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Preface
Additional copies are available from the Internet. You may also
send an e-mail request to
dsmica@fda.hhs.gov to receive an electronic copy of the
guidance or send a fax request to 301-827-8149 to receive a hard
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Introduction
Scope
Background- 3.1 The Statutory Standard for Safety and Effectiveness
- 3.2 Types of Scientific Evidence
- 3.3 Benefit-Risk Determinations
Factors FDA Considers in Making Benefit-Risk Determinations- 4.1 Measures for Effectiveness of Devices
- 4.2 Measures for Safety of Devices
- 4.3 Additional Factors for Weighing Benefits and Risks of
Devices
Examples of Benefit-Risk Determinations- 5.1 Hypothetical Examples
- 5.2 Examples Based on Actual FDA Benefit-Risk
Determinations
Draft Guidance for Industry and Food and Drug
Administration Staff
Factors to Consider when Making Benefit-Risk
Determinations in Medical Device Premarket Review
This draft guidance, when finalized, will represent
the Food and Drug Administration’s (FDA’s) current thinking on this
topic. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements of
the applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate
FDA staff, call the appropriate number listed on the title page of
this guidance.
FDA has developed this draft guidance document to provide
greater clarity for FDA reviewers and industry regarding the
factors FDA considers when making benefit-risk determinations
during the premarket review process for certain medical devices.
FDA believes that the uniform application of the factors listed in
this guidance document will improve the predictability,
consistency, and transparency of the premarket review process.
FDA’s guidance documents, including this one, do not establish
legally enforceable responsibilities. Instead, guidance documents
describe the Agency’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or
statutory requirements are cited. The use of the word
should in Agency guidance documents means that something
is suggested or recommended, but not required.
This guidance document explains the factors that FDA considers
when making benefit-risk determinations in the premarket review of
certain medical devices. The processes discussed in this guidance
are applicable to devices subject to premarket approval (PMA)
applications and, in limited cases, devices subject to premarket
notification (510(k)) requirements. This guidance applies to both
diagnostic devices and therapeutic devices. Although guidance is
not binding, the concepts and factors described herein generally
capture how benefit-risk determinations are made by FDA during the
premarket review process.
3.1
The Statutory Standard for Safety and Effectiveness
Under §513(a) of the Federal Food, Drug & Cosmetic Act
(“the FD&C Act”), FDA determines whether PMA
applications provide a “reasonable assurance of safety and
effectiveness” by “weighing any probable benefit to
health from the use of the device against any probable risk of
injury or illness from such use”. To aid in this process, PMA
applicants submit valid scientific evidence, including one or more
clinical investigations where appropriate, which FDA reviews to
determine whether “the device will have the effect it
purports or is represented to have under the conditions of use
prescribed, recommended, or suggested in the labeling of the
device.”
1 FDA staff review the data submitted as part of the PMA
and determine – based on a number of factors – if the
data support the claims made by the sponsor for the device, i.e.,
intended use and/or indications for use, and data analysis
demonstrates that the benefits of the device outweigh its risks.
This process may also occur on a case-by-case basis in the review
of 510(k) devices when there are differences between the target
device and the predicate device that can adversely affect the
safety and/or effectiveness of the target device.
2
3.2
Types of Scientific Evidence
Medical devices can be evaluated using clinical and non-clinical
testing methods. Clinical testing methods for medical devices can
include, when appropriate, randomized clinical trials in the
appropriate target population, partially controlled studies,
studies without matched controls, well-documented case histories
conducted by qualified experts, reports of significant human
experience, and testing on clinically derived human specimens.
Non-clinical testing methods can encompass an array of methods
including bench testing for product safety/reliability, animal and
cell-based studies, and computer simulations. These tests
characterize mechanical and electrical properties of the devices
that include wear, tensile strength, compression, flow rate, burst
pressure, biocompatibility, toxicity, electromagnetic compatibility
(EMC), sterility, stability/shelf life data, software validation,
and testing of synthetic samples, including cell lines. For in
vitro diagnostics, analytical validation, or assurance that the
technical measurement aspect of the product is accurate and
reliable, is also considered as part of a demonstration of
reasonable assurance of safety and effectiveness. The data derived
from any clinical and/or non-clinical testing are taken into
account during the premarket review process and FDA’s
benefit-risk determination.
