Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 41
3
Components of US Medical-Device
Regulation
F
rom the inception of device regulation under the 1976 Medical Device
Amendments, it was understood that devices would be subject to vari-
ous degrees of premarket review, depending on their risk classification
(see Chapter 2). In addition, all devices, once they entered the marketplace
(by whatever review mechanism) would be subject to a wide array of regu-
latory requirements. Premarket review and regulatory control after market
entry were intended to operate together to provide a structure that would
protect the public’s health while not inhibiting innovation.
The committee notes several times throughout this report that the
510(k) process does not operate in isolation. It is part of a larger framework
of regulatory tools. This chapter provides an overview of the components of
medical-device regulation that come into play after a product is marketed
and then an introduction to the available paths for premarket review of
devices, including the 510(k) clearance process.
TOOLS AND AUTHORITIES FOR
REGULATING MARKETED DEVICES
In general, medical-device regulation is described by following the typi-
cal life cycle of a device, starting with research and development, progressing
to premarket review by the Food and Drug Administration (FDA), follow-
ing with regulatory requirements while the device is marketed, continuing
with evolution of the device into several (often many) iterations and newer
variants, and ending with product obsolescence (IOM, 2010; Kahan, 2009).
To focus attention on the incremental aspects of premarket review, however,
41
OCR for page 42
42 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
this chapter will begin with the FDA’s “general controls”—the regulatory
system applicable to devices once they enter the marketplace. Once the
“postmarket” system is understood, the supplemental controls provided by
premarket review can be better appreciated.
In its “Preliminary Report and Recommendations,” the FDA Center
for Devices and Radiological Health (CDRH) 510(k) Working Group states
(FDA, 2010a) that
the aim of the 510(k) program is two-fold: (1) to assure, through a quality
review process, that marketed devices, subject to general and applicable
special controls, provide a reasonable assurance of safety and effective-
ness; and (2) to foster innovation. Robust premarket review is an essential
component of CDRH’s medical device oversight. CDRH’s postmarket
tools, while valuable, have important limitations and are not sufficient to
serve as a substitute for high-quality premarket review [emphasis added].
This chapter explores those potential or perceived limitations and the
procedures by which the controls are imposed and enforced.
Controls Affecting Marketed Devices
The statute establishes a combination of prohibitions and mandates
with which a device and its manufacturer must comply. Some of the man-
dates are imposed on specific devices by order of the FDA at its discretion;
others are adopted through regulations issued by notice-and-comment rule-
making. This discussion covers only the legal authority of the FDA, not how
that authority may have been used through individual enforcement actions
or the exercise of discretion not to act.
Many of the controls apply to all devices, regardless of risk presented
or classification; others apply to a subset of devices based on risk but not
classification; and a few apply only to devices classified in Class II or Class
III. Compliance with the controls is monitored and enforced by the FDA
through its own resources and with the assistance of the US Department of
Justice (DOJ) and federal courts.
The following text will review prohibitions and mandates related to
all devices, prohibitions and mandates related to higher-risk devices, FDA
monitoring systems, FDA enforcement powers, and procedural require-
ments that may affect the FDA’s ability to use the powers granted by law.
OCR for page 43
43
COMPONENTS OF US MEDICAL-DEVICE REGULATION
Controls Applicable to All Devices
Prohibitions
Contamination
A device may not consist in whole or in part of any filthy, putrid, or
decomposed substance1 or contain an unsafe color additive.2
Container Contamination
The container of a device may not be composed in whole or in part of
any poisonous or deleterious substances that may render its contents injuri-
ous to health.3
False Claims of Compliance
The marketer of a device may not claim that it complies with a perfor-
mance standard established by or recognized by the FDA, unless the device
conforms in all respects to the standard.4
False or Misleading Labeling
The labeling of a device may not be false or misleading in any par-
ticular.5 It may not fail to make all required disclosures conspicuous and
accessible to potential users under customary conditions of sale.6 Whether
labeling is misleading is determined both by what is said and by what mate-
rial information is omitted in light of what is said.7
Unsafe When Used in Accordance with Instructions
A device may not be dangerous to health when used as suggested in its
labeling.8
Mandates
Registration of Manufacturers
A US-located manufacturer, processor, packager (or reprocessor and
repackager9) of a medical device must register with the FDA the business’s
1Federal Food, Drug, and Cosmetic Act [hereinafter FFDCA] § 501(a)(1); 21 USC § 351(a)
(1) (2006).
2FFDCA § 501(a)(4), 21 USC § 351(a)(4)(B) (2006).
3FFDCA § 501(a)(3), 21 USC § 351(a)(3) (2006).
4FFDCA § 501(e), 21 USC § 351(a)(1) (2006).
5FFDCA § 502(a), 21 USC § 352(a) (2006).
6FFDCA § 502(c), 21 USC § 352(c) (2006).
7FFDCA § 201(n), 21 USC § 321(n) (2006).
8FFDCA § 502(j), 21 USC § 352(j) (2006).
9Reprocessors and repackagers may sterilize, refurbish, or repackage previously used devices.
There are special requirements for those who reprocess single-use medical devices. Section
502(v); 21 USC 352(v) (2006).
OCR for page 44
44 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
name and all places of business.10 Any additional place of business must be
registered immediately.11 Registration is also required for establishments
outside the United States where devices are made for importation into the
United States.12 Registration is to be electronic.13
Listing of Products
Each registered person must file with the FDA a list identifying each
device made or processed for commercial distribution in the United States.14
The label and labeling15 for each listed device and a representative sample
of other labeling must be provided.16 The FDA may request a registrant to
provide a statement as to why it believes that any product listed is not sub-
ject to a performance standard or a premarket approval (PMA) application
requirement.17 If a device previously listed is no longer made, the registrant
must provide a notice of discontinuance regarding the product.18 Listings
are to be electronic.19
Label Information
The label is affixed to the device or its immediate container.20 The label
of a device must prominently disclose the company name, trade name, or
trade symbol of the original manufacturer.21 It must also disclose the name
and place of business of the manufacturer, packager, or distributor and the
quantity of contents in the package.22 The device must be identified by its
established or common nonproprietary name (if any).23
Labeling with Adequate Instructions for Use
The labeling of a device must provide adequate directions for use and
adequate warnings against unsafe use.24 The FDA has historically required
10FFDCA § 510(c), 21 USC § 360(c) (2006).
