
Class II Devices

Devices categorized as Class II present more risk than Class 1 devices. For a Class II device to be legally marketed, the manufacturer must usually submit a notification of intent to market and receive FDA clearance under “510(k)” provisions (referring to the applicable section of the Federal Food, Drug, and Cosmetic Act, 21 USC 360(k); see also FDA, 2004w). These 510(k) provisions cover devices that are “substantially equivalent” to a “predicate” or “pre-amendment” device, which is one that was either marketed before May 28, 1976 or one that has been shown (through the notification and clearance process) to be substantially equivalent to such a device.4

FDA considers a device substantially equivalent if it has the same intended use and the same technological characteristics as the predicate (pre-amendment) device. A device may also be considered substantially equivalent when it has the same intended use but different technological characteristics if these differences do not raise different questions of safety and effectiveness and if information (which can include clinical data) is provided to show that the device is as safe and effective as a legally marketed device. This latter definition allows FDA “the flexibility to clear some fairly novel devices through the 510(k) process” (Kahan, 1996, p. 89).

In assigning devices to Class II, FDA has determined that (1) general controls are not by themselves sufficient to provide reasonable assurance of safety and effectiveness, but (2) sufficient information is available to develop special controls for that purpose. These controls are discussed below.

For certain Class II devices, FDA issues guidance documents that describe what kinds of bench, animal, and clinical data should be submitted to show that a device is substantially equivalent to a predicate (preamendment) device. In 2002, for example, the agency issued guidance for manufacturers of carbon dioxide and oxygen monitoring devices about the kinds of information they should submit to document safety and effectiveness as part of a 510(k) submission (FDA, 2002d). Submission of clinical data is required for about 10 to 15 percent of devices covered by the 510(k) process (Tillman and Gardner, 2004). FDA also has the authority to require further studies for devices that are covered by regulations authorizing postmarket surveillance studies as discussed below.

4  

The provisions also apply to pre-amendment devices that have been classified as Class III devices but for which FDA has not yet issued regulations calling for premarket approval applications. A few Class II devices are exempt from the provisions, including pediatric hospital beds, enuresis alarms, and hematocrit measuring devices (FDA, 1998j).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×
Class III Devices

Class III devices are intended to support or sustain life or play an important role in preventing impairment or are considered to pose an unreasonable risk of illness or injury. For devices in this class, FDA has determined that general controls are inadequate to reasonably assure safety and effectiveness and that available information is insufficient to develop adequate special controls.5 As indicated by percentages cited earlier, many more devices enter the market through the clearance process than through the approval process (more than three times as many in 2004).

Usually, manufacturers of Class III devices must submit premarket approval (PMA) applications to FDA. As part of such applications, they must present the results of investigations—including data from clinical studies—that support the device’s safety and effectiveness for the use or uses proposed. After a device is approved, changes in the device, its labeling or packaging, or its manufacturing may require approval under a supplemental PMA application if the changes affect safety or effectiveness. Such supplemental applications also cover changes or other actions related to any postmarket studies that were required as a condition of approval of a device.

The 1997 legislation provided that manufacturers have an opportunity to meet with FDA to discuss their clinical investigation plan prior to submitting a PMA application. They may request a “determination meeting” to discuss what kind of scientific evidence (e.g., a randomized clinical trial) FDA considers necessary to demonstrate that a device is effective for its intended use. The resulting determination is binding on the agency, unless it is subsequently judged to be “contrary to public health” (FDA, 2001d, p. 1). In addition, the legislation provided the opportunity for an “agreement” meeting to those planning a PMA application or a 510(k) submission for certain devices. The purpose of such a meeting is to reach agreement on the main elements of the investigational plan, including the clinical protocol. The results of an agreement are again binding in most circumstances.

An alternative to the PMA application is the product development protocol (PDP), which was provided for by the 1976 Medical Device Amendments but not implemented until the 1990s (FDA, 1999e). The PDP pathway allows a manufacturer, with FDA agreement, to consult with FDA

5  

A new device may also be automatically classified as a Class III device because no predicate device exists, that is, the new device is not substantially equivalent to any other Class I or Class II device marketed before May 28, 1976, or to any device that was placed into Class I or Class II after that date. If a device is automatically classified into Class III because no predicate device exists to which it can be claimed equivalent and if the device presents a low risk to patients, the FDA Modernization Act of 1997 allows FDA to reclassify the device into Class I or II under a “de novo” or “risk-based” procedure (FDA, 1998k).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

to develop and implement a mutually acceptable device development testing protocol for a device. The manufacturer can then secure approval by submitting and having FDA accept a notice that it has fulfilled the requirements of the protocol.6 FDA considers this pathway appropriate for “those devices in which the technology is well established in industry” (FDA, 2003c, unpaged).

To comply with the FDA Modernization Act of 1997 (P.L. 105–115), FDA revised procedures for expedited review of PMA applications. Expedited review is allowed for devices that are intended to treat or diagnose life-threatening or irreversibly debilitating diseases or conditions and that also represent (1) breakthrough technologies, (2) technologies for which no approved alternatives exist, (3) technologies that offer significant advantages over existing approved alternatives, or (4) technologies the availability of which is in the best interest of patients (FDA, 2003i). Expedited review may involve advance consultation with FDA. (Provisions for expedited review also exist for products requiring premarket clearance.)

When a device is approved for marketing, FDA may impose requirements for further study of or reporting about a device to expand knowledge about its safety or effectiveness (21 CFR 814.82). These required studies are often referred to as condition-of-approval or post-approval studies. These studies and their monitoring by FDA are discussed further in Chapter 5.

Investigational Devices

For certain devices that have not been approved or cleared for marketing or that are being tested for indications not previously approved or cleared, use of the device during testing occurs under an “investigational device exemption” or IDE (21 USC 360j(g); 21 CFR 812.2(c)). An IDE is required for a “significant risk” device, which regulations define as one that presents a potential for serious risk to the health, safety, or welfare of a research participant (21 CFR 812.3(m)).7 The IDE regulations specifically

6  

The protocol is to include a description of (1) the device, including modifications; (2) any preclinical or clinical studies completed, underway, or planned; (3) manufacturing methods, facilities, and controls; (4) applicable performance standards, if any; (5) proposed labeling; and (6) other information deemed necessary by FDA. The manufacturer must also submit progress reports and information on studies described in the protocol.

7  

FDA may allow clinical use of unapproved devices in other situations, including certain emergency situations and certain situations in which a clinical study has been completed but the marketing application has not yet been approved. In addition, under so-called “compassionate use” provisions, FDA may allow use of an investigational device when it might benefit a patient who does not meet criteria for inclusion in research but who has a serious medical condition and no satisfactory alternative (FDA, 2003e).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

mention the potential for serious risk related to implants, life-supporting or life-sustaining devices, and devices that are substantially important in preventing impairments in health.

An IDE application must include information on preclinical studies and any already available clinical data. The sponsor must also submit an investigational plan that describes the research design and analytic methods to be used. The study cannot proceed until the IDE is approved by FDA and an Institutional Review Board (IRB).8 For studies involving significant risk devices, FDA and investigators or sponsors may engage in extensive communication and negotiation about the characteristics and objectives of research studies to support claims of product safety and effectiveness.

An IDE application is not required for a “non-significant risk” device study. The sponsor must, however, comply with certain recordkeeping and reporting requirements. In addition, even if an IDE is not required, research involving human participants is still subject to certain other requirements, including IRB review (see, e.g., FDA, 2003d). A study involving a “nonsignificant” risk device is said to have an “abbreviated IDE” or “deemed approved IDE.”

Humanitarian Use Devices

In addition to the clearance and approval processes described above, Congress has allowed devices to be approved for marketing under a Humanitarian Device Exemption (HDE). To qualify, a device must be intended for patients with a rare disease or condition for which no comparable device is available that has a 510(k) clearance or an approved PMA application for the proposed indication (21 USC 360j(m)). “Rare” is defined to mean that the condition affects or is manifested in (causes symptoms in) fewer than 4,000 individuals in the United States per year. Among other requirements, manufacturers seeking an HDE must present evidence that (1) provides a reasonable assurance of product safety when the device is used as proposed and (2) indicates that the probable health benefits of the device outweigh the potential for harm, taking into account the risks and probable benefits of available alternative therapies. Evidence of effectiveness is not required.

Granting of an HDE allows a company to market a device as a Humanitarian Use Device (HUD). Except in certain emergency situations, such a

8  

An IRB is a group of qualified individuals charged under federal regulation with protecting the rights and welfare of people involved in research in accord with federal regulations. IRBs review and approve plans for research involving humans.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

device can only be used in a health care facility following IRB approval and continuing review. (The IRB may approve use of the device on a case-by-case basis or under a research protocol or without any further restrictions.)

