Best Practices for Interventional Cardiovascular

Transcription

GLOBAL MEDICAL DEVICE CRO
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Best Practices for Interventional
Cardiovascular Medical Device Trials
This paper addresses the four clinical trial aspects Novella Clinical considers most
critical for medical device developers seeking to enter the US market with implantable
cardiovascular devices. These factors are regulatory requirements, reimbursement
strategy, clinical challenges and vendor selection.
A Novella Clinical White Paper
Moving Potential. Forward.
Medical
Global Device
MedicalDevelopment
Device CRO
Interventional Cardiovascular Medical Device Trials
Best Practices for Interventional Cardiovascular
Medical Device Trials
Heart disease is the leading cause of death worldwidei, and the global cardiac medical
devices market could expand to reach $65.6 billionii by 2015, due to aging populations and
the prevalence of heart disease, stroke and diabetes. Significant advances in technologybased treatments continue, and bringing interventional cardiac devices to market is big
business – and one that is complex. Sponsors seeking to bring implantable cardiovascular
products to market, whether they are stents, valves, pacemakers, ventricular assist
devices or other novel technologies, face several
significant factors in designing and conducting
clinical trials. Working with an experienced
medical device clinical research organization
(CRO) such as Novella Clinical can ensure sponsors
consider and confidently address these factors with
expertise and efficiency. This paper addresses the
four clinical trial aspects Novella Clinical considers
most critical for medical device developers seeking
to enter the US market with implantable cardiovascular devices. These factors are regulatory
requirements, reimbursement strategy, clinical
challenges and vendor selection.
Sponsors seeking to bring
implantable cardiovascular
products to market, whether
they are stents, valves,
pacemakers, ventricular
assist devices or other novel
technologies, face several
significant factors in
designing and conducting
clinical trials.
2
©2014 Novella Clinical
Medical Device Development
The Heart of the Matter: Leading Global Health Issue
Heart disease and stroke are the two leading causes of death globallyiii and rank first and
fourth in the United States, respectively.iv Moreover, the total number of inpatient cardiovascular
disease (CVD) operations and procedures in the US tallied almost 7.6 million in 2010, an increase of 28 percent since 2000.v Even with noted declines in the prevalence of cardiovascular
(CV) risk factors, such as uncontrolled high blood pressure, elevated “bad” cholesterol, and
smoking, as well as improvements in treatments and quality of care, other influencers of CVD
rates such as diabetes are on the rise. The American Heart Association (AHA) notes that at
least 65 percent of people with diabetes die from heart disease or stroke.vi
While CVD drugs remain the mainstay of the global CV treatment market, one conservative
forecast predicts the global cardiac medical devices market will grow to $65.6 billion by 2015.
Regionally, North America accounts for 40 percent of the worldwide CV devices market and
Europe, nearly 30 percent.vii
Setting the Pace: Regulatory Requirements for Cardiovascular Devices*
The existing US dominance of the CV device landscape drives many sponsors to have a strong
FDA-focus in their development strategy. However, the size and duration of CV trials, the
review cycles involved with the FDA, and pressures to bring a CV device to market quickly or
in geographically diverse areas have many sponsors
considering trial sites outside the US, which presents
regulatory and study execution complexities. Some
sponsors may consider the EU as the first step of their
trial strategy, especially because of the potential speed
to market. Indeed, a 2011 analysis found that complex medical devices received EU approvals nearly
Some sponsors may consider
the EU as the first step of their
trial strategy, especially because
of the potential speed to market
four years before US approvals.viii Historically,
the EU system has required less data than the FDA
for approval, particularly for new products deemed substantially equivalent to approved
devices. However, the European Society of Cardiology (ESC) has called for more stringent,
data-based regulatory decision making in the EU. Recently proposed EU regulations would
increase the safety and efficacy scrutiny of high-risk devices. If the regulations are adopted, and
more are in the works, the EU approval process may decelerate to resemble the US system.
Notably, the FDA’s review time of Premarket Approval (PMA) applications for medical devices
increased by 75 percent from 2007 to 2011, driven by intense pressure to focus on trial-documented
risks and safety in comparison to benefits.ix
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*For this paper, references to devices address single-use interventional devices and
implantable cardiovascular devices.