Although a great deal of emphasis is placed on the importance of
clinical data in demonstrating the safety and effectiveness of a
medical device, non-clinical data also can be critical to
understanding device safety and effectiveness. Medical devices
often have attributes that cannot be tested using clinical methods
alone and that play a major role in the safety or effectiveness of
the device. For example:
- For certain types of invasive diagnostic catheters, the only
way to identify and diagnose disease in the specimens they gather
is through examining the tissue under a microscope. In some cases,
clinical studies may provide supportive evidence with respect to
the safety and effectiveness of these devices, i.e., evidence that
the device can be inserted safely into the patient and perform as
expected. However, it may be sufficient to use non-clinical methods
to determine some of the characteristics of the device, without
conducting more expensive, difficult, and perhaps invasive clinical
trials. As a result, non-clinical testing can be used to evaluate
the diagnostic effectiveness (accuracy, precision, etc.) of the
device. This testing can be performed using histopathology methods
on non-clinical samples where the device is tested on tissue
samples from animals or cadavers that are then evaluated under a
microscope to determine the properties of that tissue. For these
devices, even though clinical testing was performed, the results of
the non-clinical histopathology testing may also influence FDA’s
benefit-risk determination. - In the case of some implants, the most robust long-term
evidence comes from engineering tests that are able to challenge
the device under worst-case conditions, test the device to failure
and simulate many years of use. In contrast, clinical studies are
usually limited in duration of follow-up, and, as a result, may be
less informative with respect to the long-term performance of the
device. In this case, the results of engineering testing may
significantly influence FDA’s benefit-risk determination
independent of the clinical findings.
Both clinical and non-clinical data can play a role in the
FDA’s benefit-risk determinations, and the factors discussed
in this guidance are informed by both types of data.
3.3
Benefit-Risk Determinations
There are many factors that go into weighing the probable
benefit of a device versus its probable risk. These factors
include, among others, whether the device is a first-of-a-kind
treatment or diagnostic, whether the device provides significant
improvement in diagnosis and patient management of a serious
disease, how known risks of the device can be mitigated,
reliability of the study, whether there are multiple studies and
the strength of those studies, what amount of risk the target
population will tolerate in light of the condition being treated or
diagnosed and the probable benefit of the device, and whether there
are alternate treatments or diagnostic techniques available.
The factors FDA considers as part of the benefit-risk
determination are explained in detail below. We also give examples
of how the factors interrelate and how they may end up affecting
FDA’s decisions. By providing greater clarity about
FDA’s decision-making process, we hope to improve the
predictability, consistency, and transparency of the review process
for applicable devices.
We have also included for public comment a proposed draft of a
worksheet that reviewers would use in making benefit-risk
determinations. The worksheet is attached as
Appendix A to this guidance. We believe that the level of
documentation proposed by the worksheet would be very helpful to
maintaining the consistency of review across different review
divisions and better assuring that an appropriate decision is
reached. In addition, by documenting reviewers’ thought
processes as part of the review file and, in certain cases, the
publicly available summary of our decision, sponsors will have a
better idea of the basis for FDA’s decisions and gain a
greater understanding of what factors were considered in reaching
an approval or clearance decision. After receiving feedback from
stakeholders and FDA staff, we may integrate use of this or a
similar worksheet as part of the premarket review process. However,
because the weighting of the factors for a type of device may
change over time – such as a device no longer being a
first-of-a-kind or the only available treatment as new therapies
are approved – the benefit-risk determination for a specific
device at one point in time may no longer represent the proper
weighting of the factors for a similar type of device in the
future.
4. Factors FDA Considers in
Making Benefit-Risk Determinations
The factors described below are considered within the intended
use of the device, including the target population.