As is the case for a PMA application, FDA may order a manufacturer to conduct further studies as a condition of approval for an HDE (21 CFR 814.126(a), 814.82(a)(2)). For example, when FDA approved an HDE for the use of a left ventricular assist device with children, it required that the first 50 children receiving the device be followed to heart transplantation, death, or other outcome.

Least Burdensome Approach

The FDA Modernization Act of 1997 specified that the procedures and information required of manufacturers to demonstrate substantial equivalence for 510(k) clearance involve the “least burdensome means” for such demonstration (21 USC 360c(i)(1)(D)). Likewise, for devices requiring premarket approval, regulators are to “consider, in consultation with the applicant, the least burdensome appropriate means of evaluating device effectiveness that would have a reasonable likelihood of resulting in approval” (21 USC 360c(a)(3)(D)(ii)). Although the statutory provisions involve premarket clearance and approval processes, FDA has said it will apply the least burdensome concept to postmarket and other activities as well (FDA, 2002q, unpaged).

In attempting to put the least burdensome concept into practice, FDA has stated that it would apply these basic principles. First, “[t]he basis for all regulatory decisions will be found in sound science and the spirit and the letter of the law.” Second, “[i]nformation unrelated to the regulatory decision should not be part of the decision-making process.” Third, “[a]lternative approaches to regulatory issues should be considered to optimize the time, effort, and resources involved in resolving the issue consistent with the law and regulations.” Fourth, “[a]ll reasonable measures should be used to reduce review times and render regulatory decisions within statutory timeframes.” (All text quoted from FDA, 2002q.)

User Fees

In the Medical Device User Fee and Modernization Act of 2002 (P.L. 107–250), Congress authorized FDA to charge a fee for the review of 510(k) submissions and PMA applications. One major objective was to help speed the clearance or approval of devices by augmenting FDA resources. In contrast to the provisions for prescription drug user fees, device user fees are expressly allowed to be used for evaluating condition-of-approval postmarket studies and identifying safety and effectiveness issues

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

for devices (see 21 USC 379i(5)(j) and (k) and 21 USC 379j(h)(2)(A)(ii) for devices compared to 21 USC 379g(6) for drugs).

The legislation provided a complete waiver of fees for certain reviews involving pediatric use of a device. Specifically, if a company seeks clearance or approval of a device solely for pediatric use, the fee may be waived. If the company later seeks to add an adult indication, the user fee would be assessed at the regular level for a PMA review. If, however, a company has a device that has been cleared or approved for an adult indication and then seeks clearance or approval for a use that involves only a pediatric population, the fee may be waived.

According to FDA, 32 applications for FDA approval or clearance were exempted from user fees in FY 2004 (personal communication, Heather Rosecrans, Director, Premarket Notification, Office of Device Evaluation, CDRH, January 18, 2005). Two applications involved premarket approvals; the other 30 were applications for clearance under 510(k) procedures (7 of which involved a determination that the product in question was not a device). User fees do not apply to requests for Humanitarian Device Exemptions.

Off-Label or Unlabeled Use of Devices

A typical FDA letter granting approval of a PMA application states the indications for use of the device. Sometimes the approval letter may note limitations, for example, that the use is for those over a certain age. Likewise, each 510(k) clearance letter includes an accompanying “indications for use” page that states the cleared indications and any limitations on use (FDA, 2002f).

Once a device is approved or cleared, physicians may use the device for indications that are not mentioned in the device’s labeling but are not specifically restricted. Such use is sometimes called “off-label” or “unlabeled” use (see, e.g., FDA, 1998c, 2002f). It is considered part of the practice of medicine, which FDA—by statute—does not regulate (21 USC 396; FDA, 1998h).

When General or Special Controls Apply

General controls apply to all three classes of medical devices (FDA, 1998d). They include requirements for actions both prior to and after a device reaches the market. General controls require device manufacturers to

  • register each manufacturing location with FDA;

  • list their marketed devices with FDA;

  • comply with device labeling regulations;

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×
  • submit premarket notifications unless exempt;

  • follow quality system regulations (which incorporate good manufacturing practice requirements) in device production;

  • adhere to regulations banning adulterated and mislabeled devices;

  • comply with regulations related to record keeping and reporting; and

  • follow FDA requirements related to any notifications, recalls, or other actions associated with a defective device.

FDA can exempt Class I devices from certain general controls, including most quality system regulations/good manufacturing practices (21 USC 360c(d)(2)(A)). Examples of Class I devices that are exempt from most such practices are components of casts (e.g., a cast heel or cast toe cap), manual toothbrushes, mechanical walkers, and tuning forks used to test for hearing disorders (FDA, 2004r). Quality system regulations, which apply both prior to and following the marketing of most devices, are discussed further at the end of this chapter.

Special controls are intended to ensure the safety and effectiveness of Class II devices when general controls are not adequate to do so. Specific controls vary by device type. They may include special labeling requirements, guidance documents, performance standards, and required postmarket studies.

Labeling requirements vary for different kinds of devices. Generally, a device label must contain information about the name and place of business of the manufacturer and the device’s intended use or uses. The labeling should also include adequate directions for the safe use of the device. Devices aimed at patients or lay caregivers are to have labels that these individuals can understand and use whether or not they have also received instructions from health care professionals (FDA, 2001g). For some categories of devices, such as hearing aids, latex condoms, and menstrual tampons, FDA has established specific user or professional labeling requirements as well. In addition to the usual information about intended uses, hazards, contraindications, and similar matters, labels for investigational devices must state that they are limited by law to such uses (21 CFR 812.5(a)).

Mandatory performance standards have been developed for only a handful of product categories involving electronic or radiation-emitting products, some of which (e.g., microwave ovens and cell phones) are not medical devices (21 CFR 1010–1050).9 The only standard for a medical

9  

In 1995, FDA issued a proposed rule to establish a mandatory performance standard for apnea monitors, but the agency withdrew the rule in 2000 (FDA, 2000d). At the same time, it issued a guidance document on the monitors that described minimum performance, testing, labeling, and clinical criteria (FDA, 2000a).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

device is that for electrode lead wires and patient cables (FDA, 1997a). Rather than promulgating mandatory performance standards, FDA has focused on cooperation with other countries and private groups to develop national and international voluntary, consensus standards (Phillips and Less, 1999; see also Merrill, 1994).

Based on provisions of the Safe Medical Devices Act of 1990 (P.L. 101–629), FDA has developed special control guidance documents for several kinds of Class II devices. For example, when it created a separate device category for apnea monitors (to distinguish these devices from the generic category of breathing frequency monitors), FDA presented minimum performance, testing, and labeling recommendations (FDA, 2002m). Other special control guidance documents have been issued in conjunction with the reclassification of a device from Class III to Class II, as was recently done for arrhythmia detector and alarm devices (FDA, 2003h).

Another type of special control, Postmarket Surveillance (as narrowly defined in section 522 of the Federal Food, Drug, and Cosmetic Act) may be ordered by FDA for certain Class II or Class III devices. These orders, which can include the collection of clinical data, are discussed further below and in Chapters 5 and 6. In a 1998 document discussing the elimination of statutory requirements for Section 522 Postmarket Surveillance for certain devices, FDA stated that it “will consider the potential to collect postmarket surveillance data to allow more rapid progress [of a device] to market” (FDA, 1998g, p. 1).

In addition, as a condition of approval for a device that requires premarket approval, manufacturers are to provide FDA with an annual report that describes any changes made to the device during the reporting period. The report must also include a bibliography and summary of published and unpublished reports (that were not part of the PMA application) of clinical or laboratory studies involving the device or similar devices (21 CFR 814.84(b)(2)). (These requirements do not apply to devices cleared under 510(k) provisions.) In certain cases, FDA may request copies of the reports. The summary does not in itself amount to an assessment of the information reported.

BASICS OF POSTMARKET SURVEILLANCE

In this report, postmarket surveillance for medical devices refers primarily to activities that may be required or promoted by FDA or voluntarily undertaken by manufacturers or others to learn more about the safety and effectiveness of marketed medical devices and to respond to safety concerns. Some surveillance activities such as adverse event reporting cover all classes of medical devices whereas others, notably required postmarket surveillance studies, are restricted to a small subset of devices.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

As described in more detail below, FDA’s postmarket surveillance programs include adverse event reporting and analysis, medical device tracking for certain devices, and focused studies of selected products, including epidemiologic and other analyses undertaken or supported by FDA and studies required of manufacturers. When surveillance activities identify an important problem with a device, FDA is also responsible for identifying an appropriate response, for example, a public notice suggesting precautions for physicians or a request that a manufacturer recall a product.