While the EU regulatory timeline and requirements will likely change, Novella Clinical still frequently advises sponsors seeking global markets to consider beginning their clinical testing with a
safety and efficacy pilot trial in the EU, which affords an opportunity to identify issues that must
be addressed before a new clinical study protocol is submitted to the FDA. Sometimes, these data
also can support an investigational device exemption (IDE) submission to the FDA. Novella
Clinical often counsels sponsors seeking medical device approval supported by exclusively
foreign data and can assist such sponsors as they prepare to meet with the FDA officials in a
presubmission meeting.
For sponsors who already have an FDA-approved
protocol but wish to use it to expand clinical trials
to other countries, Novella Clinical has found the
national competent authorities and site-based ethics
committees in India, the Czech Republic and Poland
generally accept FDA-approved protocols without
... beginning clinical testing with a safety
and efficacy pilot trial in the EU affords
an opportunity to identify issues that must
be addressed before a new clinical study
protocol is submitted to the FDA.
changes. In contrast, the United Kingdom frequently
requests significant changes, which can create issues
for sponsors seeking to pool study data, particularly if the changes affect patient populations, diagnostic tests or follow-up routines. For example, during its approval of a recent study for a novel
device designed to treat mitral valve regurgitation, the UK Medicines and Healthcare Products
Regulatory Agency asked for a significant limitation of the age range for patients as an inclusion
criteria, as well as for additional imaging procedures, which have the potential to increase adverse
events from radiation exposure and contrast agents and can complicate data analyses when
pooled. Some sponsors seeking to market their devices in the UK have found it worthwhile to
conduct a separate trial series to satisfy its regulatory requirements, even if the data cannot
directly support a separate FDA or EU submission.
Novella Clinical counsels sponsors undertaking any cross-border trials to carefully account for the
standards of care that will vary from country to country because these differences will impact data
acceptance in both the FDA’s and subsequent regulatory reviews. These differences can include
everything from routine medical care, to screening tests to diagnose a particular condition, to
concomitant medications, to treatment paradigms, to protection of participants as outlined in the
Declaration of Helsinki, to data validation. In the US, the FDA may approve a PMA based solely
on foreign clinical data if these data apply to “the US population and medical practice,”
the clinical investigators have “recognized competence” and the FDA considers the data valid
without the need for an on-site inspection or such an inspection or “appropriate means” can
validate the data.x Sponsors need to capture this information using a detailed rationale that
addresses why any variations from US standards will not affect the evaluation of a device’s safety
and efficacy.
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The US IDE process has three main categories of devices based on risk: significant risk (SR),
nonsignificant risk and exempt. For US clinical studies, sponsors must receive an IDE approval
from the FDA before beginning a study for a SR device. Studies for permanent implantable CV
devices usually are considered SR because these devices present a potential for serious risk to
the health, safety or welfare of a study participant and may support or sustain human life. The
SR determination is the responsibility of the study sponsor, but the FDA is willing to help sponsors,
investigators and institutional review boards (IRB) make such classification decisions.
Institutional Review Board Consideration of Significant Risk Devices*
Like pharmaceutical clinical trials,
pacemaker might be viewed by an IRB:
human studies of devices require the
Would, for example, new leads, battery
approval of IRB. A CRO, based on
pack or software pose a SR because
first-hand experience with each trial
the device is used to support or sustain
site’s IRB, can counsel a sponsor on the
human life and it presents a potential
proper documentation and presenta-
for serious harm to the patients? The
tion of data an IRB will review for its
SR designation applies, the FDA says,
decision making. One aspect of device
even though the changed pacemaker
trials an IRB must consider is risk,
may potentially pose less risk, or only
particularly for SR devices. The FDA
slightly greater risk, in comparison to
asks IRBs to consider if a SR device
the commercially available model.