4.1 Measures for Effectiveness of Devices
3
Extent of the probable benefit(s) : The extent
of the probable benefit(s) is measured by taking into account the
following factors:
- The type of benefit(s) – examples
include but are not limited to the device’s impact on
clinical management of the patient, the patient’s physical
health and patient satisfaction in the target population, and can
range from significantly improving patient management or reducing
the probability of death, to aiding in some improvement of
management or reducing the probability of loss of function, to
providing relief from minor symptoms. For diagnostics, benefits may
be measured according to the public health impact of identifying
and preventing the spread of disease. Other benefits of diagnostics
include earlier diagnosis of disease and identification of patients
more likely to respond to a given therapy. - The magnitude of the benefit(s) in the
individual patient – the magnitude measures the size of the
benefit. We often measure benefit along a scale or according to
specific endpoints or criteria (types of benefits). The change in
the patient’s condition or their clinical management as
measured on that scale, or as determined by an improvement or
worsening of the endpoint, is what allows us to determine the
magnitude of the benefit for an individual patient. - The probability of the patient experiencing a benefit
– based on the data provided, it is sometimes
possible to predict which patients may experience a benefit but
sometimes this cannot be well predicted. A benefit may only be
experienced by a small portion of patients in the target
population, or a benefit may occur frequently in patients
throughout the target population. It is also possible that
different patient subgroups will experience different benefits or
different levels of the same benefit. - The duration of effect(s) (i.e. how long the
benefit lasts for the patient) – some treatments are
curative, whereas, some may need to be repeated frequently over the
patient’s lifetime. Treatments that are curative may be
considered to have greater benefit than treatments that must be
repeated because repetition may introduce greater risk or the
benefit experienced may diminish each time the treatment is
repeated.
4.2
Measures for Safety of Devices
4
Extent of the probable risk(s)/harm(s): The
extent of the probable risk(s)/harm(s) is measured by taking into
account the following factors:
- Number, severity, and types of harmful events
associated with the use of the device: -
- Device-related serious adverse events –
an injury or illness that is life-threatening, results in permanent
impairment or damage to the body, or requires medical or surgical
intervention to prevent permanent harm to the body.
5 - Device-related non-serious adverse events
– those events that result directly from use of the device
and that do not meet the criteria for classification as a serious
adverse event. - Procedure-related or indirect harms –
harm to the patient that would not be considered a serious or
non-serious adverse event, and that indirectly results from use of
the device.For example,breast implants have serious (e.g., capsular
contraction) and non-serious (e.g., scar) adverse events associated
with them. If a patient chooses to have her physician remove her
breast implants, she may experience negative aesthetic
consequences, such as deformation of her body, which would be an
indirect harm from having had breast implants. This event is not
necessarily considered an adverse event associated with breast
implants, but is nonetheless an indirect harm resulting from the
treatment. Similarly, risks associated with the collection of human
biological materials would factor into the benefit-risk
assessment.
- Device-related serious adverse events –
- Probability of a harmful event – the
percent of the intended population that would expect to experience
a harmful event. - Duration of harmful events (i.e. how long the
adverse consequences last) – some devices can cause
temporary, minor harm; some devices can cause repeated but
reversible harm; and other devices can cause permanent,
debilitating injury. - Risk from false-positive or false-negative for
diagnostics – if a diagnostic device gives a
false-positive result, the patient may receive an unnecessary
treatment and incur all the risks that accompany that treatment, or
may be incorrectly diagnosed with a serious disease. If a
diagnostic device gives a false-negative, the patient may not
receive an effective treatment and will miss out on the benefits it
would confer, or may not be diagnosed with the correct disease or
condition.
We also consider the number of different types of harmful events
that can potentially result from using the device and the severity
of their aggregated effect. When multiple harmful events occur at
once, they have a greater aggregated effect. For example, there may
be a harmful event that is considered minor when it occurs on its
own, but, when it occurs along with other harmful events, the
aggregated effect on the patient can be substantial.