Beyond these kinds of regulatory postmarket programs, many kinds of knowledge-building activities may occur after a device is approved for marketing. Such activities may be undertaken or funded by manufacturers or by other government agencies (e.g., National Institutes of Health [NIH] or Veterans Administration) for primary purposes other than surveillance. Such purposes include expanding the evidence base for clinical decisions, supporting coverage decisions by Medicare or other payers, identifying less costly ways of delivering health care, or extending the indications for use for which a device is explicitly approved. Thus, a manufacturer’s self-initiated postmarket study of a device to support FDA approval of a new use arguably does not meet the definition of surveillance, although such a study might generate information, including adverse event reports, that is also relevant to approved indications. Likewise, the investigation of radiation doses to children from repeated computer-assisted tomography might be undertaken in the first instance to generate knowledge to guide clinical practice, but such knowledge might also prompt adaptations by manufacturers of these devices and safety guidance from FDA (see, e.g., Feigal, 2001b).

In addition to clinical studies, clinicians may present or publish case reports of patients who have had a device-related problem that fits the definition of an adverse event. Although these clinicians may not knowingly be engaged in surveillance, their case reports may prompt attention from FDA or manufacturer surveillance programs. One challenge for FDA and for others interested in early warning of potential safety problems involves how to take better advantage of physician experiences in recognizing such problems without creating unduly burdensome or unproductive procedures or programs. Chapter 4 returns to this issue.

Mandatory and Voluntary Adverse Event Reporting

The Federal Food, Drug, and Cosmetic Act authorizes FDA to establish a system for the reporting of adverse events associated with legally marketed medical devices (21 USC 360i). Current FDA programs, which cover all classes of medical devices, provide for mandatory reporting from manufacturers, importers, and user facilities and voluntary reporting from others, including consumers and health care professionals. (Chapter 4 looks at adverse event reporting in more depth.)

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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The objective of adverse event reporting is to gain information about a medical device that assists FDA in protecting the public’s health by helping “to assure that such device is not adulterated or misbranded and to otherwise assure its safety and effectiveness” (21 USC 360i(a)). Although the statute uses the words “safety and effectiveness,” the specific reporting requirements focus on safety.

Mandatory Medical Device Reporting Program

In response to the Medical Device Amendments of 1976, FDA created the Mandatory Medical Device Reporting (MDR) program (21 CFR 803) for device manufacturers and importers.10 The implementing regulations became effective in 1984.11 The Safe Medical Devices Act of 1990 expanded reporting obligations to cover hospitals and other “user facilities” and device distributors. The Medical Device Amendments of 1992 (P.L. 102–300) added definitions of certain terms and established a single reporting standard for device manufacturers, distributors, and user facilities. Subsequently, the FDA Modernization Act of 1997 eliminated most reporting requirements for distributors, although they are required to maintain complaint files that include reports of adverse events (FDA, 2001i; 21 CFR 803.18(d)). The 1997 amendments also provided for a new surveillance system for user facilities as described later in this chapter.12

10  

In 1973, FDA created a limited, voluntary adverse event reporting program, the Medical Device Laboratory Product Problem Reporting Program (PRP). The program was replaced by the mandatory program in 1984 (Gardner and Flack, 1999).

11  

In addition to these requirements, FDA also requires reporting of adverse device reaction and device defect reports under regulations specifying post-approval requirements for manufacturers that are intended “to provide reasonable assurance, or continued reasonable assurance, of the safety and effectiveness” of an approved device (21 CFR 814.82(a)(9)). Reporting is required when the manufacturer learns of (1) a “mix-up” of the device or its labeling with another product; (2) an “adverse reaction, side effect, injury, toxicity, or sensitivity reaction that is attributable to the device” and that either is not covered by the device’s labeling or is covered by labeling but is unexpectedly more severe or frequent; or (3) “any significant chemical, physical or other change or deterioration in the device, or any failure of the device to meet the specifications established in the approved PMA that could not cause or contribute to death or serious injury but are not correctable by adjustments or other maintenance procedures described in the approved labeling” (FDA, 2002e, unpaged). If the deterioration or other change can be corrected by procedures described in the device’s labeling, then the manufacturer can report the event in its annual report. If reporting is required under these provisions and the MDR provisions, FDA specifies that the MDR provisions shall apply so that duplicate reports are not submitted.

12  

As of July 13, 2005, a “plain language” statement of the reporting rules was in effect, which might change some citations of regulations in this chapter (Federal Register, June 15, 2005, p. 34652).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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BOX 3.1
Selected Definitions Related to Medical Device Reporting Requirements

Manufacturer

One who manufactures, prepares, propagates, compounds, assembles, or processes a device by chemical, physical, biological, or other procedure. Also includes U.S. agents of foreign manufactures, those who establish specifications for devices manufactured by another party and who then distribute those devices, and those who repackage or otherwise change the container, wrapper, or labeling of a device.

Importer

One who imports a device into the United States and who furthers the marketing of a device from the original place of manufacture to the person who makes final delivery or sale to the ultimate user. Does not include those who repackage or otherwise change the container, wrapper, or labeling of the device or device package.

Distributor

One who furthers the marketing of a device from the manufacturer to the entity that makes final delivery or sale to the ultimate user.

Device user facility

A hospital, ambulatory surgical facility, nursing home, outpatient diagnostic facility, or outpatient treatment facility.a Does not include physician’s offices, school nurse offices, or employee health units.

Reportable event

  1. An event about which a user facility becomes aware of information that reasonably suggests that a device has or may have caused or contributed to a death or serious injury; or

  2. An event about which a manufacturer or importer has received or become aware of information that reasonably suggests that one of its marketed devices:

    1. may have caused or contributed to a death or serious injury; or

    2. has malfunctioned and that the device or a similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

Box 3.1 defines several terms used in the reporting regulations. Under FDA regulations, home health care agencies are considered to be user facilities. Those who supply medical equipment to patient’s homes are considered to be distributors.

Box 3.2 summarizes adverse event reporting requirements for medical

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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Serious injury

An injury or illness that (1) is life threatening, (2) results in permanent impairment of a body function or permanent damage to body structure, or (3) requires medical or surgical intervention to preclude permanent impairment or damage.

Caused or contributed

When a death or serious injury was or might have been attributed to a medical device or when a medical device was or might have been a factor in a death or serious injury, including events that result from

  1. failure,

  2. malfunction,

  3. improper or inadequate design,

  4. manufacture,

  5. labeling, or

  6. user error.

User errorb

An error made by the person using the device that may be the sole cause of or merely a contributor to a reportable event.

Complaint

A written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.

Remedial action

An action, other than routine maintenance or servicing of a device, that is necessary to prevent recurrence of a reportable event.

a  

Nursing homes primarily provide skilled nursing care and related services for persons who require medical or nursing care. They may also provide hospice care to the terminally ill or rehabilitative services. Outpatient treatment facilities provide nonsurgical therapeutic (medical, occupational, or physical) care on an outpatient basis or in a home health care setting. The category includes ambulance providers, rescue services, and home health care agencies.

b  

The term “user error” was defined in a guidance document rather than regulations (FDA, 1997b). The generally preferred term is now “use error,” which is consistent with a systems perspective that deemphasizes individual blame for errors and focuses on circumstances that put users of a device at risk of making errors.

SOURCES: 21 CFR 803.3 and 820.3(b).

device manufacturers and importers.13 In general, regulations require that they (1) report deaths and serious injuries that a device has or may have

13  

For a device designed and labeled for single use that is reprocessed, the manufacturer for purposes of adverse event reporting is the entity that does the reprocessing (e.g., a reprocessing company or a health care facility that does its own reprocessing) (FDA, 2004q).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

BOX 3.2
Medical Device Reporting Requirements for Device Manufacturers

  1. Report individual adverse events to FDA within 30 calendar days after learning of a reportable death, serious injury, or device malfunction;

  2. Report individual adverse events within 5 working days after learning of (a) an event that requires remedial action to prevent an unreasonable risk of substantial harm to the public health or (b) an event for which FDA has made a written request for reports;

  3. Submit supplemental reports within 1 month after obtaining additional information that was not provided in an initial event report;

  4. Submit baseline reports that provide basic information (e.g., brand name, model number) about a device after the first reportable event involving that device;

  5. Provide annual updates of changes in baseline information;

  6. Maintain complete medical device reporting files that include, among other items, information about deliberations and processes used to determine whether an event was reportable; and

  7. Develop and follow written procedures for reporting adverse events.

SOURCES: 21 USC 360i; 21 CFR 803.10; FDA, 1997b, 2000f.

caused or played a role in causing, (2) report device-related malfunctions that could cause a death or serious injury, (3) establish and maintain adverse event and complaint files, and (4) submit certain follow-up or summary reports to FDA. In contrast to the provisions for adverse drug event reporting, the reporting requirements for medical devices do not distinguish between expected (e.g., listed in a drug’s labeling) and unexpected adverse events (21 CFR 314.80; FDA, 2001f).

In their reports, manufacturers must include information about whether a device was returned and evaluated, the method and findings of evaluation, and any remedial action such as a recall or labeling change. In addition to requirements for adverse event reporting, separate “quality system” regulations include requirements for timely review and evaluation of complaints and for maintenance of complaint files (21 CFR 820.198).