may cause harm or requires additional
procedures that might cause potential
harm. In some situations, the IRB must
weigh the potential benefits and risks
of an investigational device against
those of an existing, approved drug
or device. The FDA cites how a trial to
examine the safety and efficacy of a
The sponsor may send the device to the
IRB to aid in its review, but the study
cannot begin until the FDA approves
the IDE application. Of note, trial sponsors must obtain agreement from the
investigators to comply with the applicable regulations governing SR studies.
modification to an already approved
* FDA, “Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors;
Significant Risk and Nonsignificant Risk Medical Device Studies,” January 2006. Accessed at
www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf on Feb. 7, 2013
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The FDA and EU Regulatory Paths for Class III Devices
The FDA requires Class III device sponsors to submit a PMA application that demonstrates
“sufficient valid scientific evidence that provides reasonable assurance that the device
is safe and effective for its intended use or uses.”xix That evidence comes from nonclinical laboratory studies (e.g., design
verification testing such as bench,
simulated-use, animal, or biocompatibility studies) and controlled
clinical trials.
Human studies for these devices
have their own set of regulatory
requirements, including the FDA’s
US
FDA
EU
Agencies
Class III
HIGH RISK
granting of an IDE so the investigational device may be used in a
clinical trial. An IDE is required if
the device is novel, is a significant
modification of an earlier model
or if the application is for a new intended use of an already approved
and legally marketed device.
Sponsors
must
demonstrate
Safety
and
EFFECTIVENESS
+
PREMARKET
APPROVAL
(PMA)
Sponsors
must
demonstrate
Safety
and
PERFORMANCE
Both the FDA and
the EU classify most
permanent implantable CV devices in
their highest risk
category (Class III)
but the requirements
for approval differ
between the agencies.
In contrast, EU member states use
Notified Bodies to evaluate devices
and render European Conformity
(CE) certification decisions, in addition to National Competent Authorities that oversee
the Notified Bodies, approve clinical protocols and direct post-marketing surveillance.
Because there is no central authorizing organization, a sponsor must choose one
Notified Body, which then conducts a device evaluation that will be used for the entire EU.
As of February 2014, the European Commission had authorized 73 Notified Bodies in 24
countries to issue CE decisions for medical devices. The same Notified Body will then
review future changes to the device.
Of note, in May 2011, the ESC called for the EU to create a unified regulatory system,
prompted by removal from the EU market of implantable CV devices proven unsafe or
ineffective in trials subsequently required by the FDA.xx The ESC asked for an EU system
with stronger clinical data requirements and more accountability for Notified Bodies.
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Novella Clinical recommends sponsors become familiar with the regulations and requirements of each regulatory jurisdiction in which they plan to commercialize their
device. One of the first documents written for the Design Control process should be a
detailed regulatory assessment for each agency that must be specific to the device type
and its intended use. The FDA requirements generally are the most stringent globally,
so following the Agency’s assessment project plan should work well for most other
jurisdictions. For the US, these assessments should include, at minimum:
• Rationale for product classification
• Rationale for risk significance
• Summary pathway to clearance
• Applicable consensus standards
• Applicable guidance documents
• Comparison to predicate devices (if any)
• Design verification (bench) testing requirements
• Animal (or cadaver) study requirements
• Clinical study requirements
• Post-market requirements
• Submission type / content / format requirements / ancillary document list
Readying for Reimbursement: Value Data Considerations for Cardiovascular Devices
Escalating health care costs have prompted public and private payers as well as hospital
purchasing departments to increasingly scrutinize device costs. As a result, sponsors should
include the collection of health economic data and its assessment in clinical trial designs.
Moreover, CVD trial protocol planning must include
how to measure value, no longer exclusively the purview
of drug development. Value is more than the cost of
manufacturing and implanting a device. Value also
includes measures such as quality adjusted life-years,
which helps characterize how a device affects or improves the quality and length of a patient’s life beyond
simple measures of functions of daily living and longevity. In addition, sponsors should consider including
“soft” health economic measures such as OR/procedure
Escalating health care costs have
prompted public and private payers as
well as hospital purchasing departments
to increasingly scrutinize device costs.
