For the majority of marketed products, no, or very limited, clinical data are required.
POSTMARKET SURVEILLANCE CONTEXT
For
the majority of marketed products, no, or very limited, clinical data are
required. Of 783 Class I device regulations (each of which typically pertains
to more than one device), 720 (92%) are exempt from premarket notification.
Similarly, of the 898 Class II device regulations, 75 (8%) are exempt. For the
Class I and II products requiring premarket notification, many applications do
not include clinical data. Even when clinical trial information is provided
(for Class III devices), these data have some of the same inherent limitations
noted in drug trials [i.e. limited size, dura-tion, and select patient
population (e.g. restrictions in age, gender, disease complexity)]. In
addition, inves-tigators in premarket device clinical trials tend to be those
physicians at the ‘cutting edge’ of product devel-opment and who are most
familiar with the device’s characteristics and application. Thus, limited
informa-tion may be generated on human factor concerns such as optimal design
for ease of use, optimal use envi-ronment (e.g. free of electromagnetic
interference), labeling that anticipates less sophisticated use or that
minimizes maintenance error, or the consequences of re-use on device
performance and safety. Once in the marketplace, devices are likely be used by
a wide array of physicians and other clinicians of varying skill levels,
training, and experience. In addition, less stringent diagnostic and other
criteria may be applied reflecting either non-optimal product choice or
off-label use, the latter a hallmark of the evolving practice of medicine.
Since
no device is free from adverse events and product problems and since premarket
clinical data are limited, postmarket oversight is needed as a ‘safety net’ to
ensure the continued safety and effectiveness of marketed products. Postmarket
oversight refers to both postmarket surveillance (and risk assessment) as well
as postmarket enforcement. The former refers to the systematic process of
adverse event/product prob-lem reporting, monitoring, and evaluation as well as
the subsequent, more formal, assessments of identified potential patient risks.
The latter refers to investiga-tions of a device firm’s compliance with
statutory and regulatory requirements. Both processes are integral to product
development and evolution. This chapter will focus on the FDA programs
constituting postmar-ket surveillance.
As
with drugs, the goals of device postmarket surveil-lance and risk assessment
are: (1) identification of previously unknown or not well-characterized adverse
events/product problems (‘signals’); (2) identifica-tion and characterization
of sub-groups at risk; (3) collection and evaluation of information on issues
not directly addressed in premarket submissions (e.g. long-term effectiveness
or changes in use envi-ronment, from professional to home use); and (4)
development of a public health context to interpret these data. This process
ultimately aims to disseminate information regarding newly emerging device
prob-lems to appropriate stakeholders (particularly health professionals and
the public), incorporate the infor-mation into the device approval process, and
provide findings to the device industry to aid in product corrections and
improvements. The principal postmar-ket ‘tools’ utilized by the agency to
achieve these goals are: (1) adverse event/product problem report-ing [through
the Medical Device Reporting (MDR) system and MEDWatch, PMA conditions of
approval, the pilot Medical Device Safety Network (MedSuN), and international
vigilance]; (2) mandated postmar-ket studies (including condition of approval
and Section 522 studies); and (3) applied epidemiology.
The
FDA monitors postmarket device-related adverse events/product problems (AEs),
through both volun-tary and mandatory reporting, to detect ‘signals’ of
potential public health safety issues. Voluntary report-ing to the FDA began in
1973 and presently continues under MEDWatch (Kessler, 1993), a program created
in 1993 to encourage voluntary reporting by all inter-ested parties (but
principally among healthcare profes-sionals) as a critical professional and
public health responsibility.
It
was not until 1984 that the FDA implemented mandatory reporting as per the MDR
regulation. This regulation required device manufacturers and importers to
report device-related deaths, serious injuries, and malfunctions to the FDA.
Additional legislative initiatives in the 1990s resulted in significant changes
to mandatory reporting. Under the Safe Medical Devices Act of 1990, universal
reporting of adverse events by user facilities (hospitals, nursing homes,
ambulatory surgical facilities, outpatient diag-nostic and treatment
facilities, ambulance services, and health care entities) and distributors was
enacted. Under the FDA Modernization Act of 1997 (FDAMA, Section 213 of the
Act), and in response to expe-rience with distributor and user facility
reporting, the US Congress mandated that distributor reporting be repealed and
that universal user facility report-ing be limited to a ‘subset of user
facilities that constitutes a representative profile of user reports ’. The
conceptual framework for these ‘sentinel sites’, collectively referred to as
the Medical Device Safety Network (MedSun; formerly Medical Product
Surveil-lance Network), is discussed below.