Manufacturers are not required to report all complaints or information received but rather must evaluate this information to determine whether it involves a reportable event. Companies may receive information or complaints by telephone, fax, mail, or e-mail from consumers, health care workers, health care facilities, vendors, or their own sales or service representatives or other employees. They may also become aware of possible problems through scientific articles, news reports, professional conference presentations, or communications from FDA or other government agencies.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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BOX 3.3
Medical Device Reporting Requirements for User Facilities

  1. Report to both FDA and the manufacturer within 10 working days any death that a device might have caused or to which it might have contributed;

  2. Report to the manufacturer (or to FDA if the manufacturer is not known) within 10 work days any serious injury that a device might have caused or to which it might have contributed; and

  3. Provide annual summary to FDA of the number of adverse events (deaths or serious injuries) reported to FDA or manufacturers.

SOURCES: 21 USC 360i; 21 CFR 803; FDA, 2001i.

Box 3.3 summarizes reporting requirements for user facilities (as defined in Box 3.1). (The requirements apply to devices, but not to drugs or biologics for which reporting is voluntary.) User facilities must report deaths to both FDA and the manufacturer but need to report serious injuries to FDA only if they do not know the manufacturer of the device. Unlike manufacturers, facilities are not required to report device malfunctions unless they actually cause death or serious injury. That is, they need not report close calls that had the potential to cause serious harm, although reporting of such close calls is increasingly recognized as providing an opportunity to make changes in systems or devices to prevent harm (see, e.g., IOM, 2000c; Wald and Shojania, 2001a). In addition, the regulations do not require facilities to investigate adverse events, although they may do so under their own patient safety policies and procedures or voluntary accreditation standards.

FDA has emphasized that the privacy provisions of the Health Insurance Portability and Accountability Act of 1996 (P.L. 104–191) should not “disrupt or discourage adverse event reporting” (FDA, 2003b, unpaged). That legislation explicitly allows for the reporting to FDA and manufacturers of adverse events and other information related to the quality, effectiveness, and safety of FDA-regulated products. The forms and procedures for mandatory reporting are described further in Chapter 4.

The adverse event reporting regulations described above do not apply to investigational devices. Rather, FDA regulations that govern use of investigational devices require that researchers report any adverse device “effect” to the research sponsor and the Institutional Review Board that approved the research (21 CFR 812.150; see also 21 CFR 812.46(b)). Sponsors are then to evaluate such reports and, in turn, report “unanticipated adverse device effects” to FDA and all participating investigators and review-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

ing IRBs. Some clinical trials have special data monitoring committees (or—in NIH terminology—data and safety monitoring boards) with special responsibilities for monitoring the safety of clinical trials, including evaluating adverse event reports and outcome data. FDA has issued guidance on the use of such bodies (FDA, 2001c).

Alternative Summary Reporting for Manufacturers

Although required reporting is not limited to unexpected adverse events involving medical devices, FDA is most interested in the detection of unexpected, serious problems or recognized problems that are occurring more frequently than expected (e.g., given the data from clinical studies on which marketing approval was based). FDA has created an Alternative Summary Reporting program that allows manufacturers to submit abbreviated reports for certain well-known and well-documented problems. Examples include breast implant ruptures and shearing of central line catheters (FDA, 2004b).

Approximately 80 manufacturers and 40 different types of classified devices were participating in this alternative reporting program in 2004 (personal communication, Thomas P. Gross, M.D., Director, Division of Postmarket Surveillance, CDRH, October 8, 2004). Participation in the program requires FDA agreement (FDA, 2000c). Summary reports do not include information that allows identification of events involving children.

Voluntary Reporting for Health Professionals and Consumers

In addition to the mandatory reporting requirements for manufacturers, importers, and user facilities, FDA also provides health professionals and consumers the opportunity to report adverse events on a voluntary basis through its MedWatch program.14 (See Chapter 4 for further discussion.) MedWatch covers drugs, biologics, and nutritional supplements as well as devices. It also provides information about medical product safety, including recall announcements and safety advisories. The introductory online reporting information provided to health care professionals emphasizes that MedWatch is not to be for reporting adverse events associated with clinical studies, vaccines, veterinary products, or mandatory reporting

14  

The MedWatch website also includes information and forms for mandatory reporting. FDA uses the term medical device reporting or MDR to refer to mandatory reporting while describing MedWatch as its program for voluntary reporting for consumers and health professionals (FDA, 2002l). The MedWatch website, however, has the banner “The FDA Safety and Adverse Event Reporting Program” (see website at http://www.fda.gov/medwatch/).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

situations (FDA, 2004z). A separate reporting system exists for vaccines, the Vaccine Adverse Event Reporting System (VAERS), which is managed jointly by FDA and the Centers for Disease Control and Prevention (CDC).15

Adverse Event Information Available to the Public

FDA maintains electronic files of adverse event reports for its own use. It makes a subset of the information available for public access. The Manufacturer and User Facility Device Experience (MAUDE) database includes all voluntary consumer and professional adverse event reports since June 1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since August 1996. Manufacturer reports for 1992 through July 1996 are maintained in the Device Experience Network database.

Before information from adverse event reports is made available to the public, FDA deletes

  • information involving trade secrets or confidential commercial or financial data;

  • personal medical or other information (including the serial number of implanted devices) that could identify individual patients or family members; and

  • identifying information about consumers or health care workers who submit a voluntary report.

To protect patient privacy, records in the FDA public file do not include categories of potentially identifying patient information from the reporting forms, for example, patient birth date, age, weight, or sex. In some cases, the narrative information for an individual adverse event report may make it evident (by using terms such as child, baby, or infant) that a child was involved. Although FDA staff have access to the complete information, the deletions mean that users of the public files are more limited in their ability to identify reports involving children. As noted above, HIPAA

15  

Congress established VAERS in the National Childhood Vaccine Injury Act of 1986 (P.L. 99–660). The legislation required health professionals as well as manufacturers to report, and reports are also submitted by state and local health departments and by patients and parents. Following direct mailings, continuing medical education, and other efforts to increase reporting by professionals, the proportion of all reports that were attributed to health care professionals increased from 11 percent in 1991 to 35 percent in 2001 (Zhou et al., 2003). The 1986 legislation also created a no-fault compensation system for people thought to have been injured as a result of certain recommended childhood immunizations.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

privacy provisions explicitly allow for adverse event reporting as set forth in FDA regulations. (Confidentiality and trade secret issues are discussed further below.)

Pilot Program for Adverse Event Reporting: MedSun

As discussed in Chapter 4, passive surveillance systems have a number of limitations as means of monitoring the safety of medical devices after they have reached the market. Limitations in user facility reporting have been a particular concern. According to FDA, manufacturers reported 980 device-related deaths to the agency in 1998 while user facilities reported 277 such deaths that year. FDA concluded that the discrepancy between the two figures is “one measure of underreporting” by user facilities (Gardner and Flack, 1999, unpaged).

The FDA Modernization Act of 1997 directed FDA to develop a new system for adverse event reporting by a subset of user facilities that offers a “representative profile of user reports” of deaths and serious illnesses or injuries related to a device (21 USC 360i(b)(5)). The legislation did not otherwise specify the characteristics of this new system, which, when fully implemented by regulation, is to replace the existing requirements applicable to all user facilities.

Prior to the 1997 legislation, FDA had already begun work on a sentinel surveillance system based on an analysis of problems with the existing reporting system. It launched an initial pilot study (Devicenet) that involved some 23 health care facilities in the Washington/Baltimore and Raleigh/Durham areas plus one Boston hospital (Gardner and Flack, 1999). In a second phase starting in 2002, FDA began to recruit a larger number of facilities, primarily from the East Coast. By the end of 2004, recruitment had extended to the West Coast, and more than 300 facilities were participating (FDA, 2004b; personal communication, Marilyn Flack, M.A., Policy Analyst, CDRH, January 3, 2005). This expanded system is known as the Medical Product Surveillance Network or MedSun.

MedSun participants agree to submit both mandatory and voluntary user facility reports. If participants submit an adverse event report that is mandated under current regulations, MedSun staff forward the report to the manufacturer. For voluntary reports (e.g., “close calls” that do not result in harm), participants can tell MedSun staff whether they want such reports to be forwarded or not (although FDA encourages such forwarding).