11FFDCA § 510(d), 21 USC § 360(d) (2006).
12FFDCA § 510(i), 21 USC § 360(i) (2006 & Supp. II 2008).
13FFDCA § 510(p), 21 USC § 360(p) (2006).
14FFDCA § 510(j)(1), 21 USC § 360(j)(1) (2006).
15A label is written matter affixed to a device or its immediate packaging. Labeling includes
labels and other written materials accompanying the device (for example, an operator’s manual
or detailed product information). The FDA also includes some promotional materials in the
scope of labeling. For this chapter, promotional labeling is treated with advertising, below.
16FFDCA §§ 510(j)(1)(A)–(B), 21 USC § 360(j)(1)(A)–(B) (2006).
17FFDCA § 510(j)(1)(D), 21 USC §§ 360(j)(1)(D) (2006).
18FFDCA § 510(j)(2)(B), 21 USC § 360(j)(2)(B) (2006).
19FFDCA § 510(p), 21 USC § 360(p) (2006).
20FFDCA §§ 201(k)–(l), 21 USC §§ 321(k)–(l) (2006).
21FFDCA § 502(u), 21 USC § 352(u) (2006).
22FFDCA § 502(b), 21 USC § 352(b) (2006).
23FFDCA §§ 502(e)(2), (4), 21 USC §§ 352(e)(2), (4) (2006).
24FFDCA § 502(f), 21 USC § 352(f) (2006).
OCR for page 45
45
COMPONENTS OF US MEDICAL-DEVICE REGULATION
that directions be adequate for a layperson, both as to the conditions for
which the device is to be used and as to the safe and effective way to use
the device.25 The statute permits the FDA to exempt devices from these re-
quirements, which the agency has done by declaring them (or allowing their
manufacturers to declare them) to be prescription devices,26 for which the
labeling need only be written for healthcare professionals, not laypersons.27
To take advantage of that exemption, however, the labeling must also pro-
vide information that permits a healthcare practitioner to use the product
safely and for the purpose for which it is intended.28
If a device is intended for use in healthcare facilities or by healthcare
professionals, labeling required for a prescription device may be made avail-
able solely by electronic means and need not be included physically with
the device package.29
Design and Manufacture of Products
Every device must be designed, manufactured, packed, stored, and in-
stalled in conformity with current good manufacturing practice regulations
established by the FDA.30 The regulations mandate use of design validation,
investigation of complaints, a corrective and preventive action plan to iden-
tify root causes of product nonconformance with standards and specifica-
tions and to implement effective actions to prevent recurrence, and a quality
system to oversee and ensure compliance with the FDA requirements and
internal company procedures.31
Reports of Removals and Corrections
A manufacturer or importer must report to the FDA any device correc-
tion (for example, a software upgrade, change in operating instructions, or
field modification) or removal (for example, recall, field recovery, or replace-
ment) if the correction or removal was undertaken to reduce a risk to health
posed by the device or to remedy a violation of the FFDCA caused by the
device that may have presented a risk to health.32 The FDA has promulgated
regulations to implement this provision.33
2521CFR § 801.5 (2009).
26Prescriptiondevices are not the same as restricted devices, although an individual device
may be both. See below regarding restricted devices.
27FFDCA § 502(f), 21 USC § 352(f) (2010); 21 CFR § 801.109 (2009).
2821 CFR § 801.109 (2009).
29FFDCA § 502(f), 21 USC § 352(f) (2006).
30FFDCA §§ 501(h), 520(f)(1), 21 USC §§ 351(h), 360j(f)(1) (2006).
3121 CFR pt. 820 (2009).
32FFDCA § 519(g), 21 USC § 360i(g) (2006).
3321 CFR pt. 806 (2009).
OCR for page 46
46 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
Reporting of Adverse Medical Events by Manufacturers and Importers
In general, each manufacturer or importer of a medical device legally
marketed in the United States must keep records and make reports to the
FDA regarding deaths or serious injuries that the device may have caused
or to which it may have contributed.34 Malfunctions that did not cause or
contribute to deaths or serious injuries must also be reported if a death or
serious injury would be likely to result should the malfunction recur.35 The
agency has implemented this authority through regulations.36
Reporting of Adverse Medical Events by Device-User Facilities (Not
Manufacturers)
Hospitals, ambulatory surgical facilities, nursing homes, and outpatient
diagnostic and treatment facilities (other than physician offices) are required
to report to the FDA information that reasonably suggests that a device has
or may have caused or contributed to the death or serious illness of or seri-
ous injury to a patient of the facility.37 There is no comparable user-facility
reporting requirement for drugs. This requirement has been implemented
through regulations issued by the FDA.38 (Adverse-event reporting is dis-
cussed in detail in Chapter 5.)
Controls Applicable Only to Higher-Risk Devices
Restricted Devices
If the FDA determines that a device’s potential for harm or collateral
measures necessary for its use are such that there cannot be reasonable as-
surance of its safety and effectiveness without the restriction, the agency is
authorized to require that the device be restricted to sale, distribution, or
use, only on the written or oral authorization of a healthcare practitioner
or “upon such other conditions as [the FDA] may prescribe.”39 The statute
goes on to suggest both the types of other conditions that the FDA might
consider and limitations of these conditions if used:
No condition . . . may restrict the use of a device to persons with specific
training or experience in its use or to persons for use in certain facilities
unless [the FDA] determines that such a restriction is required for the safe
and effective use of the device. No such condition may exclude a person
34FFDCA § 519(a), 21 USC § 360i(a) (2006). See 21 CFR pt. 803 (2009) (implementing
regulations).