As a result, sponsors should include the
collection of health economic data and its
assessment in clinical trial designs.
time, blood loss, time in hospital, and time to return
to work which all affect the cost of the product beyond
that of the purchase price. Such health economic data are useful for pricing strategies and are
necessary for reimbursement decisions by both the Centers for Medicare & Medicaid Services
(CMS), private payers as well as hospital purchasing departments. McKinsey & Company
foresees that without such evidence, products that feature smaller changes and innovations
compared to predicate products, for example a new coating on an implant, will be less likely to
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receive incremental pricing and reimbursement.xi Some private payers have already gone as far
as to decline reimbursing procedures involving devices lacking available safety, efficacy as well
as health economic data, even if such data were not required for market release of that device,
like those approved via the FDA’s 510(k) process.
In many instances Novella Clinical counsels that trial protocols should capture cost-effectiveness
data. Such data helps address the question as to whether the device provides economic benefits
compared to already available therapies or the standard of care. All sponsors submitting a PMA
aim to answer the question of efficacy and safety of the
therapy, but sponsors to date have not fared as well on
such comparative value questions. In the past, the question of health economics has been left to post-market
studies, but with the current economic climate, the better
strategy may be to include measures of health economic
data in earlier phase trials.
Device sponsors are also beginning to face comparative
efficacy scrutiny, which has largely focused on drug
development as a means to help inform health care decisions by understanding the relative clinical effectiveness
and appropriateness of different treatments for the same
condition based on patient’s health, the quality of care,
Comparative effectiveness data
may include evidence of savings,
offsets or outcome value. In
considering comparators,
Novella Clinical recommends
selecting treatments that reflect
current standards of care to
meet CMS needs, even if the
FDA guidance permits sham
treatment or historic data.
health outcomes and costs as well as other factors.
Indeed, a review of high-risk CV devices approved by the FDA from 2000 to 2011 revealed
the majority lacked data comparing efficacy at the time of their premarket approval.xii In this
analysis, the authors defined comparative efficacy as use of active controls in evaluating primary
end points, such as a (preferably randomized, concurrent) control group that received a validated
intervention that was not the investigational device. For example, the trial might compare a
drug-eluting stent with a bare metal stent; carotid endarterectomy to carotid stenting; or
catheter ablation to flecainide for recurrent paroxysmal atrial fibrillation (AF).
The Results?
• Of 353 primary end points, only 40% were evaluated against an active control.
• The use of active controls varied by device category:xiii
–
–
–
–
0% bridge-to-transplant LVAD
14% for intracardiac devices
39% for cardiac stents
82% for hemostasis devices
The authors noted that use of active controls may not always be possible, such as when testing
ventricular-assist devices, and suggest that in such cases the use of a comparator group may
provide the information needed for both clinical and regulatory decisions.
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Going forward, the rates for data comparing effectiveness for devices will increase, in part
because of the US government’s investment in such research but also as a part of the national
healthcare agenda. In the US, the Institute of Medicine developed a list of the top 100 comparative effectiveness priorities, which include devices. AF therapies are in the list’s top quartile,
catheter-based treatment of vascular claudication is in the second quartile, while coronary
stenting and innovative congestive heart failure therapies are in third quartile.xiv
Comparative effectiveness data may include evidence of savings, offsets (higher device cost but subsequent disease-related costs are reduced) or outcome value. In considering comparators, Novella
Clinical suggests sponsors select treatments that reflect current standards of care to meet CMS
needs, even if the FDA guidance permits sham treatment or historic data. However, if validated
historic data will allow a comparison, this standard might not need to be an active control arm in the
trial. Sponsors might also need to define additional endpoints such as functional status or quality of
life for CMS evaluation, rather than just clinical data like heart function or blood pressure.
Also, given the purview of CMS, sponsors should ensure that participants include older individuals
in substantial numbers so that findings are readily extrapolated to a Medicare population.
Taking the Vitals: Clinical Trials of Cardiovascular Devices
The careful consideration and selection of principal investigators, sites and patients as well as
treatment protocols, data and endpoints are vital to the success of CV device trials.