To
better understand reporting of AEs under the current MDR regulations governing
mandatory report-ing [Title 21 Code of Federal Regulations (CFR) Part 803],
requirements should be noted and terms defined. Manufacturers and importers are
currently required to submit reports of device-related deaths, serious
injuries, and malfunctions. User facilities are required to report deaths to
the FDA and deaths and serious injuries to the manufacturer. Seri-ous injuries
are defined as life-threatening events – events that result in permanent
impairment of a body function or permanent damage to a body structure, and
events that require medical or surgical interven-tion to preclude permanent
impairment or damage. Malfunctions are defined as the failure of a device to
meet its performance specifications or otherwise perform as intended. The term
‘device-related’ means that the event was or may have been attributable to a medical
device, or that a device was or may have been a factor in an event, including
those occurring as a result of device failure, malfunc-tion, improper or
inadequate design, poor manufac-ture, inadequate labeling, or use error.
Guidance is issued to reporting entities as needed to more clearly define the
reporting of specific events, for example implant failures.
Since its inception in 1973, the FDA’s database of voluntary and mandatory reports of device AEs has received slightly more than 1 million reports and currently averages approximately 200 000 per year, with mandatory reports accounting for about 98% of the total. The reports are submitted on the same standardized voluntary and mandatory forms used to submit drug-related events and capture information on device specifics (e.g. brand name, model number), event description, pertinent dates (e.g. event date), and patient characteristics. The reports are also coded (either by reporters or inter-nally) using a coding thesaurus of patient and device problem codes. Manufacturers also supply meth-ods, results, and conclusion codes relevant to their report investigation. To enhance report handling and signal detection, the FDA has established methods of triage:
• emergency reports (e.g. a cluster of deaths
or seri-ous injuries in a dialysis facility) are handled under agency-wide
standard operating procedures;
• pre-designated high priority reports are
reviewed within 24 hours of receipt and include, among others, reports of
pediatric death, exsanguination, explosion/fire, or anaphylaxis;
• other individual reports (account for about
24% of all reports) are reviewed within 5–15 workdays of receipt;
• autoscreen reports (account for about 12%)
are those that are computer-screened (by pre-designated device and event) where
events are considered to be familiar, but text may be particu-larly valuable in
assessing event or events that are coded inconsistently; 10% of screened
reports are later individually reviewed; and
• summary reports (account for about 64%)
capture well-characterized and well-known device events and amount to a
quarterly submission by manu-facturers of line-listed data. The data elements
per event include the manufacturer, model-specific device, event and receipt
dates, and patient and device problem codes. A system is being developed to
perform automated numerator-only trend analyses looking for month-to-month
vari-ation, monthly moving averages, and 12-month trends.
When
potential hazards are detected (either based on internal individual or
aggregate review) or upon noti-fication by the manufacturer (under voluntary
recalls), denominator data can be obtained from manufacturers upon request. The
denominator data most appropriate to the analysis tend not to be generic
higher-order data (such as number manufactured of that brand during the past
year) but typically are model-specific, many times lot-specific (and thus
time-specific), and may be sub-group-specific (e.g. pediatric use).
Compli-cating the selection of appropriate denominator data are the myriad types
of devices (e.g. single-use disposables to multi-component durable medical
equipment) and the inherent difficulties in assess-ing potential population
exposure (e.g. factoring in multiple uses, average shelf-life, component
replacement).
A
staff, predominantly of nurses, review the individual reports from a variety of
perspectives including the potential for device failure (e.g. poor design,
manufacturing defect), use error (e.g. device misassembly, incorrect clinical
use, misreading instructions), packaging error, support system fail-ure,
adverse environmental factors, underlying patient disease or co-morbid
conditions, idiosyncratic patient reactions (e.g. allergy), maintenance error,
and adverse device interaction (e.g. electromagnetic inter-ference) (ECRI,
1998). Since many devices involve complex human interaction, great emphasis is
placed on human factor considerations. Simply put, these considerations ask:
(1) To what extent did sub-optimal device design, packaging, or labeling induce
human error? (2) To what extent was anticipated use (and abuse) of the product
factored into device design, packaging, or labeling?