35FFDCA § 519(a)(8), 21 USC § 360i(a)(8) (2006).
3621 CFR pt. 803, subpts. D–E (2009).
37FFDCA § 519(b), 21 USC § 360i(b) (2006).
3821 CFR pt. 803, subpt. C (2006).
39FFDCA § 520(e), 21 USC § 360j(e) (2006).
OCR for page 47
47
COMPONENTS OF US MEDICAL-DEVICE REGULATION
from using a device solely because the person does not have the training
or experience to make him eligible for certification by a certifying board
recognized by the American Board of Medical Specialties or has not been
certified by such a Board.40
That authority is exercised at the FDA’s discretion and may by imposed
in any of three ways: by regulation issued through a notice-and-comment
rule-making (usable for devices in any class),41 as part of a performance
standard established by notice-and-comment rule-making (usable only for
Class II devices),42 or as a condition for the approval of a PMA application
(usable only for Class III devices).43
Although the language is quite similar to that used by the FDA to de-
termine whether a device should be a prescription device,44 the designations
as “restricted device” and “prescription device” are technically distinct.
Numerous devices are recognized as “prescription devices” by their manu-
facturers and the FDA through labeling and fall under exemptions from the
“adequate directions for use” requirements.45 Those devices, however, are
not “restricted devices” unless separately designated by the FDA.
The FDA has generally used the restricted-device authority via the PMA
application process and rarely by regulation (Hutt et al., 2007). Only a very
few Class II devices are formally “restricted.”46
As early as 1983, however, the FDA was being criticized in Congress
for failing to use its power to impose other conditions on use:
The legislative history [of the 1976 amendments] explains that Congress
sought to supersede and add to the existing authority used by the FDA to
limit sale or use of certain devices except by prescription. Authority beyond
prescription was necessary because many . . . believed that major problems
arose from misuse of devices by practitioners, and not just from manu-
facturing or design defects. Establishing conditions under which devices
could be used, or limiting or describing the facilities where they could be
used, or the training or qualification of those who use them in treatment,
was envisioned as a way to address user-related problems. Controls such
as these were not contemplated by the lone previously existing authority
to limit devices to a practitioner’s prescription.47
40Id.
41Id.
42FFDCA § 514(a)(1), (b), 21 USC § 360d(a)(1), (b) (2006).
43FFDCA § 515(d)(1)(B)(ii), 21 USC § 360e(d)(1)(B)(ii) (2006).
4421 CFR § 801.109(a) (2009).
45See above regarding “Labeling with Adequate Instructions for Use.”
4621 CFR § 801.420, 21 CFR § 809.30, 21 CFR § 864.4020(d).
47Subcomm. on Oversight and Investigations of the H. Comm. on Energy and Commerce,
98th Cong., Medical Device Regulation: The FDA’s Neglected Child (Comm. Print 98-F).
OCR for page 48
48 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
Once a device is designated as a restricted device, two additional im-
portant legal consequences—apart from limiting access to the device to or
through physicians—result:
• dvertising and Promotional Materials. The promotion of medical
A
products is generally regulated by the Federal Trade Commission
(FTC), with no official role for the FDA with two exceptions. The
FDA has jurisdiction to regulate the advertising of prescription drugs.
With regard to prescription devices, however, the agency is given
jurisdiction only to regulate advertising for prescription devices that
are also restricted devices. The marketer is prohibited from advertis-
ing a restricted device with materials that are “false or misleading
in any particular.”48 In addition, all advertisements for a restricted
device must provide the device’s established or common name (if any)
and a brief statement of the product’s intended uses, side effects, and
contraindications.49 Because the FDA has declined to restrict almost
all Class II devices, responsibility for preventing false or misleading
advertising for these devices has remained exclusively with FTC.
• nspections. During inspections of manufacturing plants, the FDA is
I
authorized by one provision of the statute to see the production and
distribution records related to restricted devices but not to devices
that are not restricted.50 A separate provision, however, empowers
the FDA to inspect any records that are required by law to be kept.51
The agency has directed that specific production and distribution
records on all devices be kept as part of good manufacturing practice
requirements.52 Thus, the failure to designate devices as restricted has
not adversely affected the FDA’s ability to examine manufacturing
records.
Controls Related Only to Class II or Class III
Device Tracking
The FDA may require a manufacturer to adopt a method for tracking
a Class II or Class III device whose failure might be reasonably likely to
have serious adverse health consequences, that is intended to be implanted
for more than 1 year, or that is a life-sustaining or a life-supporting device
48FFDCA § 502(q)(1), 21 USC § 352(q)(1) (2006).
49FFDCA § 502(r), 21 USC § 352(r) (2006).
50FFDCA § 704(a), 21 USC § 374(a) (2006).
51FFDCA § 301(e), 21 USC § 331(e) (2006).
52FFDCA §§ 501(h), 520(f)(1), 21 USC §§ 351(h), 360j(f)(1); 21 CFR pt. 320, subpt. M.
OCR for page 49
49
COMPONENTS OF US MEDICAL-DEVICE REGULATION
used outside a device-user facility.53 In 2002, the FDA set forth three new
nonbinding criteria in addition to those in the statute to determine whether
device tracking might be required: the likelihood of sudden, catastrophic
failure; the likelihood of serious adverse clinical outcomes; and the need for
prompt professional intervention.54
Tracking requires that the manufacturer keep records of the name
and address of each patient who received the device, the physician who
prescribed the device, and (if different) the physician who is following the
patient. The agency has issued regulations creating the general requirements
for complying with this provision.55 The authority to impose tracking re-
quirements is discretionary with the FDA and is exercised by an “order” to
individual manufacturers covering each affected device.56
Postmarket Surveillance
The FDA may require a manufacturer to conduct surveillance of a
Class II or Class III device that meets any of the criteria for device tracking
(above) or is expected to have substantial use in pediatric populations.57
“Postmarket surveillance” is a specific activity defined by the statute and is
not to be confused with “postmarketing surveillance,” which encompasses
a wide array of programs, including adverse-event reporting by manufac-
turers and user facilities, third-party safety monitoring, and FDA–academic
collaborations. Surveillance generally cannot last more than 36 months and
must be designed to provide useful data that could reveal unforeseen adverse
events or other information necessary to protect public health.58 The FDA
has issued general regulations governing requirements when surveillance is
ordered.59 Imposing a requirement for surveillance is discretionary with the
FDA60 and is done by an “order” to the manufacturer of the affected device
or, in the case of pediatric devices, as a condition for clearance of a Class II
device or approval of a Class III device.61
53FFDCA § 519(e), 21 USC § 360i(e) (2006).