Principal Investigators and Sites
Because many subspecialists are involved in the treatment of patients with CVD, sponsors
may find themselves in competition for particular physicians to participate as principle investigators. In addition, when recruiting investigators for a particular trial one must consider
that individual interventional cardiologists, for example, may be experts in angioplasty and
stenting or in mitral valve repair, but not both. When considering investigators, a sponsor
cannot assume that board certification and expertise with one type of device will translate
to a different technology. Operator performance also plays a role in selection. An experienced
CRO will know which forms of expertise can make an investigator ideal to test a new technology,
with appropriate training, guidance and oversight, or if the learning curve is not appropriate for a
particular study. Unlike drug trials, device sponsors must plan for lengthy and individualized
training to ensure that each investigator can efficiently, safely and accurately use or implant
the device and that this training leads to consistent implementation of the procedure across
all investigative sites. Frequently, the sponsor, assisted by the CRO, provides such training and
is present for each investigator’s first participant procedure.
Many sponsors come to a CRO with a desired list of investigators and sites based on their previous
device trials or scientific advisory board’s advice. However, while Novella Clinical recognizes the
importance of including established key opinion leaders for a company, an experienced CRO can
also provide additional context regarding candidates’ availability and suitability and can identify
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new experts or sites. In addition to working with sites that enjoy top-tier reputations, Novella
Clinical has also had great success with sites that have less extensive clinical research portfolios.
We have found that quality of care is seldom an issue and including such sites may enhance the
speed of patient recruitment because of often shorter start-up timelines and less trial competition.
One aspect of site selection is determining the facility locale in which the trial procedure will
be done. Some hospitals have a cardiac catheterization suite while others may need to book a
general operating room. Such infrastructure variations can affect access, i.e., booking time for
trial procedures versus ongoing patient care, and can determine the presence of dedicated
clinical teams and ancillary personnel with the appropriate CV experience.
Treatments
CV device trials usually involve patients age 65 and older who are likely to have a higher BMI
and other health issues, particularly diabetes. For such patients, a CV device is seldom their
only medical treatment, and data collection must carefully account for all interventions, whether
investigational or not. For example, a patient may be taking antiplatelet medications or a statin
and, because of the frequency of diabetes in the CVD population, perhaps a sulfonylurea, a SGLT2
inhibitor or insulin. The thorough documentation of such concomitant medication is essential for
determining if changes in endpoint measures or occurrences of adverse events stem from
patients’ illness, treatment, or the investigational device.
Another aspect of trial design is the stratification of
patients into treatment groups and the goal of the
treatment. For example in AF, current guidelines
suggest that “rate control may be reasonable initial
therapy in older patients with persistent AF who have
hypertension or heart disease, while for younger in-
... a CV device is seldom their
only medical treatment, and
data collection must carefully
account for all interventions,
whether investigational or not.
dividuals, especially those with paroxysmal lone AF,
rhythm control may be a better initial approach.”xv
The guidelines suggest use of medications, then catheter-based endocardial ablation for
patients in whom drugs failed to control the AF. However, in a trial setting, both treatments
may need to be considered before use of the investigational device, which may be considered
the “last option” for a patient. Such treatment algorithms create complexity in data collection.
In addition to examining a device against a standard of care, some trials designs also may involve
sham treatments or no interventions, as it is not common for device trials to be double-blinded.
A review of PMAs for CV devices approved between 2000 and 2007 found that only 14 percent
were blinded.xvi In a drug trial, double- or single-blind studies may use placebos as controls, but
in device trials the use of sham devices often is transparent to clinical teams or patients or both.
To compensate for this trial design necessity, the evaluation of study data by a single, blinded core
laboratory often is essential. For example, investigators will use a baseline angiography to gather
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data documenting how a mitral valve is insufficient in controlling blood flow within the heart, but
the core lab will define the degree of insufficiency and determine if the patient can enroll in the
study based on the entry criteria. After the intervention, with the investigational valve or sham
device, the same core lab will assess and define the degree of residual mitral regurgitation.
Of note, in many device feasibility studies, patients serve as their own controls, such as in the
evaluation of the degree of mitral regurgitation before and after the implantation of the investigational device. In many pivotal device studies, the design calls for randomization of such
patients in comparison to those receiving the standard of care to define the device’s long-term
safety and efficacy, usually a minimum of five years.