After FDA has gained extensive experience with MedSun and before writing new regulations for user facility reporting, the agency will evaluate the program to determine which aspects are most useful in promoting reliable, accurate reporting of adverse device events. The pilot program is discussed further in Chapter 4.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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Required Postmarket Surveillance Studies and Condition-of-Approval Studies

As discussed in Chapter 1, Section 522 of the Federal Food, Drug, and Cosmetic Act uses the term Postmarket Surveillance to describe one type of surveillance, specifically, studies and other information collection that FDA may require manufacturers to undertake to gather additional safety and efficacy data for a small group of Class II and Class III devices (21 CFR 822). As originally provided for in the Safe Medical Devices Act of 1990, such surveillance was required for devices introduced into interstate commerce after January 1, 1991, that were (1) permanent implants that could cause serious adverse outcomes or death if they failed, (2) devices intended for use in supporting or sustaining human life, or (3) devices that presented a potential serious risk to human health. The legislation also provided that FDA could require this kind of Postmarket Surveillance for other devices, regardless of the date introduced to the market, if FDA deemed it necessary to protect the public health.

The FDA Modernization Act of 1997 eliminated the provisions for required Section 522 Postmarket Surveillance. Instead, it gave FDA the discretion to order studies or other information collection for any Class II or Class III device that (1) would be reasonably likely to have serious adverse health consequences if it failed; (2) is intended for implantation for more than 1 year; or (3) is intended to be life sustaining or life supporting and to be used outside a health care (“device user”) facility. Devices in the last category include those intended to be used at home. The legislation also provided for greater latitude in the methods that could be used in undertaking this kind of surveillance activity. According to FDA guidance, approaches might include a review of scientific literature, analysis of secondary datasets (e.g., Medicare data), nonclinical testing of a device, analysis of a manufacturer’s complaint file for a device, and various types of experimental or observational studies (FDA, 1998g).

In 1998, FDA announced the end of mandatory Postmarket Surveillance for several device categories, including pacemakers (generators), replacement heart valves, and coronary vascular stents (FDA, 1998e). Requirements continued for several other devices, including silicone breast implants, pacemaker leads, and temporomandibular joint prostheses. According to FDA staff, only two Section 522 Postmarket Surveillance studies have been ordered since the 1997 legislation (Tillman and Gardner, 2004). (See Chapter 5 for further discussion of these studies.)

As described by FDA, the primary objective of this particular type of surveillance “is to study the performance of the device after marketing as it is to be used in the general population for which it is intended … [with a focus on] morbidity or mortality … [and on] device failure and its atten-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

dant impact on the patient” (FDA, 1998b, unpaged). The criteria FDA considers in determining whether to order this kind of surveillance include the existence of an important unanswered surveillance question (e.g., how well home users of a device retain training for devices that have moved from professional to home use), the potential for other postmarket tools to answer the question, significance of the risk to public health related to the question, and the feasibility of a study (FDA, 1998g). Manufacturers ordered to conduct a Section 522 Postmarket Surveillance study must submit a surveillance plan for approval within 30 days of receiving the order.

Section 522 studies are not explicitly required to have IRB approval or informed consent (in contrast to IDE investigations, which are covered by Section 520(g). Although FDA regulations do not mention IRB review and approval of postmarket clinical studies, they do not explicitly exclude them from such requirements (21 CFR 56.104). FDA has said that its review of a manufacturer’s plans for required postmarket surveillance would consider whether appropriate patient protections are needed and included (FDA, 2002o). Depending on the specifics of the surveillance plan, other federal regulations or research institution policies may require IRB review even if FDA does not.

As noted above, only two Section 522 studies have been ordered in recent years. More common are study requirements imposed at the time a PMA application is approved. Although these condition-of-approval studies necessarily take place after a device has entered the market, the studies traditionally have not been considered part of the postmarket surveillance program. Recently, however, the agency shifted responsibility for monitoring and evaluating these studies from the Office of Device Evaluation to the Office of Surveillance and Biometrics.

Medical Device Tracking

The tracking of medical devices is intended to assist the prompt notification of users when a device presents a serious, immediate risk to health and to speed the recall of such a device when appropriate. The Safe Medical Devices Act of 1990 required that certain medical devices (those with the same characteristics as those for which the legislation required postmarket surveillance studies) be tracked so their location could be determined if needed. The FDA Modernization Act of 1997 made tracking of such devices discretionary. In the following 2 years, FDA rescinded dozens of mandatory device tracking orders across several product categories (FDA, 1998a).

In considering whether to issue a tracking order, FDA may consider the likelihood that a device will experience a sudden, catastrophic failure; the potential for a significant adverse health outcome in the event of such a

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

failure; and the potential need for prompt professional intervention in such a situation (FDA, 2003j). Such orders may apply to devices already on the market or to newly cleared or approved devices. FDA now requires tracking for 12 implantable devices, including temporomandibular joint prostheses, implantable pacemaker pulse generators, mechanical heart valves, and implantable infusion pumps (FDA, 2003j). It also has required tracking for four devices used outside hospitals and similar facilities. The requirement covers ventricular bypass assist devices, breathing frequency monitors, continuous ventilators, and direct-current defibrillators and paddles.

Manufacturers should be able to provide key information to FDA about the location of a tracked device within 10 working days for devices that have already been distributed to patients and within 3 days for those that have not. For tracked devices not intended for reuse, required information includes the name and contact information for the patient, the prescribing physician, the physician who is following the patient, and all distributors of the device. For a device intended for reuse, the manufacturer must be able to provide information about the distributor, the patient currently using the device (if available), the prescribing physician, and the date the device is returned to the manufacturer, destroyed, retired from use, or remarketed. Tracking continues for the life of the device, unless FDA rescinds the tracking order. Device distributors, including hospitals and physicians that supply tracked devices to patients, must make their tracking records available to manufacturers when requested. Patient consent for tracking is not required, but patients may refuse to provide or authorize release of their personal information for purposes of having their device tracked.

RESPONSES TO POTENTIAL SAFETY PROBLEMS

When it is reasonably clear that a problem exists, understanding that problem and evaluating an appropriate response may take considerable analysis. For example, after a 6-year-old boy suffered fatal skull injuries when a magnetic resonance imaging (MRI) scanner pulled an oxygen device into the scanner’s magnetic field, what is now the Office of Science and Engineering Laboratories studied the effects of large magnetic fields on such devices and found that effects were too inconsistent to support general conclusions (OST, 2002). The broader problem of MRI magnetization of nearby metal items, including certain implanted medical devices, has been recognized by FDA, clinicians, and manufacturers for many years (FDA, 2001k). Various groups, including FDA, ECRI, American College of Radiology, and International Electrotechnical Commission (which publishes international standards for electrical, electronic, and related technologies) have issued safety guidance and standards for MRI use.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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FDA and manufacturers have several options in responding to an identified safety problem. Responses may differ depending on whether the problem is newly recognized or already known.

Recalls and Corrections

Once a manufacturer or FDA concludes that a problem with a device exists, several steps are possible. At one extreme, a manufacturer may recall all units of a device and cease manufacturing it temporarily or permanently. For example, after a children’s hospital reported a number of infections following use of a device for detecting carbon dioxide in tissues and then identified an infectious agent in the saline packaging for the device, the manufacturer issued a voluntary recall of the device and ceased production pending determination of the source of the contamination problem (Tyco, 2004; also FDA, 2004u).

To cite another example, a manufacturer of a disposable blood pressure cuff for neonates recalled some 26,000 units after problems were noted with the inflatable portion of the cuff (FDA, 2004g). Subsequently, after FDA noted deficiencies in good manufacturing practices, the company initiated another recall of more than 220,000 units (FDA, 2004f). Recalls may involve only certain specific lots or units, for example, units that were affected by a transient and since-corrected manufacturing problem.

One recent recall involved only the revised instructions for use of a stent that had been cleared for treatment of certain bile duct obstructions (Cordis, 2004). The recall was based on two concerns: first, the revised instructions involved indications for vascular use that had not been cleared by FDA, and second, several injuries and malfunctions had been reported with use of the device outside of the approved indications (FDA, 2004s).

Recalls may be undertaken at a manufacturer’s own initiative, as a result of an FDA request, or—rarely—after an FDA order. The agency almost always relies on voluntary manufacturer action to recall hazardous products. Voluntary device recalls not undertaken at the request of FDA must be reported to the agency if they meet certain requirements specified in the regulations (21 CFR Part 806.10) (see Class I or Class II recalls, as defined below). FDA has the statutory authority to order a recall of a medical device under very restricted circumstances—only after a finding that there is a reasonable probability that a device “would cause serious, adverse health consequences or death” and when certain other conditions are met (e.g., a company refuses to recall a product voluntarily following an agency request (21 CFR 810.10).

FDA guidelines categorize recalls into three classes based on the extent of the hazard (FDA, 2004j). They are

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×
  • Class I recalls involve dangerous or defective products that have a reasonable probability of causing serious health problems or death. Example: recall of the carbon dioxide sensor described above. Example: recall of a ventilator for a malfunction that might result in overpressure, culminating in serious injury or death in patients whose body weight is less than 20 kilograms (FDA, 2000e).

  • Class II recalls involve products that might be expected to cause a temporary health problem or that pose only a slight threat of a serious nature. Example: recall of certain unimplanted cochlear implants because of the potential presence of moisture in the internal circuitry of the devices, which could cause loss of function (FDA, 2004i).