54Medical Devices; Device Tracking, 67 Fed. Reg. 5,943, 5,944 (Feb. 6, 2002) (codified at
21 CFR pt. 821).
5521 CFR pt. 821 (2009).
5621 CFR § 821.20 (2009).
57FFDCA § 522(a), 21 USC § 360l(a) (2006).
58FFDCA § 522(b), 21 USC § 360l(b) (2006).
5921 CFR pt. 822 (2009).
60FFDCA § 522(a)(1), 21 USC § 360l(a)(1) (2006).
61FFDCA §§ 522(a)(1)(A)–(B), 21 USC §§ 360l(a)(1)(A)–(B) (2006).
OCR for page 50
50 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
Special Controls
Class II devices may be subject to one or more “special controls” to
supplement the general controls to provide reasonable assurance of safety
and effectiveness.62 The definition of a Class II device specifies that it is
a device which cannot be classified as a Class I device because the general
controls by themselves are insufficient to provide reasonable assurance of
the safety and effectiveness of the device, and for which there is sufficient
information to establish special controls to provide such assurance, includ-
ing the promulgation of performance standards, postmarket surveillance,
patient registries, development and dissemination of guidelines . . ., recom-
mendations, and other appropriate actions as [the FDA] deems necessary
to provide such assurance63 [emphasis added].
In parallel, the definition of Class III covers devices that cannot be clas-
sified as Class I because general controls are insufficient to ensure safety and
effectiveness and that cannot be classified as Class II because “insufficient
information exists to determine that the special controls . . . would provide
reasonable assurance of its safety and effectiveness.”64
The statute does not require, however, that every Class II device be
subject to special controls. Although the definitional sentences just quoted
state that “general controls . . . are insufficient,” the definition of Class II
goes on to provide that
for a device that is purported or represented to be for a use in supporting
or sustaining human life, [the FDA] shall examine and identify the special
controls, if any, that are necessary to provide adequate assurance of safety
and effectiveness and describe how such controls provide such assurance65
[emphasis added].
By implication, for a Class II device that is not so represented, the FDA
is not even obliged to consider special controls. In addition, the various
types of special controls identified in the statute (discussed below) are all
written to be discretionary with the agency. As a practical matter, the FDA
has always treated special controls as a discretionary matter. Today, roughly
15% of all device types classified in Class II are subject to special controls
(Desjardins, 2010).
The statutorily authorized “special controls” can include one or more
of the following:
62FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).
63Id.
64FFDCA § 513(a)(1)(C), 21 USC § 360c(a)(1)(C) (2006).
65FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).
OCR for page 51
51
COMPONENTS OF US MEDICAL-DEVICE REGULATION
• evice tracking (patient registries) and postmarket surveillance, as
D
discussed above. Each authority is exercised in individual cases by
order of the agency.
• Performance standards” that are promulgated either by the FDA
“
(through an elaborate notice-and-comment rule-making)66 or by a
third party and recognized by the FDA (through a simple published
notice).67 Performance standards may cover the construction, com-
ponents, ingredients, and properties of a device and its compatibility
with power systems and connections with these systems; testing
requirements; provisions for measurement of performance; and
requirements for submission of test results to demonstrate confor-
mity. A performance standard may also specify that the device is a
restricted device in the same manner in which the FDA might restrict
the device under separate authority (see above).68
• DA guidelines, including guidelines on the submission of clinical
F
data with a 510(k) notification.69 The FDA has adopted a form of
notice-and-comment procedure for the adoption of guidelines (which
the FDA now calls guidances).70
• DA recommendations. The statute refers only to “recommenda-
F
tions” without specifying what they might address or how a rec-
ommendation would become an enforceable control.71 The agency
may, in issuing recommendations, use the same procedures as for
guidances.72
• ny “other appropriate actions.” The FDA is authorized to adopt
A
any other special control that it deems necessary to provide a reason-
able assurance of safety and effectiveness.73
For a number of reasons, however, special controls have not trans-
formed and cannot transform the 510(k) process into one based on safety
and effectiveness rather than one based on substantial equivalence to a
predicate device. First, as noted above, only about 15% of all Class II device
types are subject to special controls. Second, some premarket special con-
trols are focused on a particular aspect of the device, such as medical devices
that include an antimicrobial agent, or on generic procedures for conducting
research for a class of devices, such as animal studies for cardiovascular
66FFDCA § 514(b), 21 USC § 360d(b) (2006).
67FFDCA § 514(c), 21 USC § 360d(c) (2006).
68FFDCA § 514(a)(2), 21 USC § 360d(a)(2) (2010).
69FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).
7021 CFR § 10.115 (2009).
71FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).
7221 CFR § 10.90(c) (2009).
73FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).
OCR for page 74
74 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
FIGURE 3-1 Federal government, Department of Health and Human Services, and
FDA funding, FY 2008.
Figure 3-1.eps
SOURCE: GAO, 2009a.
bitmap
ary spending (GAO, 2009b). CDRH’s funding is augmented by user fees.
However, as described in Chapter 2, there are limitations to how those
funds can be used.