4.3 Additional Factors for Weighing Probable Benefits and Risks
of Devices
Uncertainty – there is never 100% certainty
when determining reasonable assurance of safety and effectiveness
of a device, nor need there be to show that the probable benefits
outweigh the probable risks. However, the degree of certainty of
the benefits and risks of a device is a factor we consider when
making benefit-risk determinations. For example, when the probable
benefits are large, less certainty regarding the probable risks may
be acceptable to support the approval of the device. On the other
hand, factors such as poor trial design, conduct, or analysis can
make the data produced by the study unreliable. Furthermore, the
repeatability of the study results, the results of other similar
studies and whether the study is the first of its kind or a
standalone investigation can all influence the level of certainty.
In addition, the generalizability of the trial results to the
intended treatment and user population is important. For example,
if the device requires in-depth user training or specialization,
the results of the clinical study may not be generalized to a wider
physician population. Likewise, if the device is intended to
diagnose a disease in a subpopulation, it may not be useful in the
general population.
Characterization of the disease – the
treated or diagnosed condition, its clinical manifestation, how it
affects the patients who have it, how and whether a diagnosed
condition is treated, and the condition’s natural history and
progression (i.e., does it get progressively better or worse for
the patient) are all important factors to consider when
characterizing disease.
Patient tolerance for risk – if the risks are
identifiable and definable, different patients will have a
different risk tolerance and will make a decision as to whether the
risks are acceptable. For diagnostic devices, the availability and
nature of the treatment for the condition diagnosed may affect
patients’ tolerance for risk. Different factors can influence
patient risk tolerance, including:
- Disease severity – patients suffering
from very severe diseases (i.e. those that are life-threatening)
may tolerate more risk for devices used in treatment. For
diagnostic devices, individuals with severe diseases may be more
adverse to the risk of a false negative. - Disease chronicity – some patients with
chronic diseases who have adapted to their illness and minimized
its interference with their daily lives may tolerate less risk and
require risky devices to deliver a greater treatment benefit;
whereas, patients who have suffered from a debilitating chronic
illness over a long period of time may tolerate higher risk to gain
less benefit. - Availability of alternative treatment/diagnostic
options (also see below) – if there are no other
treatment/diagnostic options available, patients may tolerate more
risk for even a small amount of benefit.
Availability of alternative treatments or
diagnostics – when making benefit-risk
determinations, FDA considers whether other treatments or
diagnostics, including non-device products, have been approved or
cleared for the intended condition and patient population, how
effective are they, and what known risks they pose; what off-label
uses of approved or cleared devices, other products or procedures
are available, if there are no devices or other products approved
or cleared for the intended condition and patient population, and
their benefit-risk profiles; and how well the alternatives address
the needs of patients and providers. For example, if a new device
has a very small benefit and there is significant uncertainty about
that benefit, we may still approve the product if there are no
available alternative treatments or diagnostics and the risk
profile is acceptable.
Risk mitigation – the use of mitigations,
when appropriate, can minimize the likelihood of a harmful event
occurring. The most common form of risk mitigation is to include
warnings in labeling, or to restrict the indication to a more
limited use. Another important consideration in risk mitigation is
the type of intervention required to address the harm. Some harms
may require surgery; whereas, others may require only minimal
intervention. Thus, even if there is a high likelihood of harm and
the harm resulting from the risk is severe, it may be easily
mitigated with a non-invasive treatment. Finally, some harms can be
mitigated through changing device design features.
Novelty of technology – devices
representing or incorporating new technologies, especially those
that are first-of-a-kind, may provide a less than optimal benefit,
but may also offer advantages that did not previously exist. With
subsequent iterations of the device its benefit-risk profile may
improve, the expected level of safety and effectiveness may
increase, and later versions may offer significant advantages over
the initial device. In these circumstances, we may approve a device
with less benefit or more risk than would be generally tolerated
for more established technologies, particularly where providers and
patients have limited alternatives available, to facilitate patient
access and encourage innovation.
5. Examples of
Benefit-Risk Determinations
The examples below are hypothetical or simplified and are only
offered for illustrative purposes. The decisions described in these
examples are not predictive of future FDA decisions, rather they
are hypothetical outcomes and are only intended to demonstrate how
FDA considers the factors described in this guidance when making
benefit-risk determinations. Similar scenarios or devices may
result in different approval outcomes depending on the individual
characteristics of a particular device.