  • Class III recalls involve products that are unlikely to cause any adverse health reaction but that violate FDA labeling or manufacturing regulations. Example: a nephroureteral stent system that was mislabeled as to size (FDA, 2004h).

Depending on the danger involved, FDA may or may not publicize a manufacturer recall beyond including the information in its list of enforcement actions (which can be found at http://www.fda.gov/po/enforceindex/2004enforce.html). Likewise, the intensity of FDA monitoring of the recall process varies depending on the risk presented by the device problem (Blevins, 2003). Recently, FDA began issuing press releases for all Class I recalls (personal communication, Thomas P. Gross, M.D., Director, Division of Postmarket Surveillance, CDRH, May 13, 2005).

Rather than seeking the physical removal of a device from user facilities (or from patients, in the case of some implants), a manufacturer may institute a correction, a type of recall that involves the “repair, modification, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a product without its physical removal to some other location” (FDA, 2002i, unpaged).16 A correction might involve a manufacturer representative visiting affected facilities and replacing or otherwise fixing a malfunctioning device. A corrective action, in contrast, is intended to eliminate the basic cause of the problem, for example, through redesign of a device.

16  

FDA’s MedWatch website lists safety-related changes in labeling for drugs but not for devices (see FDA, 2005d). To cite a well-publicized example, in March 2004 FDA issued a public health advisory that asked manufacturers to change the labels of several antidepressant drugs to warn physicians to monitor patients for worsening of depression and evidence of suicidal thoughts or behavior (FDA, 2004l; see also FDA, 2004k).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

Public Health Notifications

For many device-related problems, a less dramatic response than a recall is appropriate. One option is for FDA to issue a Public Health Notification, a term that FDA has recently decided to apply comprehensively to what had been distinguished as Safety Alerts, Public Health Notifications, and Public Health Advisories (Schultz, 2004). (All notifications since 1983 are provided or listed at http://www.fda.gov/cdrh/safety.html#web).

The information provided in Public Health Notifications is quite varied. Some notifications involve individual products (e.g., a particular brand of drug-eluting stent), whereas others concern a general type of product (e.g., hospital beds). Notifications may discuss newly identified problems (e.g., the notification about meningitis linked to cochlear implants, which included recommendations for recognizing the condition, treating it, and vaccinating to prevent it (Pressly, 2003)). As discussed below, notifications may also provide safety tips or information related to previously recognized problems.

Information included in a Public Health Notification may be disseminated to user facilities, health professionals, health educators, and consumers in various ways designed to fit the topic and the audiences. Methods include letters, e-mail notifications, items in FDA electronic newsletters, posting on various FDA webpages, press releases, articles and other communications in professional journals, and conference and other presentations.

Consistent with FDA requirements, manufacturers likewise may use a number of strategies for alerting user facilities, professionals, or consumers about device problems, including phone calls and certified letters. For notifications that do not involve company-initiated recalls and other actions, FDA does not require companies to disclose the existence of a Public Health Notification about their product, although they may do so voluntarily.

Device Redesign and Preventive Design

Again, depending on the nature of an identified problem and discussions with FDA and others, a manufacturer may respond to a problem by modifying the design of a device (e.g., relocating or shielding a switch, discontinuing the use of a troublesome material) or changing the manufacturing process (e.g., redesigning sterilization procedures). Analyses undertaken by FDA of data on device recalls from 1983 to 1989 found that more than 40 percent of the quality problems that prompted recalls could be traced to product design deficiencies (FDA, 1990). That same year, another study conducted by the Inspector General of the Department of Health and Human Services reached similar conclusions (OIG, 1991).

Depending on initial information, FDA staff may become involved in

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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analyses of the design of devices associated with multiple adverse event reports. Examples include glucose meters, infant apnea monitors, ventilators, and infusion devices (Wiklund, 2003). Although not expressed in terms of design changes per se, in 2002 FDA issued a guidance document for apnea monitors that identified risks to health associated with the monitors and recommended device features or testing procedures to mitigate each risk (FDA, 2002c).

In addition to considering whether design problems have contributed to reported adverse events, FDA also seeks to prevent safety problems related to design deficiencies. Quality system regulations, which apply to the development and manufacture of devices (and, thus, apply both before and after a device is marketed), emphasize the detection and correction of problems during the manufacturing process. The goal is to prevent the problems that would trigger a recall or Public Health Notification.17

Responses to Familiar Problems

As noted above, the focus of adverse event reporting and other postmarket surveillance activities is on the detection of unexpected, serious problems or recognized problems occurring more frequently than expected. Sometimes, however, the agency targets familiar, well-recognized problems for special initiatives and collaborations with other public and private groups.

For example, in 2001, FDA issued a notice on reducing the radiation risk from computed tomography for pediatric and small adult patients (Feigal, 2001b). The agency acknowledged that the recommendations were not new, but it decided it was important to emphasize that radiation doses for small patients should be kept as low as possible, consistent with achieving clinical objectives.

On another front, FDA has created a home health care committee to review what FDA has done and might do to respond to problems with the use of complex medical devices in the home (see, FDA, 2004c). The agency has recognized that the use of sophisticated medical devices in the home, while an accepted and necessary part of modern health care, “adds an additional level of risk of unintended adverse events” (Arcarese, 2002a, unpaged). Based on discussions with a range of interested parties, the home health committee has decided to focus in particular on safe use of infusion pumps in the home. It

17  

The relevance of design controls to the prevention of safety problems is suggested by this FDA description of what might be required of a manufacturer planning a new defibrillator for use by hospital and emergency medical personnel. “Designers would have to consider all aspects of use in both settings … [including] storage temperatures in the ambulance, road shock and vibration, two-way radio interference, electrical noise generated by the siren and many other factors” (FDA, 1996a, unpaged).

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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has asked pump manufacturers to provide basic information and use instruction for every infusion pump marketed since 1984. The information will be included on the committee’s website to allow ready access to such information by patients, family members, and home care nurses.18

CONFIDENTIALITY OF INFORMATION OBTAINED BY FDA

Much information that FDA receives is confidential or is treated as confidential. The scope of agency confidentiality requirements or practices has been a prominent focus of criticism during recent controversies about the availability of information from postmarket studies of drugs. As discussed in Chapters 5 and 6, the committee’s efforts to learn more about the status or findings of postmarket studies ordered by FDA were limited by agency confidentiality policies (as well as by the agency’s lack of an adequate study monitoring system).

Confidentiality protections for information submitted to FDA are provided by three key federal statutes: the Federal Food, Drug, and Cosmetic Act (21 USC 301 et seq.), the Freedom of Information Act (5 USC 552), and the Trade Secrets Act (18 USC 1905). Implementing regulations clarify how these protections apply to study protocols and to preclinical and clinical study data, as well as to information relating to product design, product composition, and manufacturing methods and processes. Confidentiality provisions of the Privacy Act (5 USC 552a) also restrict the disclosure of information about individuals, including patients and health care personnel. Confidential information can, of course, be leaked or released mistakenly, but the provisions described here normally operate as intended to restrict disclosure of covered categories of information.

FDA personnel are prohibited from disclosing (or from using to their own advantage) information acquired under their statutory authority that concerns “any method or process which as a trade secret is entitled to protection”19 (21 USC 331(j)). This provision covers information acquired by FDA under investigational device exemption applications, 510(k) premarket notifications, and premarket approval applications, or otherwise acquired under authority of various statutory provisions. The provision does not expressly include Section 522, which authorizes FDA to require

18  

The home care committee has already issued a pamphlet for consumers on blood glucose monitors and prepared a checklist for consumers to promote safe use of devices in the home (FDA, 2003m).

19  

This provision does not authorize the withholding of information from the U.S. House of Representatives, Senate, or a committee or subcommittee thereof with jurisdiction over the specific subject matter.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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postmarket surveillance and requires a manufacturer to submit a plan for the required surveillance (21 USC 360(l)). FDA, however, treats such plans as protected from public disclosure under provisions of the Freedom of Information Act and FDA’s implementing regulations. Interim and final reports of postmarket surveillance studies or data are treated similarly, although limited findings may be made public in connection with a safety advisory, the approval of a new indication for a product’s use, a labeling change, or similar action. Data and information relating to postmarket studies conducted under an IDE would be protected consistent with the IDE confidentiality regulations.

More broadly, the federal Trade Secrets Act prohibits federal employees from disclosing information which “concerns or relates to the trade secrets, processes, operations, style of work, or apparatus or to the identity, confidential statistical data, amount or source of any income” or other financial information of any person or company (18 USC 1905). The Trade Secrets Act is a criminal statute. Likewise, a violation of disclosure provisions of the FDA statute (21 USC 331(j)) is subject to criminal penalties (21 USC 333(a)). Congress can, however, request or subpoena information including trade secret and confidential commercial information, and that is not subject to 331(j) nondisclosure.