The funding for CDRH has grown from $159 million in 1999 to $275.3
million in 2008—a 73% increase (GAO, 2009a). Despite the increase in
funding, agency officials reported that the limitations placed on the use of
the user-fee funds seriously undermine their ability to meet their responsi-
bilities in programs not supported by user fees (GAO, 2002, 2009a). About
two-thirds of all the funding for medical-products program centers (both
user-fee funding and discretionary funding) supports user-fee–related ac-
tivities (for example, submission review). Funding for the program centers
increased three times as fast as funding for the FDA’s field operations, which
are responsible for inspecting manufacturing facilities (GAO, 2009b).
Staffing
The FDA is concerned about its ability to attract and retain key staff
who have essential expertise, such as biologists, chemists, computer pro-
grammers, and epidemiologists (GAO, 2009b). For all the FDA centers—
CDRH, the Center for Biologics Evaluation and Research (CBER), and the
Center for Drug Evaluation and Research (CDER)—full-time equivalents
(FTEs) funded by user fees increased by 113% from 1999 (856 FTEs) to
2008 (1,825 FTEs), whereas FTEs funded through appropriations declined
OCR for page 75
75
COMPONENTS OF US MEDICAL-DEVICE REGULATION
by 7% from 1999 (4,069 FTEs) to 2008 (3,802 FTEs).139 In an effort to re-
duce staffing levels in programs funded through appropriations, the agency
offered buyouts to some employees in FY 2004–2006 (GAO, 2009b).
CDRH and the Office of Regulatory Affairs (ORA) estimated that they
increased their use of contractors to fulfill their responsibilities during that
period but were unable to provide the Government Accountability Office
(GAO) documentation of total number of contractor hours. The decrease
in FTEs resulted in a backlog in work (GAO, 2009b).
CDRH staff are required to respond within 90 days of receipt of a
510(k) notification. In 2009, the FDA’s goal was to review 90% of 510(k)
submissions within 90 days and 98% within 150 days (GAO, 2009b).140
Given the variability in the 510(k) submissions, FDA staff report that re-
view times did not allow sufficient review of complex issues (FDA, 2011a).
Over a 7-year period, the number of FTEs dedicated to processing 510(k)
submissions has risen dramatically, from 166 in 2003 to 249 in 2009. The
number of FTEs dedicated to processing PMA applications has grown from
133 to 152 in the same period (Desjardins, 2011). The FDA reported that it
takes about 2 years to train new staff to review applications (GAO, 2009b).
This long training period makes average annual turnover of 11–13% in the
centers (CDER, CBER, and CDRH) an important issue for the FDA (GAO,
2009b).
In 1989, GAO recommended that the FDA collect basic management
information, such as staffing (including contractors), to estimate its future
needs better (GAO, 1989). The FDA disagreed with that recommendation,
indicating that the resources needed to collect the information would detract
from the agency’s oversight responsibilities. In a 2009 report, GAO reiter-
ated its recommendation with the assertion that the collection of this infor-
mation is essential for the agency to be able to fulfill its mission adequately.
Without the information, it is also impossible for external groups to verify
whether the FDA is fulfilling its oversight requirements and optimizing its
performance (GAO, 2009b).
Third-Party Review
In August 1996, the FDA initiated a voluntary third-party review pilot
program for selected devices. The pilot’s purpose was to provide manufac-
turers of eligible devices an alternative review process that might yield more
rapid marketing clearances and enable the FDA to use its scientific review
resources for higher-risk devices. All Class I and 30 select Class II device
types were eligible for third-party review. The eligible Class II devices were
139These numbers do not include contractors.
140Compared with PMA reviews, for which the goals are 60% of original PMA submissions
within 180 days and 90% within 295 days (GAO-09190).
OCR for page 76
76 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
subject to a device-specific guidance or a recognized consensus standard.
Well-recognized road maps for establishing device performance were con-
sidered important in choosing products to be reviewed in the pilot because
such documents would, it was believed, standardize the review process
among third-party organizations. The FDA developed an accreditation and
training process to ensure that third-party reviewers had the capacity to
perform credible reviews and to avoid conflict of interest.
The 1997 FDAMA formally recognized and extended the program.
The FDAMA directed the FDA to accredit third parties to review devices
of low to moderate risk and to set limits on the number of Class II devices
that would be ineligible for third-party review. In September 1998, the FDA
published an expanded list of Class II device types eligible for third-party
review for which there were no device-specific guidances or standards. For
a third party to review a device not subject to a guidance or standard, it
must (FDA, 2009)
• ave completed three successful 510(k) reviews in the program.
H
• gree to contact the appropriate CDRH branch chief or designee to
A
discuss issues and review criteria.
• repare a summary of the discussion and submit it to the Office of
P
Device Evaluation with its 510(k) review.
The third party charges a fee to submitters for review. Once a review
has been completed, it must be submitted with a cover letter, a letter from
the submitter authorizing submission, a summary of the presubmission dis-
cussion described above, the complete 510(k) submission, and a completed
review. In addition, there must be a certification that the reported informa-
tion accurately reflects the data reviewed. The FDA supervisory official is
expected to review the third-party submission and make a decision on the
submission within 30 days of receipt.
GAO found that often the third-party review could be faster than FDA
review for traditional 510(k) submissions but that, as FDA review has be-
come more efficient, the number of third-party reviews is likely to decrease
(GAO, 2009c).
As of February 2011, 670 Class I and Class II device types were eligible
for third-party review. No Class II devices that are intended to be perma-
nently implanted, that are intended to be life-sustaining or life-supporting,
or whose 510(k) submission requires clinical data are eligible for third-party
review (GAO, 2009c). Since 2004, about 250 510(k) submissions have par-
ticipated in the third-party process per year (see Figure 3-2).