Data and Endpoints
Planning for such complex data collection and analyses in CV trials requires a careful definitions process during the protocol design, not just efficient “facts and figures” capturing and
database input when the study is underway. Definitions vary, so sponsors, working with the
CRO team, should agree on the markers, measures and methods that will precisely define the
trial endpoints and assure those assessments are uniformly available at each trial site. Some
endpoint definitions are straightforward, such as how to measure blood pressure, while others
are characterized by how they are measured or used. A best practice is to consider how other
medical professionals and researchers define and use such information, whether for clinical
practice or research settings. Some endpoint resources also include well-regarded databases,
which may also provide historic data useful for baseline comparisons.
For example, a heart attack, which may be a study entry
criteria or an endpoint, can be defined by electrocardiographic
(ECG) findings, elevated values of biochemical markers,
imaging or pathology. The World Health Organization (WHO)
has used symptoms, ECG patterns and enzyme elevation
to define heart attacks, but as science and technology have
advanced, clinicians may now measure tissue-specific cardiac
biomarkers or employ advanced imaging techniques that
... use historic or predicate
device data in premarket
approval to carefully review
composite endpoint definitions so the comparisons
are accurate.
enable detection of very small myocardial injuries or tissue
death. Another complication of heart attack definition is that
improvements in the management of patients have reduced tissue injuries and necrosis, despite
similar presentation in a clinical setting. Moreover, health care professionals can now add to
their definitions the cause of a heart attack, such as spontaneous or procedure-related.
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What constitutes a heart attack as trial entry criteria was defined by a global taskforce comprised
of ESC, the American College of Cardiology (ACC) Foundation, AHA and World Heart Federation
experts in 2012, and the WHO subsequently adopted this universal definition. However, the taskforce noted that as a trial outcome, heart attack definitions still differed, “hampering comparison
and generalization between these trials. ... No matter what, investigators should ensure that a trial
provides comprehensive data for the various types of MI and includes the 99th percentile [upper
reference limit] decision limits of [cardiac troponin] or other biomarkers employed.”xvii
Many cardiac device trials use composite endpoints that combine events. For example, a recent
study evaluating patients who underwent percutaneous coronary intervention with a drug-eluting
stent versus those who received a coronary artery bypass graft used the number of cardiac-related
deaths, heart attacks and cerebrovascular events at five years after the intervention as a composite endpoint. The study also had an additional endpoint that included these three events as
well as target lesion revascularization (TLR) and target vessel revascularization (TVR).xviii
However, Novella Clinical counsels sponsors that use historic or predicate data in their PMA
to carefully review composite endpoint definitions so that the comparisons are accurate.
Collecting clinical data and adverse events is frequently not the only aspect of trial data management. In studies where a TLR or TVR is an endpoint, imaging data also must be collected to allow
determination of why the blockage reoccurred. For example, did a drug-eluting stent incompletely
destroy the plaque or move it during the attempt to open a blocked artery? Many CV data assessments require imaging to show the baseline patient status, accurate device placement per the
protocol parameters as well as intermediate and long-term effects of the intervention. Unlike a
drug trial in which medication is consumed, CV device trials frequently require the investigators
to use their own judgment of a visual assessment of the intervention, with the image subject to
subsequent data review. Some of these imaging procedures, such as angiograms or IVUS (intravascular ultrasound), have risks, ranging from the contrast agents to radiation exposure to clot
formation or dislodgement. Consequently, adverse events can potentially occur each time a visualization procedure is performed, so the trial design should limit imaging as much as possible.
For the evaluation of images and other endpoint data, Novella Clinical advises sponsors to
control for possible variations via the use of centralized processes. For example, images can
be evaluated in a core lab, which provides quality control to the trial by efficiently using the
same expert team to provide consistent criteria to their evaluations as well as including QC
checks on the image quality and acquisition process used at each site.