In addition, FDA can require that a summary of safety and effectiveness information be submitted to document the basis for premarket approval, and the agency can release the summary to the public once it has issued an approval order. Such a summary “shall include information respecting any adverse effect on health of the device” (21 USC 360j(h)(2)). Much of the committee’s understanding of the kinds of studies submitted to support PMA approvals was obtained by reading individual approval summaries, which are posted on the CDRH website.

Otherwise, by statute, information contained in a PMA application is to be held confidential and is not to be used by FDA to approve another manufacturer’s PMA application, to establish a performance standard or special control, to reclassify a device, or to approve a product development protocol (21 USC 360j(c)). An exception is that information from preclinical or clinical tests or studies that demonstrate safety or effectiveness can be used by FDA for these purposes 6 years after the approval of the PMA application, but this exception does not cover information regarding “methods of manufacture and product composition and other trade secrets” (21 USC 360(j)(h)(4)).

An FDA regulation provides confidentiality protections for PMA filings (21 CFR 814.9). It provides that the existence of a PMA filing will not be disclosed by FDA if its existence has not been disclosed by the applicant, up until the time the PMA application is approved or denied approval. An exception permits FDA to disclose a summary of portions of the safety and

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

effectiveness data prior to approval “if disclosure is relevant to public consideration of a specific pending issue” (21 CFR 814.9(d)(1)). After approval, FDA can disclose certain information in the PMA application, except for trade secret or confidential commercial information. FDA can disclose: (1) safety and effectiveness data “previously disclosed to the public”; (2) a protocol for a test or study “unless the protocol is shown to constitute trade secret or confidential commercial or financial information” protected under the Freedom of Information Act and implementing regulations; (3) adverse reaction reports, consumer complaints, and similar data and information—but only after deleting trade secret or confidential commercial or financial information and deleting personnel, medical, and similar information the disclosure of which would constitute an unwarranted invasion of personal privacy; (4) assay methods and other analytical methods, unless they do not serve a regulatory purpose and they are trade secret or confidential commercial information; and (5) a list of components previously disclosed to the public. FDA cannot disclose: (1) safety and effectiveness information not previously disclosed to the public that constitute trade secret or confidential commercial information; (2) manufacturing methods or processes, including quality control procedures; (3) quantitative or semi-quantitative formulas; and (4) production, sales, distribution, and other similar data and information.

Data and information contained in an IDE is handled in accordance with the PMA regulation in Section 814.9 (21 CFR 812.38(d)). Similar confidentiality provisions apply to data and information contained in a 510(k) notification and disclosure of the existence of a 510(k) notification prior to its clearance (21 CFR 807.95). An exception exists under all these regulations that permits FDA to disclose a summary of portions of the safety and effectiveness data prior to approval or clearance “if disclosure is relevant to public consideration of a specific pending issue.”

The Freedom of Information Act directs federal agencies to make information in agency files available to the public, but certain information is exempted from public disclosure. Among the types of exempted information are (1) “trade secrets and commercial or financial information obtained from a person and privileged or confidential,” (2) “personnel and medical files and similar files the disclosure of which would constitute a clearly unwarranted invasion of personal privacy,” and (3) information specifically exempted from disclosure by statute (5 USC 552(b)(3), (4), and (6)). FDA has issued regulations implementing these exemptions. Under the regulation applicable to trade secrets and confidential commercial information (21 CFR 20.61), FDA has defined these terms as follows:

(a) A trade secret may consist of any commercially valuable plan, formula, process, or device that is used for the making, preparing, com-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

pounding, or processing of trade commodities and that can be said to be the end product of either innovation or substantial effort. There must be a direct relationship between the trade secret and the productive process.

(b) Commercial or financial information that is privileged or confidential means valuable data or information which is used in one’s business and is of a type customarily held in strict confidence or regarded as privileged and not disclosed to any member of the public by the person to whom it belongs.

FDA’s regulation applicable to medical information provides that names and “information which would identify patients or research subjects in any medical or similar report, test, study or other research project” shall be deleted prior to public disclosure of the record (21 CFR 20.63(a)). “The names and any information that would identify the voluntary reporter or any other person associated with an adverse event” shall not be publicly disclosed by FDA or by a manufacturer who reports such an event (21 CFR 20.63(f)). The names of entities required by statute to make adverse event reports are not protected from disclosure.

FDA’s definitions of trade secret and confidential commercial information were drafted to be consistent with judicial determinations that “any technical or scientific information developed by a company may be considered a trade secret where it is not generally known or readily ascertainable and when it is protected and maintained as confidential by the developer and is of value to him” (FDA, 1974, p. 44613). Testing data, including protocols used for testing the product and test results, can be protected from disclosure under the Freedom of Information Act (e.g., Heeney v. FDA, 2001).

Sometimes other statutes may affect the confidentiality protections usually afforded to confidential commercial or financial information under the Federal Food, Drug, and Cosmetic Act and the Freedom of Information Act. For example, public companies subject to regulation by the Securities and Exchange Commission (SEC) are required to disclose certain information that might be “material” to decisions by investors and potential investors. To comply with these SEC requirements, a public company might publicly disclose in SEC filings or press releases certain information about the existence of a clinical trial, the results of a clinical or preclinical study, or the fact that a PMA application or 510(k) submission has been submitted to FDA. Companies that are privately funded (such as by venture capital or private investors) might not disclose such information if they are not subject to disclosure requirements. As discussed above, FDA is bound by confidentiality requirements to the extent the information has not been previously disclosed to the public.

Companies provide the highest confidentiality protections to device design information, manufacturing processes and methods, and quality con-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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trol information. Protocols for clinical studies and preclinical testing are also typically protected from public disclosure. Aggregate results of a safety and effectiveness study may be disclosed in summary form, but raw data or site-specific data are often protected as confidential, unless published in a scientific journal.

As applied in the context of postmarket surveillance, FDA would be required by the three statutes discussed above to protect from public disclosure information that constitutes trade secrets or confidential commercial information. For example, a postmarket study protocol and the results of condition-of-approval studies would be submitted as supplemental PMA applications and thus would be governed by the confidentiality requirements of the Federal Food, Drug, and Cosmetic Act and Section 814.9 of FDA’s regulations.

Under the postmarket surveillance provision in Section 522 of the Act, a manufacturer is required to submit a plan for FDA-required postmarket surveillance, but FDA treats such plans as protected from public disclosure under provisions of the Freedom of Information Act and FDA’s implementing regulations. Interim and final reports of postmarket surveillance studies or data are treated similarly, although limited findings may be made public in connection with a safety advisory, the approval of a new indication for a product’s use, a labeling change, or similar action. Data and information relating to postmarket studies conducted under an IDE would be protected consistent with the IDE confidentiality regulations.

FDA PROGRAMS THAT CROSS THE PREMARKET/POSTMARKET BOUNDARY

In addition to premarket and postmarket programs, FDA has programs that cross the market approval boundary to promote device safety both before and after a device is marketed. This is consistent with the agency’s analysis of its range of activities as they relate to a product’s total life cycle from initial concept to obsolescence (see Figure 1.2).

Research, Analysis, and Methods Development

As described above, CDRH has active research programs to evaluate elements of device technologies or their effects, to support the development of standards or guidance, and otherwise to build the knowledge base for device design, testing, manufacture, regulation, and clinical use. CDRH’s 2003 Annual Report described its epidemiological research program, which provides consultative services on topics or problems requiring epidemiological expertise (e.g., literature reviews, risk assessments, design of obser-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

vational studies). The report listed studies that produced journal publications and conference presentations on a broad range of topics, including allergic reactions to platinum in breast implants, breast implant rupture, tampon-associated toxic shock syndrome, gender differences in pulmonary artery rupture, and uses and outcomes associated with transmyocardial revascularization (a procedure sometimes used to relieve chest pain). Other studies focused on methodology or process issues, for example, the use of the National Electronic Injury Surveillance System (NEISS) to assess the frequency of injuries due to medical devices. CDRH epidemiologists have also participated, on an exploratory basis, in premarket approval assessments to help determine whether and what kind of postmarket evaluations would be appropriate.

Concern about deficiencies in device design has prompted FDA to direct more attention to general principles and strategies for safe device design and use, including human factors engineering. Human factors engineering analyzes how people employ technologies and how user characteristics (e.g., cognitive capacities, expectations) interact with characteristics of their environments (e.g., workload, lighting) to affect the safe and effective use of technologies (FDA, 2003s). Such analysis can be applied to adverse events involving medical devices and potential means to prevent them.

Quality Systems Regulations

A major boundary crossing program involves quality system regulations, which encompass good manufacturing practices. These regulations are among the general controls described earlier in this chapter.