Quality assessments were completed on 75% of third-party reviews
received during the last 9 months of FY 2005. Overall, major problems
were observed by supervisors who reviewed submissions in 31% of reviews;
OCR for page 77
77
COMPONENTS OF US MEDICAL-DEVICE REGULATION
Percentage of Total 510(k) Received
Percentage of Total 510(k)s Received Number of Third-Party 510(k)s Received
FIGURE 3-2 Third-party 510(k) submissions as percentage of total 510(k) submissions
Figure 3-2.eps
received, FY 1999–2009.
bitmap
SOURCE: FDA, 2010a.
the most common problems were lack of rationale for conclusions and rec-
ommendations, failure to provide an adequate comparison with a legally
marketed device, and failure to resolve deficiencies in the 510(k) submis-
sion or to address FDA requests (see Table 3-4) (von Eschenbach, 2007). A
review of recall data from 2003–2009 found that 510(k) devices cleared via
third-party review were more common among recalled devices than among
nonrecalled devices (9.9% vs 7.3%) (IOM, 2011). Given the rate of review
deficiencies and the higher recall rate, it is not certain that the program has
met its goal of assisting the FDA in reducing its work burden.
Information-Sharing and Technology
Inadequacies in information-sharing and technology in the FDA are
felt at all levels and centers in the agency. In 2007, the FDA produced a
strategic action plan that focused on four strategic goals: strengthening the
FDA, improving the safety of patients and consumers, increasing access to
new medical and food products, and improving the safety and quality of
manufactured products and the supply chain (FDA, 2007a). Improvement
of the medical-product review process to increase the predictability and
transparency of decisions was identified as a priority. The initiatives included
in the plan were the integration of premarket-decision information into a
OCR for page 78
78 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
TABLE 3-4 Frequency of Problems with Third-Party Reviews of 510(k)
Submissions
% Rated as % Rated as
Review Element Minor Issue Major Issue
Presubmission consultation with the FDA 15 4
Rationale for conclusions and recommendations 11 6
Comparison with legally marketed devices— 11 5
identification and analysis of key similarities and
differences
Summary of device characteristics, intended use, 10 4
performance, and reason for 510(k)
Organization and format of review documentation 13 1
Use of guidance and standards 10 2
Scope of reviewer expertise 8 3
Resolution of 510(k) deficiencies and FDA requests 3 5
Determination of device eligibility for third-party 3 4
review
Determination of 510(k) administrative completeness 6 1
NOTE: Data based on quality assessments completed by FDA supervisors when making final
determinations on 510(k)s with third-party review. The FDA initiated the quality assessments
in January 2005.
SOURCE: Adapted from von Eschenbach, 2007.
single comprehensive tracking warehouse accessible to all staff and the pilot
testing and evaluation of a Web-based tracking system for premarket review
of medical devices (GAO, 2009d).
In a 2009 report, GAO found that although the FDA has an information-
technology (IT) modernization project underway, it has failed to develop
a comprehensive IT strategic plan to inform the modernization process. A
plan would include a well-defined set of goals, strategies, milestones, and
performance measures and would allow the agency to consider the human,
infrastructure, and funding resources needed. Without a clear plan, GAO
asserts, the FDA lacks a roadmap needed to develop an effective system
(GAO, 2009d). In addition, CDRH has acknowledged that it is difficult for
staff to share knowledge throughout the center (FDA, 2011a). The inability
to communicate with other staff, seek essential expertise, and share relevant
information can be attributed to problems of individual workload, the lack
OCR for page 79
79
COMPONENTS OF US MEDICAL-DEVICE REGULATION
of a system to institutionalize cross-center communication, the rigidity of
review-turnaround expectations, and the presence of multiple information
systems (FDA, 2010b).
In an effort to address its information-systems issues, the FDA has
implemented a number of pilot programs that have met with various de-
grees of success. A program called eConsults is intended to facilitate the
exchange of scientific information and staff expertise throughout CDRH.
The program, in place for 5 years, fosters communication within CDRH
by managing expert-consultation requests and allowing staff to access in-
formation and analysis as needed (Desjardins, 2011). It prompts discussion
among CDRH offices to access different types of expertise in premarket
device submissions, postapproval studies, and compliance and enforcement
actions (FDA, 2011b).
CDRH included several items related to the improvement of IT systems
in its 2010 strategic priorities. For example, the iReview program, a pilot
application begun in 2008, automated the premarket certification of medi-
cal devices. The iReview system is a workflow-management tool intended
to automate the end-to-end 510(k) review process and to ensure that work
is not duplicated in multiple systems, that technical risk is reduced, that
future changes in the 510(k) process can be incorporated easily without af-
fecting other applications, and that reviewers, supervisors, and consultants
can use one system as a single repository for all 510(k) review status and
work products (FDA, 2011c). However, during user-acceptance testing in
May 2010, reviewers determined that iReview did not meet the center’s
most pressing needs, namely, internal searches, reporting, and electronic
document routing. As a result, iReview implementation was canceled, and
CDRH will work to improve existing tracking systems to perform key func-
tions (Desjardins, 2011).
A nother pilot that proved unsuitable was the Appian business-
management program introduced in the 2010 strategic priorities. In No-
vember 2010, the FDA announced that it would sign a 5-year contract to
use this platform in all its centers. The program was intended to improve
and align processes between groups and departments and to improve man-
agement of several core business processes. Because most of CDRH’s core
functions involve knowledge creation, the business-management program
did not survive the evaluation process and was determined to be the wrong
tool for CDRH’s work (Desjardins, 2011).
One successful pilot program is the @work toolset, internally known
as Traction. Traction is a collaborative tool that combines the attributes of
a wiki and a blog with networking capability to forge connections between
people throughout the organization. Traction was piloted by CDRH and is
now used throughout the FDA (Desjardins, 2011).
OCR for page 80
80 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
Finding 3-4 The Center for Devices and Radiological Health faces
persistent challenges because of a lack of or limitations on human,
fiscal, and technologic resources and capabilities.
Quality Assurance
The preliminary report of the CDRH 510(k) Working Group finds that
“CDRH does not currently have an adequate mechanism to regularly assess
the quality, consistency, and effectiveness of the 510(k) program” (FDA,
2010a). That finding is amply supported by the results of the reviewer
survey in Appendix D to the preliminary report. The survey asked CDRH
personnel who review 510(k) submissions and their managers about their
understanding of and opinions on a variety of issues related to making
510(k) substantial-equivalence decisions. In a number of cases, reviewers
selected the correct answer only 50–60% of the time, and managers did not
do much better (FDA, 2010a).