5.1
Hypothetical Examples
Example 1
An implantable device is developed to treat a severe condition.
There are alternative treatments available for the condition, but
they are only effective for certain subgroups of patients and all
of them pose significant risks.
The device is studied in a pivotal clinical trial with a design
where all patients are implanted with the device but the device is
only turned on in half of them. After completion of the trial,
inactive devices can be turned on. The primary endpoint for the
trial is the magnitude of the benefit, i.e., the trial is designed
to measure how well the device reduces the patient’s
symptoms.
The results of the pivotal clinical trial revealed the
following:
Effectiveness: The probability that a patient
would experience a substantial benefit was only approximately 15%.
However, for the small portion of patients who did respond, their
symptoms were significantly reduced and their quality of life was
significantly improved due to improved mobility. As a general
matter patients with this disease who are able to maintain good
mobility longer tend to have a longer life expectancy. However, the
duration of the benefit cannot be determined because the patients
were only followed for one year.
Safety: There is a very low occurrence of
harmful events after device implantation. However, all implanted
devices that require a surgical procedure carry with them their own
set of risks. In addition, permanent implants pose additional
risks, namely, they typically remain with the patient for life and
may be difficult or impossible to remove. Even in cases where the
device is deactivated, it remains implanted and a risk of device
fracture, mechanical failure, or an adverse biological response to
the device remains. Finally, the surgery to implant the device is
not routine and carries with it high risks.
Additional Factors
Uncertainty : The results of the pivotal clinical trial
are unreliable because both treatment and control groups suffered
significant patient lost-to-follow-up (the clinical status of many
patients in the study was not known at its conclusion); therefore,
it is difficult to tell if patient symptoms improved because of the
device action, the placebo effect, or the effect of the surgery
itself.
Patient Tolerance for Risk : Patients who are willing
to take the risk of having the device implanted even for a small
probability of benefit because they have no other treatment options
and their symptoms are severe.
Risk Mitigation : The surgery to implant the device is
risky, but the risks can be mitigated by requiring the device be
implanted by a skilled surgeon.
Approval/Non-Approval Considerations: The device
effectiveness is limited because the probability that a patient
will experience a benefit is low (15%). In this case, FDA does not
have the option to limit the use of the device to only those
patients who are most likely to experience a benefit because there
is no way to determine the subset of patients who would definitely
experience the benefit. Moreover, this type of permanent
implantable device poses significant risks and there is moderate
uncertainty associated with the trial results. However, for those
patients who do experience a benefit, symptom relief and
improvement in quality of life is impressive and the risks,
although substantial, could be somewhat mitigated through limiting
the device use to specialized surgeons. Finally, the device treats
a severe and chronic disease for which there are few, if any,
alternative treatments. Therefore, FDA is likely to approve the
device.
Example 2
A revolutionary device that replaces a patient’s memory is
developed to treat Alzheimer’s, dementia, and other memory
disorders. The device is permanently implantable and the patient
must undergo a brain resection in order for the device to work
properly. The device functions by downloading all of a
patient’s memories onto a computer chip. Once the device is
implanted, any residual memory the patient retained is no longer
accessible to the patient
Effectiveness: A clinical trial of the device
showed significant improvement in patients who were in the early
stages of dementia and minimal improvement in patients who were in
more advanced stages. Patients who received implanted devices when
the majority of their memory was intact experienced the greatest
benefit.
Safety: The surgery to implant the device is
highly risky and must be done at certified centers of excellence by
specially trained neurosurgeons. Even with these procedural
restrictions, there is an 8% risk of mortality from the surgery
alone. In addition, adverse events include partial paralysis, loss
of vision, loss of motor skills, and slurred speech. Non-serious
adverse events include personality shifts, mood swings, vertigo and
insomnia.
Additional Factors
Uncertainty : The number of patients eligible and
willing to enroll in the trial was small, but the data were robust
and the trial was well-designed and conducted. The results of the
trial are generalizable across all patients because different
patients experienced different levels of benefit depending upon
their stage of memory loss.