Several immediate actions, aside from routine requests for follow-up information, may be taken by the staff and include:
• Recommending directed inspections of
manufac-turers. These may lead to: (a) label changes, includ-ing those
affecting device instructions or training materials, (b) product
modification/recall, and (c) rarely, product seizure or injunction.
• Recommending internal expert safety meetings.
These may lead to public notifications, recommen-dations for additional
postmarket study, or meet-ings with the company to explore issues further.
• Alerting regulatory authorities outside the
United States through the international vigilance program (see below).
Other
internal uses of the AE data are widespread and include: input into premarket
review (by provid-ing human factor insights and information on prod-uct
experience in the general population); input into recall classifications (involving
a hazard evaluation based on AE data); monitoring of recalls (and assess-ing
reports in similar products); input into product reclassifications and
exemptions from premarket noti-fications (based, in part, on a product’s safety
profile); use in, and initiating of, standards efforts that establish device
performance; educating the clinical community through newsletters, literature
articles (peer-reviewed and professional and trade journals), and
telecon-ferences; and as a general information resource for healthcare
providers and the general public.
A
recent example of reports of AEs typifies the system in action. In June 2002,
the agency received reports of bacterial meningitis in patients with cochlear
implants for treatment of hearing loss. Early speculation by manufacturers and
implanting surgeons implicated the implant positioner (a Silastic wedge that is
inserted next to the implanted electrode to facilitate transmission of the
electrical signal by pushing the electrode against the medial wall of the
cochlea). The one manufacturer that made implants with a positioner voluntarily
withdrew their prod-uct both in Europe and the US in July 2002. Other
manufacturers, however, notified the agency of addi-tional cases of meningitis,
principally in children. A nationwide collaborative investigation was begun by
the agency and the Centers for Disease Control and Prevention (CDC) that
involved several thousand implanted children. These children were found to have
far greater risk of developing pneumococcal menin-gitis compared to children in
the general population, and those with positioners had over four times the risk
of developing meningitis compared to recipients of other cochlear implant types
(Reefhuis et al., 2003). Throughout
this process, the agency posted periodic updated public health notifications on
its website to keep the public informed (Food and Drug Adminis-tration, 2002,
2003). In addition, the CDC Advisory Committee on Immunization Practices added
cochlear implant recipients to the list of high risk patients need-ing routine
immunizations (Center for Disease Control and Prevention, 2003).
As is typical of passive surveillance systems (including those for drugs), the FDA’s system has notable weaknesses as well as strengths. Among the former are:
• data may be incomplete or inaccurate and are
typi-cally not independently verified;
• events are under-reported – causes include
lack of detection and/or attribution of device to event, lack of knowledge
about reporting system, liability concerns, perceived lack of utility in
reporting, and limited feedback;
• data reflect reporting biases driven by
factors such as event severity or uniqueness, familiarity with reporting, or publicity
and litigation;
• determination of incidence and prevalence is
not possible due to under-reporting and lack of denom-inator data; and
• causality cannot be inferred from any
individual report. [In addition, devices are often not returned to manufacturers
for assessment (for a variety of reasons) and therefore failure analyses of
data are often inadequate or lacking.]
The
system strengths are:
• it provides nationwide safety surveillance
from a variety of sources, thus providing insight into AEs related to ‘real
world’ use;
• it is relatively inexpensive considering the
scope of surveillance;
data
collected are uniform in terms of a standard-ized form with pre-specified data
elements;
• it is one of only a few means to detect rare
AEs; and
• it is accessible and the information is open
to the public.
Supplementing
this reporting system are PMA condi-tions of approval (applies to Class III
devices). All products with approved PMAs have conditions of approval, one of
those being the submission of infor-mation on AEs outside the MDR regulatory
require-ments [Title 21 CFR Part 814.82 (a)(9)]. Examples of this include
labeled AEs occurring with unex-pected severity or frequency. This requirement
helps the agency cast a wider ‘safety net’ in its surveillance of AEs.