Problems surrounding quality assurance in the 510(k) process are not
new. The first public guidance to aid reviewers and industry in the 510(k)
decision-making process was not issued until the program had been oper-
ating for a decade (FDA, 1986).141 In 1988, GAO found a lack of a clear
officewide policy and a lack of coordination among review divisions, and it
recommended steps to improve consistency in 510(k) decision-making and
documentation (GAO, 1988). The Department of Health and Human Ser-
vices inspector general (IG) in 1990 determined that CDRH lacked a com-
prehensive quality-control program to evaluate and critique the adequacy of
the 510(k) review process independently.142 Three years later, the inspector
general issued a follow-up report that concluded that CDRH had focused its
quality efforts primarily on the administrative aspects of the 510(k) process,
not on the scientific validity of the review decisions.143
CDRH has long required device manufacturers to operate a qual -
ity system.144 In an oversimplified description, the regulations prescribe
a continuous-improvement process in which specifications and operating
procedures are established, persons who have appropriate backgrounds
141Memorandum Re: Medical Device Hearing, May 4, 1987, Medical Devices and Drug
Issues: Hearing Before the Subcomm. on Health and the Env’t of the H. Comm. on Energy
and Commerce, 100th Cong. 336-47 (1987) (referred to in the statement of Rep. Henry A.
Waxman, Chairman, H. Subcomm. on Health and the Env’t).
142Memorandum Re: Internal Control Weaknesses in the Food and Drug Administration’s
Medical Device 510(k) Review Process, from the HHS inspector general to the HHS assistant
secretary for health (July 5, 1990), 2.
143Memorandum from the principal deputy inspector general to the acting assistant secretary
for health, Re: Follow-Up Review on Internal Control Weaknesses in the Food and Drug
Administration’s Medical Device 510(k) Review Process (Feb. 26. 1993), 19.
14421 CFR pt. 820.
OCR for page 81
81
COMPONENTS OF US MEDICAL-DEVICE REGULATION
are trained in the procedures, execution of the procedures is properly
documented, and the resulting output is monitored for conformity to the
specifications. When a deviation occurs, the manufacturer is to undertake a
root-cause analysis and then implement a corrective-action and preventive-
action plan to address the root problem and prevent its recurrence (for
example, by revising operating procedures, retraining employees, or revis-
ing specifications). The continuous-improvement process is overseen by
a quality manager or group and executive management of the company.
Those basic principles are as applicable to the making of 510(k) clearance
decisions—and any other regulatory decisions (such as PMA application
approvals and the use of postmarketing tools to address emerging safety
concerns)—as to the production of medical devices.
The absence of a quality system for the 510(k) process since its inception
has important consequences for the future of the process. Prior 510(k) clear-
ance decisions are by law binding on the FDA unless a predicate product is
removed from the market by the FDA or declared adulterated or misbranded
by a federal court.145 The agency is concerned that its authority to rescind
prior decisions may be subject to challenge (Shuren, 2011).
About 120,000 510(k) submissions have been cleared over the past 35
years (Tillman, 2010). As described in Chapter 2, those actions have by
and large built on a chain of devices that link a new postamendment device
to earlier postamendment devices that ultimately could be traced back to a
preamendment device from 1976. CDRH has never had an effective quality-
assurance system in the 510(k) process. In addition, at least in the early years
of implementation, the FDA may have biased the review process in favor of
finding substantial equivalence to avoid the administrative consequences of
placing too many devices in Class III (OTA, 1984). Today, CDRH cannot
reconstruct the “piggy-backing” of devices without a manual review of per-
haps thousands of files. Even if a computerized database allowed easy access
to the history, the agency would have to review every decision manually to
identify questionable ones. The cost of the exercise would be staggering;
the benefit would be, it is hoped, small in terms of identifying devices that
should not have gotten to the market by a 510(k) clearance. However, it
cannot be assumed that the number is zero.
Finding 3-5 The committee agrees with the CDRH 510(k) Working
Group that the Center for Devices and Radiological Health does
not have “an adequate mechanism to regularly assess the quality,
consistency, and effectiveness of the 510(k) program.”
145FFDCA § 513(i)(2), 21 USC § 360c(i)(2) (2006).
OCR for page 82
82 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
SUMMARY OF FINDINGS
• inding 3-1 The Food and Drug Administration has a wide array
F
of tools to address safety risks that are discovered to be posed by
marketed devices.
• inding 3-2 The Food and Drug Administration has not used the
F
tools at its disposal extensively. The Center for Devices and Radio-
logical Health has suggested that there are important limitations in
their use. The committee identified some procedural burdens on the
exercise of these tools, but these burdens do not in themselves explain
the historical and continuing sparse use of the tools.
• inding 3-3 The 510(k) clearance pathway is generally more eco-
F
nomical, faster, and less burdensome to industry and the Food and
Drug Administration than the premarket approval application route
and has substantially fewer postmarketing controls.
• inding 3-4 The Center for Devices and Radiological Health faces
F
persistent challenges because of a lack of or limitations on human,
fiscal, and technologic resources and capabilities.
• inding 3-5 The committee agrees with the CDRH 510(k) Working
F
Group that the Center for Devices and Radiological Health does
not have “an adequate mechanism to regularly assess the quality,
consistency, and effectiveness of the 510(k) program.”
REFERENCES
Desjardins, P. R. 2010. FDA response to information inquiry from the committee on the pub-
lic health effectiveness of the 510(k) clearance process. Silver Spring, MD, 09/17/2010.
———. 2011. FDA response to information inquiry from the committee on the public health
effectiveness of the 510(k) clearance process. Silver Spring, MD, 01/07/2011.