Patient Tolerance for Risk : Because of the disruptive
effect on patients’ quality of life from diseases like
Alzheimer’s, dementia, and other conditions that are
associated with severe memory loss, patients (and their families)
suffering from these diseases often have a very high tolerance for
risk. In this case, it is likely that family members responsible
for patients who are at more advanced stages of their illness and
therefore experiencing more severe symptoms will have a higher risk
tolerance than those at the beginning stages of disease.
Availability of Alternative Treatments or Diagnostics :
There are currently no alternative treatments available.
Risk Mitigation : The risks associated with this device
are great. The risks associated with implantation can be somewhat
mitigated by limiting implantation to a highly select group of
surgeons, but the risks associated with personality changes cannot
be mitigated or predicted.
Novelty of Technology : This technology is a
game-changer. There is no other similar technology like it in the
world. It is likely that future improvements of the device may
allow treatment of many other conditions that affect cognitive
function. Also, there are no other treatments that can give
patients the level of benefit that this device confers.
The device has a confirmed, substantial benefit for a defined
and predictable subset of patients and a moderate benefit for
another defined and predictable subset. Even though the clinical
trial was small, the quality of the data is good and there is
little uncertainty about the results. The risks associated with the
device are great and can be mitigated by advising that only highly
trained physicians can implant the device. And, because patients
experience the greatest benefit when the device is implanted
earlier, they must expose themselves to the risks for a longer
period of time in order to reap the greatest benefit; therefore,
the patients who stand to benefit most also have a higher risk
tolerance. Many patients who suffer from memory disorders are
willing to try anything to preserve their memories and quality of
life. The fact that there are no alternative treatments for this
condition and a known benefit with this treatment is also
compelling. Furthermore, the risks are known and quantifiable.
Therefore, this device, although risky, is approvable. The decision
as to whether or not to implant the device is a matter of
patient/family member preference and medical opinion. FDA is likely
to approve the device knowing that patients (or responsible family
members) can give informed consent to the risks the device poses
and only a very small group of skilled physicians will be able to
implant the device.
Example 3
A new in vitro diagnostic device (IVD) claims to provide early
detection of any type of cancer in the general healthy population
by testing patients’ blood. The device is studied in a
diverse population of patients with cancer, and correctly
identifies patients that have cancer 95% of the time.
Effectiveness: The IVD detects cancer well in
patients who are already known to have cancer, but who likely have
different characteristics than the general population in which
early detection might be beneficial, because they may have more
advanced cancer, they may have already received treatment, and they
may have widely different demographic features (e.g., cancer
patients are on average older than the general healthy population
in which early detection would have greatest benefit). The IVD is
effective, but not in the population that would most benefit from
its use.
Safety: The device gave mostly correct results
in patients who were known to have cancer, but was not tested in
the intended use population, i.e. the general healthy population.
If the device were to deliver a substantial proportion of false
results in the intended use population, normal healthy people might
be exposed to further invasive procedures or radiation, resulting
in significant harm. Or, people might actually have cancer and the
test would not detect it, thus preventing them from receiving
beneficial treatment, or discouraging their physicians from
monitoring them for cancer.
Additional factors:
Uncertain Diagnosis : Although the test could detect
cancers, it could not report what type of cancer; therefore, much
additional diagnostic work-up, some of it invasive, would be
required for patients that receive a positive test result.
Patient Tolerance for Risk : Although most seemingly
healthy people would probably like to know if they had early stages
of certain cancers, a large proportion of false results would not
be tolerated because patients’ health at the stage of testing
is good. For very aggressive cancers for which the patient was
known to be at risk due to exposure or family history, more risk
might be tolerable.
Uncertainty about Cancer Natural History : It is
believed that some cancers resolve without treatment, through
various immune and other natural mechanisms. It is not possible to
know which early cancers will progress and which will go away on
their own. Aggressive treatment of early cancers may result in more
morbidity than not treating.