Although
user facility reporting was mandated in 1990, it accounted for only 3% of all
reports in 1999. Furthermore, only about 2000 reports came from hospitals in
1999, representing about 800 hospi-tals out of a universe of about 7000.
Likewise, only 90 reports came from nursing homes, representing 50 nursing
homes out of a universe of about 12 000. This lack of mandatory institutional
reporting has many root causes (some alluded to above under weaknesses of AE
reporting), but basically reflects a lack of educational outreach coupled with
a lack of enforce-ment (with both tied to inadequate resources). Recog-nizing
the need for user facility reporting but also the difficulties behind universal
reporting, the US Congress mandated under FDAMA 1997 that report-ing be limited
to a ‘subset of user facilities that constitutes a representative profile of
user reports ’. Since 2002, FDA has been collecting data about problems with
the use of medical devices from a sample of hospitals and nursing homes via
MedSun. By mid-2005, this interactive Internet-based report-ing program
expanded to approximately 350 health-care institutions (mostly hospitals)
nationwide. The program’s principal objective is to increase the util-ity of
user facility reporting by recruiting a cadre of well-trained and motivated
facilities and establish a collaborative effort to better understand device use
in its natural clinical environment. It is envisioned that, in addition to
enhancing the detection of emerg-ing device problems, the network acts as a
two-way communication channel between the FDA and the clinical community and
serves as a setting for applied clinical research on device issues. To succeed,
the effort must: train staff in the recognition and reporting of AEs, assure
confidentiality to reporters, minimize burden of participation, and provide
timely feedback. To achieve its mission, MedSun staff have initiated a variety
of efforts within the network: monthly newsletters (highlighting device
reports, FDA actions, and other notable safety initiatives by other agen-cies);
clinical engineering audioconferences; device safety exchanges (highlighting
best safety practices and safety solutions); and surveys on high-profile safety
concerns.
The
reach of AE surveillance was augmented and truly became global under the
auspices of the Global Harmonization Task Force (GHTF) established in 1992. The
GHTF was established to respond to the increasing need for international
harmonization in the regulation of medical devices (www.ghtf.org). The GHTF is
a voluntary international consortium of public health officials, responsible
for administering national medical device regulatory systems, and
repre-sentatives from regulated industry. The task force acts as a vehicle for
convergence in regulatory practices related to ensuring the safety,
effectiveness and qual-ity of medical devices and promoting technological
innovation as well as facilitating international trade. This is principally
accomplished through publication and dissemination of harmonized guidance
documents on basic regulatory practices.
One
of the four GHTF study groups is charged with reviewing current adverse event
reporting, post-market surveillance and other forms of vigilance for medical
devices, and performing an analysis of differ-ent requirements with a view to
harmonizing data collection and reporting systems. A process for the global
exchange of vigilance reports between National Competent Authorities (NCAs) has
been established. Standardized reports on potentially high risk issues for
which action is to be taken (even if investiga-tions are incomplete) are
submitted electronically to a shared listserver. General and specific criteria
for categorizing issues as high risk have been established and include: the
equivalent of US Class I and high level Class II recalls, all public health
notifications, and special public health concerns (e.g. high index of
preventability or particularly vulnerable populations). Currently, the program
exchanges approximately 150 reports per year.
Part
of the information requirements for the vigilance exchange program includes the
official name of the device that is the subject of the vigilance report. Only
since 2001 has the medical device community had an official international
source for such names, the Global Medical Device Nomenclature (GMDN). The GMDN,
developed through a major international stan-dards effort, was created largely
via the merging and evaluation of six extant naming systems (including the one
used by the FDA). Currently, version 3 of the GMDN has 8000 primary terms that
abide by speci-fied naming rules and conventions as well as defini-tion
structure and content (e.g. incorporating intended use). The GMDN is based on
the level of specificity of the ‘device group’, which is best described by way
of example, that is pacemaker, cardiac, implantable or gastroduodenoscope,
flexible, fibreoptic. It is meant for use by regulatory agencies, but has the
potential for wider applications (e.g. inventory control or market-ing) and may
eventually be incorporated into admin-istrative and healthcare databases that
could be used for public health purposes. When compared with the National Drug
Classification coding system, however, the GMDN is more limited in that it does
not at present include model-specific information, or other potentially useful
data such as material composition, component parts, or size.