Evans, B. 2009. Seven pillars of a new evidentiary paradigm: The Food, Drug, and Cosmetic
Act enters the genomic era. Notre Dame Law Review 85(2):419-524.
FDA (Food and Drug Administration). 1986. Guidance on the CDRH Premarket Notification
Review Program (K86-3) (June 30, 1986). http://www.fda.gov/MedicalDevices/Device
RegulationandGuidance/GuidanceDocuments/ucm081383.htm (accessed 02/16/2011).
———. 2005. Guidance for industry and FDA staff—format for traditional and abbreviated
510(k)s. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm084396.pdf (accessed 03/14/2011).
———. 2007a. FDA strategic action plan. http://www.fda.gov/AboutFDA/ReportsManuals-
Forms/Reports/StrategicActionPlan/default.htm (accessed 12/3/2010).
———. 2007b. Premarket notification [510(k)] submissions for medical devices that in-
clude antimicrobial agents. http://www.fda.gov/MedicalDevices/DeviceRegulationand
Guidance/GuidanceDocuments/ucm071380.htm (accessed 05/31/2011).
———. 2009. Third party review. http://www.fda.gov/medicaldevices/deviceregulationand
guidance/howtomarketyourdevice/premarketsubmissions/thirdparyreview/default.htm
(accessed 02/16/2011).
———. 2010a. CDRH preliminary internal evaluations—Volume I: 510(k) working group pre-
liminary report and recommendations. Silver Spring, MD: Food and Drug Administration.
OCR for page 83
83
COMPONENTS OF US MEDICAL-DEVICE REGULATION
———. 2010b. CDRH preliminary internal evaluations—Volume II: Task force on the utiliza-
tion of science in regulatory decision making: preliminary report and recommendations.
Silver Spring, MD: Food and Drug Administration.
———. 2010c. Class II special controls guidance document: Tissue adhesive with adjunct
wound closure device intended for the topical approximation of skin. http://www.fda.
gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm233027.
htm (accessed 05/24/2011).
———. 2010d. General considerations for animal studies for cardiovascular devices. http://
www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
ucm220760.htm (accessed 05/24/2011).
———. 2010e. Postmarket drug safety information for patients and providers. http://www.
fda.gov/cder/drugSafety.htm (accessed 12/6/2009).
———. 2011a. 510(k) and science report recommendations: Summary and overview of com-
ments and next steps. Silver Spring, MD: Food and Drug Administration.
———. 2011b. FDA-track CDRH office of surveillance and biometrics (OSB) dashboard. http://
www.fda.gov/AboutFDA/Transparency/track/ucm203271.htm (accessed 02/03/2011).
———. 2011c. FDA-track CDRH premarket dashboard. http://www.fda.gov/AboutFDA/
Transparency/track/ucm201070.htm (accessed 02/15/2011).
———. 2011d. Important information on the medical device user fee rates for FY2011.
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/Medical
DeviceUserFeeandModernizationActMDUFMA/ucm109179.htm (accessed 01/12/2011).
GAO (Government Accountability Office). 1988. Medical devices: FDA’s 510(k) operations
could be improved. Report to the chairman, Subcommittee on Health and the Environ-
ment, Committee on Energy and Commerce, House of Representatives (PEMD-88-14).
Washington, DC: General Accounting Office.
———. 1989. FDA resources: Comprehensive assessment of staffing, facilities, and equipment
needed (HRD-89-142). Washington, DC: General Accounting Office.
———. 2002. Food and drug administration: Effect of user fees on drug approval times,
withdrawals, and other agency activities (GAO-02-958). Washington, DC: General Ac-
counting Office.
———. 2009a. FDA’s medical product resources (GAO-09-581). Washington, DC: Govern-
ment Accountability Office.
———. 2009b. FDA faces challenges meeting its growing medical product responsibilities and
should develop complete estimates of its resource needs (GAO-09-581). Washington, DC:
Government Accountability Office.
———. 2009c. FDA should take steps to ensure that high-risk device types are approved
through the most stringent premarket review process (GAO-09-190). Washington, DC:
Government Accountability Office.
———. 2009d. Information technology: FDA needs to establish key plans and processes for
guiding systems modernization efforts (GAO-09-523). Washington, DC: Government
Accountability Office.
———. 2011. Testimony before the Special Committee on Aging, U.S. Senate. Medical devices:
FDA’s premarket review and postmarket safety efforts (GAO-11-556T). 04/13/2011.
Hutt, P. B., R. A. Merrill, and L. A. Grossman. 2007. Food and drug law: Cases and materials.
Third edition. New York: Foundation Press.
IOM (Institute of Medicine). 2007. The future of drug safety: Promoting and protecting the
health of the public. Washington, DC: The National Academies Press.
———. 2010. Public health effectiveness of the FDA 510(k) clearance process: Balancing
patient safety and innovation. Washington, DC: The National Academies Press.
OCR for page 84
84 MEDICAL DEVICES AND THE PUBLIC’S HEALTH
———. 2011. Public health effectiveness of the FDA 510(k) clearance process: Measuring
postmarket performance and other select topics. Washington. DC: The National Acad-
emies Press.
Kahan, J. S. 2009. Medical device development: Regulation and law, Needham, MA: Parexel
International.
OTA (Office of Technology Assessment). 1984. Federal policies and the medical devices indus-
try. Washington, DC: Congress of the United States, Office of Technology Assessment.
Shuren, J. 2011. CDRH summary of public comments; issues for committee to consider. Silver
Spring, MD, 01/21/2011.
Tillman, D. B. 2010. Understanding the premarket notification (510(k)) process. Presentation
given at Public Health Effectiveness of the FDA 510(k) Clearance Process Committee,
Meeting 1, March 1, 2010, Washington, DC.
von Eschenbach, A. C. 2007. Third party review of medical device premarket notifications.
Report to the Committee on Energy and Commerce, U.S. House of Representatives, and
the Committee on Health, Education, Labor, and Pensions, U.S. Senate. Washington, DC.