This IVD device had the general benefit of detecting cancers
anywhere in the body, but the study was not designed to address the
intended use population of generally healthy people. The
differences in test performance in patients who do not have obvious
cancer (the intended use population) are unknown. The information
yielded by the test is not specific enough to allow a definitive
diagnosis without considerable further work-up. Given the risk of
serious adverse events resulting from attempts to find the cancer,
as well as the likely high risk of false results (overtreatment or
failure to treat), and the uncertain benefit of early detection for
certain cancers, FDA is not likely to approve the device because it
was not demonstrated to be effective in the intended population and
it has serious side effects without adequate available
mitigations.
5.2
Examples Based on Actual FDA Benefit-Risk Determinations
- A device to treat a very rare virus was tested in a clinical
trial that was designed to show superiority to standard antiviral
treatment. When the trial results were revealed, it was clear the
sponsor had incorrectly designed the trial and the results could
only demonstrate with significant uncertainty that the device
performed as well as standard treatment, but not better. However,
use of the device did not have harmful effects as severe as those
associated with antiviral treatment, and neither treatment was
curative. The viral infection was rapidly progressive and terminal,
so the patients had very little time to live after they were
diagnosed. FDA approved this device because it gave patients access
to a treatment that appeared to be equivalent to the standard of
care (with some uncertainty remaining), but that did not cause the
same severity of side effects. - Ultrasound techniques have been developed to destroy masses
such as kidney stones, cysts and fibroid tumors without the need
for surgery. The effectiveness of these techniques is less than
that of surgery, but the risks are far lower. Additionally, if the
device proves ineffective for certain patients, surgery remains an
option. Thus, for non-invasive therapies that do not interfere with
the effectiveness of subsequent, more-invasive treatments that have
been proven to be effective, the lower level of benefit can
outweigh the risks, which are greatly reduced. - A permanently implanted cardiovascular monitoring device is
intended to diagnose heart failure. The device is studied and shows
that its use reduces the number of days the patient is hospitalized
for heart failure by about three. However, the implantation
procedure for the device requires that the patient be hospitalized
for two days. There are similar devices on the market that provide
a similar level of benefit as this device that do not require an
implantation procedure. FDA determined that the benefit of saving
one day of hospitalization does not outweigh the risk of
complication from the surgery needed to implant the device. - Thermal imaging has been posed as an alternative to mammography
to detect breast cancer. These devices propose to produce a thermal
image of tissue that has been recommended for biopsy to determine
if it really should be biopsied, i.e., was it likely to be cancer.
For these types of diagnostic devices to be approvable, they must
be able to detect possible cancers with a level of specificity that
overcomes the risk of a false negative. Even with risk mitigation
strategies, such as restrictions on labeling or patient
populations, this device had too much uncertainty in the clinical
data to be approvable. - A permanent birth control device can be placed in a
woman’s reproductive system through the vagina using a
specialized delivery catheter. This device is a permanent implant
and is not intended to be removed. Explant of the device would
require surgery. Clinical data show that the device is effective in
preventing pregnancy over a two-year period in women and the safety
data show a low incidence of adverse clinical events. However,
study results also show that there are several cases where the
physician had difficulty correctly placing the device. In addition,
the device was noted to be fractured on a follow-up x-ray in a few
study patients. Given the uncertainty of the long-term impact of
the device, the possibility of device fracture (which was not
predicted in any of the bench and animal testing), and the safety
and effectiveness of alternative therapies, the device was deemed
to be non-approvable for the intended patient population. - An implanted device offers a unique design feature in
comparison to the standard of care used to treat similar
conditions. While the current standard of care works very
well, it has limitations associated with hindering the mobility of
the patient; whereas, the novel implanted device does not affect
patient mobility. Based upon the effectiveness data from the
clinical study, the device demonstrates that it has significantly
improved functional outcomes in comparison to the current standard
of care. However, from a safety perspective, the device did
present different adverse events than the current standard of
care. It is believed that the risks can be
appropriately mitigated with training of surgical professionals and
labeling. In the event the implant was to fail over
time, the clinician could also resort to the current
standard of care. In this situation, despite the higher risk
of harmful events, the potential benefits outweighed the risks and
the device was approved.