Congressional concern about manufacturing practices dates back at least to the 1938 Federal Food, Drug, and Cosmetic Act, when Congress specified that manufacturing methods, facilities, and controls be “adequate” for regulated products. The first FDA guidance about adequate manufacturing processes dates to the early 1940s; it followed a drug manufacturing mishap that left dozens of people dead or injured (Swann, 1999).

FDA issued the first requirements for good manufacturing practices for medical devices in 1978 (FDA, 1978). These requirements—which remained essentially the same until 1996—covered methods, facilities and controls related to the manufacture, packing, storage, and installation of medical devices. The Safe Medical Devices Act of 1990 expanded FDA authority to include control related to device design prior to actual production. That legislation also encouraged FDA to work with other countries toward commonly recognized good manufacturing practices.

In 1996, FDA published the Quality System Regulations, which it described as “revising the current good manufacturing practice (CGMP) requirements for medical devices and incorporating them into a quality sys-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
×

tem regulation” (FDA, 1996b, p. 52602). By intent, the regulations are very similar to the International Organization for Standardization (ISO) provisions (ISO, 2000), which have recently been updated. (ISO is described briefly below.) The quality system regulation is broad in scope as indicated in Box 3.4.

The quality system regulations cover a very large array of devices. For that reason, the regulation “provides the framework that all manufacturers must follow by requiring that manufacturers develop and follow procedures and fill in the details that are appropriate to a given device according to the current state-of-the-art manufacturing for that specific device” (FDA, 1996b, p. 52603). As noted earlier, special control guidance documents for particular categories of devices (e.g., apnea monitors) may be much more specific.

BOX 3.4
Topics in Medical Device Quality Systems Manual: A Small Entity Compliance Guide

  1. The Quality System Regulation

  2. Quality Systems

  3. Design Controls

  4. Process Validation

  5. Personnel

  6. Buildings and Environment

  7. Equipment and Calibration

  8. Device Master Record

  9. Document and Change Control

  10. Purchasing and Acceptance Activities

  11. Labeling

  12. Product Evaluation

  13. Packaging

  14. Storage, Distribution, and Installation

  15. Complaints

  16. Servicing

  17. Quality Systems Audits

  18. Factory Inspections

  19. Appendix

Appendix 1: The Quality Systems Regulation

Appendix 2: Application of the Medical Device GMPs [Good Manufacturing Practice] to Computerized Devices and Manufacturing Processes

SOURCE: FDA, 1999c.

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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Design Controls

As described in the quality system regulations (21 CFR 820.30), the design controls requirements for Class II and III devices, Class II and III investigational devices, and certain Class I devices cover considerable ground. Design controls involve

  • creating plans that cover design and development activities and assign responsibility for implementing them;

  • specifying design input requirements, that is, the physical and performance requirements for a device design that are appropriate given the device’s intended uses and users;

  • developing the design output, meaning the results of the design effort at each stage, including the finished design effort (the device, its packaging and labeling, and the device master record);

  • verifying that the design output is consistent with the design input requirements;

  • conducting periodic design reviews to assess the adequacy of the design requirements, evaluate whether the design will meet the requirements, and identify problems;

  • validating through tests of production units under actual or simulated conditions and other means that the device (including software) meets objectives for intended uses and users;

  • correctly translating the device design into production specifications;

  • controlling changes in design during the design process and after the device is marketed; and

  • documenting the design process in the design history file.

FDA requires that applications for premarket approval include descriptions of design controls and other quality systems information, and it evaluates compliance during a pre-approval facility inspection (FDA, 2003q,r). The agency also evaluates compliance during routine quality systems inspections for all devices covered by the design control requirements.

Corrective and Preventive Actions

In guidance on the quality system inspections of manufacturers, one focus is what FDA terms the Corrective and Preventive Actions or CAPA subsystem (FDA, 1999b). A major component of this subsystem consists of procedures to detect, understand, and correct problems during the manufacturing process. The objective of this aspect of quality system regulations is to prevent defective devices from reaching the market. Other components of the CAPA subsystem reviewed by FDA are the manufacturer’s confor-

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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mance with adverse event reporting regulations, recall and corrective actions, and procedures for any required tracking of a medical device.

Inspections

As noted above, FDA inspections of manufacturing facilities may occur before or after a medical device is approved for marketing. A pre-approval inspection is usually required as part of the PMA process. FDA staff also conduct “directed” or “for cause” inspections when they are investigating a specific problem or following up to assure that corrective actions from a previous inspection have been implemented. A program of bioresearch monitoring includes on-site inspections and data audits of sites involved in FDA-regulated research. As described by FDA in its 2002 Performance Plan, the FDA Modernization Act of 1997 has allowed firms to declare conformity to standards or quality systems requirements as part of steps to streamline the premarket clearance process (FDA, 2001h). This has increased the burden on FDA’s inspection process, which as discussed in Chapter 7, falls short of meeting statutory requirements that FDA inspect facilities that manufacture Class II and III devices every 2 years (21 USC 360(h)).

FDA’s quality system inspections focus on particular subsystems of manufacturing quality controls, specifically management, design (see above), corrective and preventive actions (see above), and production and processes. The other major subsystems involve materials controls, facility and equipment controls, and records, documents, and change controls.

To ease the inspection burden on FDA, the 2002 Medical Device User Fee and Modernization Act gave manufacturers with a good history of regulatory compliance the option, under certain circumstances, of choosing an FDA-accredited, nongovernmental entity to perform quality systems inspections (21 USC 374(g)). (This is described by FDA as its “Accredited Persons” or AP program.) FDA staff would focus on firms with a record of compliance problems and manufacturers of high-risk products, including implants and life-supporting or sustaining devices.

International Efforts to Harmonize Policies

Medical device development, research, and sales are international in scope. The ISO standards cited above are one example of a number of cross-national initiatives—some longstanding, some relatively recent—to promote consensus and consistency in regulatory and voluntary standards for medical and other products and industries, measurement and testing methods, management systems, and other areas. ISO is a nongovernmental network whose membership consists of the national standards institutes of

Suggested Citation:"3 Regulatory Framework for Postmarket Surveillance of Medical Devices." Institute of Medicine. 2006. Safe Medical Devices for Children. Washington, DC: The National Academies Press. doi: 10.17226/11313.
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nearly 150 countries (ISO, 2004). Using committees that include producers, consumers, regulators, and other relevant parties, the organization develops consensus standards on topics such as terminology, testing methods, product characteristics, and manufacturing processes. Some standards are generic, such as ISO 9000, which concerns quality management. Other standards are industry or product specific, such as ISO 13485, which concerns medical devices. The agency currently has more than 14,000 standards and related documents. Individual countries may choose to adopt the standards by regulation.

In the 1990s, the Global Harmonization Task Force (GHTF) was created specifically as a voluntary process to pursue harmonization of national policies on the regulation of medical devices. It includes participants from national regulatory agencies and industry. Of four GHTF study groups, one has focused on postmarket surveillance, including adverse event reporting programs. FDA supports this activity, but the study group findings and recommendations are advisory, not binding.

One issue for the GHTF task force on adverse event reporting is promoting the exchange of event reports among “national competent authorities” (e.g., FDA in the United States) (GHTF, 2002, p. 4). In 2003, authorities in 16 countries exchanged more than 140 “international vigilance reports,” most related to recalled devices (FDA, 2004v).

Other harmonization activities include those of the International Conference on Harmonization (ICH). ICH has, for example, provided guidance for clinical investigators, primarily those involved in drug studies (ICH, 1996). An ISO document has focused on clinical investigators studying medical devices (ISO, 2003a,b; see Giroud, 2004). FDA has not adopted that ISO standard but has said that it might do so after the next revisions (Dickinson, 2004b).

This chapter has focused on description rather than assessment. Thus, it includes no conclusions or recommendations related to the adequacy of existing laws and regulations or their implementation as they relate to children. The next chapter examines FDA’s programs of adverse event reporting and offers recommendations for improvement.

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Next: 4 Identifying and Understanding Adverse Medical Device Events »
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Innovative medical devices have helped reduce the burden of illness and injury and improve the quality of life for countless children. Mechanical ventilators and other respiratory support devices rescue thousands of fragile newborns every year. Children who once would have died of congenital heart conditions survive with the aid of implanted pacemakers, mechanical heart valves, and devices that close holes in the heart. Responding to a Congressional request, the Institute of Medicine assesses the system for postmarket surveillance of medical devices used with children. The book specifically examines:

  • The Food and Drug Administration's monitoring and use of adverse event reports
  • The agency's monitoring of manufacturers' fulfillment of commitments for postmarket studies ordered at the time of a device's approval for marketing
  • The adequacy of postmarket studies of implanted devices to evaluate the effects of children's active lifestyles and their growth and development on device performance

Postmarket surveillance of medical devices used with children is a little investigated topic, in part because the market for most medical products is concentrated among older adults. Yet children differ from adults, and their special characteristics have implications for evaluation and monitoring of the short- and long-term safety and effectiveness of medical devices used with young patients.

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