Another
‘tool’ that the FDA uses to achieve its surveillance and risk assessment goals
are mandated postmarket studies, conducted under either PMA conditions of
approval (for Class III products) or FDAMA (Section 522) authorities. A sponsor
may be required to perform a post-approval study as a condition of approval for
a PMA [Title 21 CFR Part 814(a)(2)]. The study questions may relate to
longer-term performance of an implant, or focus on specific safety issues that
may have been identified during review of the product for which additional
informa-tion is felt to be needed, postmarket. Results from these studies may
be included as revisions to the prod-uct’s labeling (including patient- and
clinician-related material).
In
addition to the PMA authority for Class III prod-ucts, the agency may, under
Section 522, impose postmarket study requirements on certain devices. The
latter provision, originally mandated in 1990 under SMDA, allows the agency,
under its discre-tion and for good reason, to order a manufacturer of a class
II or class III device to conduct a post-market study if the device: (1) is
intended to be implanted in the human body for more than one year; (2) is
life-sustaining or life-supporting (and used outside a device user facility);
or (3) failure would reasonably be likely to have serious adverse health
consequences. Although this discretionary authority overlaps the PMA
post-approval authority for some products (e.g. PMA Class III implants), it
effectively extends FDA authority to cover non-PMA products as well, that is
those subject to premarket notifi-cation. Unless there are unusual
circumstances, the Section 522 authority is typically reserved for the latter.
Prior
to issuing an order, the FDA will discuss the public health concern with the
firm. The concern may arise from questions about a product’s long-term safety,
about performance of a device in general use or involving a change in user
setting (e.g. professional to home use), or notable AEs. Upon receiving an
order, the firm has up to 30 days in which to submit their study plan and, by
statute, studies are limited to 3-year patient follow-up (or longer if agreed
to by the firm). The FDA recently issued a regulation clearly specifying, among
other items, the requirements for a study plan, conduct, and follow-up (Title
21 CFR Part 822).
The
FDA has issued guidance on criteria used in considering order issuance as well
as possible study approaches (October, 1998; www.fda.gov/cdrh/
postsurv/index.html). Briefly, the criteria include: the public health issue
must be important; other postmar-ket mechanisms cannot effectively address the
issue; the study must be practicable (i.e. feasible, timely, not
cost-prohibitive); and the issue is of high priority. The possible study
approaches vary widely (designed to capture the most practical, least
burdensome approach to produce a scientifically sound answer) and include: a
detailed review of complaint history and the literature; non-clinical testing
of the device; telephone or mail follow-up of a patient sample; use of
registries; observational studies; and, rarely, random-ized controlled trials.
Generally
speaking, these mandated postmarket studies (both via PMA conditions of
approval and Section 522) require the participation of both firms and the
clinical community. Problems, however, may arise in the conduct of these
studies if, for instance, it is difficult to recruit physician investigators or
accrue patients or if industry lacks incentive. These issues particularly
resonate with rapidly evolving technolo-gies, where rapid device evolution may
make stud-ies of prior models obsolete by the time they are completed.
Although
there may be difficulties in study conduct, an example of a Section 522 study
reveals the author-ity’s public health importance and its risk assessment role.
In 1991, FDA scientists demonstrated that it was possible for polyurethane to
break down under labo-ratory conditions to form 2,4-toluenediamine (TDA). TDA
had been shown to be an animal carcinogen. Prior to this it was thought that
breakdown could only occur at very high temperatures and pH extremes. The firm
that manufactured polyurethane foam-coated breast implants ceased sales in 1991
and agreed to a clinical study under Section 522. The study involved comparing
TDA levels in urine and serum samples from women with and without the implants.
Although minute amounts of TDA were found in the majority of women with the
implants, the increase in cancer risk was determined to be vanishingly small (1
in 1 million) (Hester et al., 1997;
DoLuu, Hutter and Bushar, 1998). The FDA issued a public health corre-spondence
(FDA Talk Paper) on the results and their reassuring implications (Food and
Drug Administra-tion, 1995).