Appendix A
Worksheet for Benefit-Risk Determinations
Factor | Questions to Consider | Notes |
---|---|---|
Measures for Effectiveness of Devices (the extent of the benefit) |
||
Type of benefit(s) |
|
|
Magnitude of the benefit(s) |
|
|
Probability of the patient experiencing a |
|
|
Duration of effect(s) |
|
|
Metrics for Safety of Devices (the extent of harmful events) |
||
Severity and types of harmful events (events and |
||
|
|
|
|
|
|
|
|
|
Probability of a harmful event |
|
|
Duration of harmful events |
|
|
Risk of false-positive or false-negative for |
||
Additional Factors for Weighing
Benefits and Risks of Devices |
||
Uncertainty: |
||
|
|
|
|
||
|
||
|
||
Patient tolerance for risk |
|
|
|
||
|
||
Availability of alternative treatments or |
|
|
Risk mitigation |
|
|
Novelty of technology |
|
Summary of the Benefit(s) | Summary of the Risk(s) | Summary of Other Factors |
Conclusions
Do the probable benefits outweigh the probable risks? |
||
1 In
addition to §513(a), the criteria for establishing safety and
effectiveness of a device are set forth in 21 CFR 860.7. Subsection
(b)(1) notes, “In determining the safety and effectiveness of
a device … the Commissioner and the classification panels
will consider the following, among other relevant
factors…The probable benefit to health from the use of the
device weighed against any probable injury or illness from such
use.” (21 CFR 860.7(b)).
To make this determination, “the agency relies upon only
valid scientific evidence.” (21 CFR 860.7(c)(1)). Valid
scientific evidence is defined as “evidence from
well-controlled investigations, partially controlled studies,
studies and objective trials without matched controls,
well-documented case histories conducted by qualified experts, and
reports of significant human experience with a marketed device,
from which it can fairly and responsibly be concluded by qualified
experts that there is reasonable assurance of the safety and
effectiveness of a device under its conditions of use.” (21
CFR 860.7(c)(2)).
A reasonable assurance of safety occurs when “it can be
determined, based upon valid scientific evidence, that the probable
benefits … outweigh any probable risks.” The evidence
of which is demonstrated by establishing, “the absence of
unreasonable risk of illness or injury associated with the use of
the device for its intended uses and conditions of use.” (21
CFR 860.7(d)(1).
Similarly, a reasonable assurance of effectiveness occurs when
“it can be determined, based upon valid scientific evidence
… the use of the device for its intended uses … will
provide clinically significant results.” (21 CFR
860.7(e)(1)). The evidence of which is demonstrated principally
through “well-controlled investigations” (see 21 CFR
860.7(e)(2)) as defined in 21 CFR 860.7(f)
2 Under
§513(a)(2)(C) of the FD&C Act, FDA may weigh “any
probable benefit to health from the use of the device against any
probable risk of injury or illness from such use” not only in
determining there is a reasonable assurance of safety and
effectiveness for a device evaluated under a PMA, but also in
determining substantial equivalence under §513(i).
For purposes of this guidance the term “studies” is
equivalent to the term “investigations.”
3 21 CFR
860.7(e) “There is reasonable assurance that a device is
effective when it can be determined, based upon valid scientific
evidence, that in a significant portion of the target population,
the use of the device for its intended uses and conditions of use,
when accompanied by adequate directions for use and warnings
against unsafe use, will provide clinically significant
results”, as demonstrated by well-controlled
investigations.
4 21 CFR
860.7(d) “There is reasonable assurance that a device is safe
when it can be determined, based upon valid scientific evidence,
that the probable benefits to health from use of the device for its
intended uses and conditions of use, when accompanied by adequate
directions and warnings against unsafe use, outweigh any probable
risks. The valid scientific evidence used to determine the safety
of a device shall adequately demonstrate the absence of
unreasonable risk of illness or injury associated with the use of
the device for its intended uses and conditions of use.”
SOURCE