Postmarket
surveillance and risk assessment would not be complete without epidemiology, a
discipline that provides the means and methods to further elucidate a device’s
postmarket safety and effective-ness in a population context. Through employing
methods of observational (as opposed to experimen-tal) study, epidemiologists
help refine AE signals, characterize sub-groups at risk, test hypotheses, and
evaluate device performance and use. The epidemiol-ogy program serves a vital
postmarket function at the agency and works to inform Center and agency device
policy, address relevant scientific questions, assess the effectiveness of
regulatory approaches, provide risk assessments, develop new postmarket
surveil-lance and other data resources, and provide important public health
information (e.g. through peer-reviewed publications). Importantly, as of 2005,
the program has been given oversight of post-approval studies (i.e. those as a
condition of approval of PMA prod-ucts). It is now the program’s responsibility
to help design, implement, track, and oversee completion of these studies of
high-risk devices. To accomplish this, the program works collaboratively with
product manufacturers and the premarket staff.
To
accomplish its overall mission, the epidemiol-ogy program makes use of a
variety of databases (e.g. the National Inpatient Sample to evaluate
in-hospital mortality associated with heart valve replace-ment; Astor et al., 2000) and develops
device-specific supplements to nation-wide surveys (e.g. US National Mortality
Followback Survey to assess characteris-tics of persons receiving pacemakers in
their final year of life; Hefflin, 1998). In addition, the program explores new
means of surveillance [e.g. through a nation-wide surveillance network of
emergency departments operated by the US Consumer Prod-ucts Safety Commission
(CPSC); Hefflin, Gross and Schroeder, 2004], explores methods of active
surveil-lance (in a large tertiary hospital; Samore et al., 2004), develops and expands existing device registries
(e.g. exploring device safety using the American College of Cardiology National
Cardiovascular Data Registry; Tavris et
al., 2004), reviews and assesses observational literature (e.g. studies of
cellular phones and their relation to brain cancer), and conducts applied
research (e.g. breast implants and rupture rates) (Brown et al., 2000).
The
ability of drug or device epidemiologists within the agency to address issues,
however, is at times limited for both practical and regulatory reasons. There
may be practical resource limita-tions (e.g. limited staff or limited funding)
or time constraints (i.e. issues requiring immediate resolution may not lend
themselves to observational study). Limits imposed by the regulatory
environment are most apparent when mandating postmarket studies. The agency
levies these studies on specific manu-facturers of specific products. In doing
so, there is no intent for comparative analyses, or pooled analy-ses, amongst
manufacturers of similar products. Nor is there any intent on assessing cost
effectiveness, or conducting other economic analyses, since this is not within
the agency’s mandate.
Other
practical limitations, with regard to medi-cal devices, have to do with the
type of infor-mation available from extant data sources. Many of the data
sources used by pharmacoepidemiolo-gists (e.g. hospital-based, public
health-based as in Saskatchewan, or health maintenance organization-based) may
not have device-specific information, whether at the ‘device group’ level such
as an ultrasonic rigid laparoscope or carbon dioxide surgi-cal laser or
certainly not at the model- or brand-specific level. Other data sources, such
as medical care claims records, often collect procedure-specific, but not
device-specific, information, leaving one to infer device use. Compounding this
situation is the relative lack of data sources for assessing device exposure
and difficulties in deriving the most appropriate denomi-nator data (as noted
previously with regard to AEs) (Bright, 2000).
These
limitations not withstanding, epidemiology continues to play a vital role in
addressing agency device concerns. The role of epidemiology is exem-plified by
the following two cases. On the basis of concerns about use and performance of
transmyocar-dial revascularization, a new and not fully understood technology,
the program undertook a collaborative effort with investigators who oversee the
Society of Thoracic Surgeons National Adult Cardiac Surgery database (Peterson et al., 2004). The study findings noted
large scale off-label use and higher operative risks in patients with a recent
myocardial infarction and unstable angina. Potential reduction in mortal-ity
was suggested through optimization of timing of the procedure. The epidemiology
program was also involved in assessing the public health impact of the only
marketed continuous glucose monitoring system in the US (Tavris and Shoaibi,
2004). A thor-ough review of the literature suggested that use of the system
could result in a substantial reduction in morbidity and mortality associated
with diabetes.
Related Topics
TH 2019 - 2024 pharmacy180.com; Developed by Therithal info.