Similarly, we suggest using a single-charter, multi-country (if a global trial) data safety
monitoring board (DSMB) to review trial outcomes as well as a clinical events committee
(CEC) to evaluate safety events, which may be part of the endpoint evaluation. Such independent peer-to-peer committees typically are blinded during their assessments regardless
of whether the trial is blinded. The use of electronic data capture and centralized databases
enable such committees to operate virtually which increases efficiency both operationally
and from a cost perspective when compared to face-to-face meetings.
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As noted by the FDA, CECs can be established in certain trials to determine whether the
endpoints reported by trial investigators meet protocol-specified criteria. CECs are particularly
valuable when endpoints are subjective or require the application of a complex definition or
when the intervention is not blinded. For example, the CEC can determine if a heart attack
recorded by a site was indeed a heart attack as defined in the study protocol, or another separate
event that might have been missed by the team, as well as if underlying factors played a role
apart from the device. Although CECs do not share responsibility with DSMBs for evaluating
interim data analyses, their assessments, when performed at frequent intervals and incorporated into the database in a timely manner, help ensure that DSMB data reviews are as accurate
and free of bias as possible. Novella Clinical has a dedicated team to help sponsors form DSMBs
and CECs for their trials to ensure independence and appropriate expertise level.
Patients
Many CV device sponsors seek to enroll patients that have long-standing heart conditions,
whether congenital or acquired, such as arterial stenosis, mitral valve regurgitation, arrhythmia,
or heart failure. While standard clinical practice may result in device treatment of patients
with acute emergency conditions, such as a heart attack, such settings present time-senstitive
levels of complexity for clinical trials to patient identification, informed consent, enrollment
and treatment decisions. Emergency room patients may be medicated for pain, unconscious,
or, as in the case of many stroke patients, unable
to speak or communicate clearly. Because of this,
patients treated and admitted via an emergency
room can be enrolled but the IRB-approved
informed consent must clearly indicate how
proxies are used for such patients, who likely
will have comorbidities.
Regardless of the care setting, specificity of a
protocol population will affect data values. For
example, in defining a stent intervention patient
population, a difference between selecting 50
While standard clinical practice may
result in device treatment of patients
with acute emergency conditions,
such as a heart attack, such settings
present time-senstitive levels of
complexity for clinical trials to patient
identification, informed consent,
enrollment and treatment decisions.
versus 75 percent stenosis can be a factor in determining the stent efficacy without a significant
difference in safety values. A CRO’s team of physicians and biostatisticians can helps sponsors
model different trial populations to evaluate the potential efficacy and safety of the device.
Although enrolling chronic disease patients may not present significant identification issues,
their retention in long-term trials is a challenge for sponsors. While most European Competent
Authorities will permit the use of just one year of follow-up safety data for approval decisions,
the FDA and UK will want at least five-year data. Consequently, it is prudent for sponsors to
consider that they may need to enroll large numbers to yield the patients needed for their
long-term assessments.
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Such long trial times, even with many intermediate follow-ups, have additional issues. For
example, many patients may stop taking their prescribed medication once they start to feel
better, while others may consider the costs of such medication too great for the benefits they
perceive. In drug-eluting stent trials, the standard of care involves taking anti-platelet therapy
for six to 12 months, but if a patient stops the medication, the data analyses must account for
whether subsequent events are due to patient compliance with medication(s), investigational
device failure, or both. Trial follow-up also is hindered by patients that develop new illnesses
and care issues, move or no longer have the independence to participate in the clinical trial,
all of which are required to be documented as discontinuations for regulatory submissions.
To help address such issues, sponsors should consider if technology might be an aid,
particularly for longitudinal studies, ranging from phone monitoring to emails to online data
collection to the use of new technologies. The development of remote cardiac telemetry first
enabled intermittent home-based monitoring, but now pacemakers and implantable cardioverter-defibrillators also are used as continuous monitoring devices to capture sporadic
episodes of AF. However, for acute care phases of a trial, face-to-face visits are still the primary
means of evaluation. Moreover, the type of intervention may dictate what follow up is acceptable
to regulatory agencies. For example, the FDA does not consider phone monitoring valid as a
way to evaluate efficacy for some treatments, such as ablation therapy for arrhythmia.
Picking Partners: Vendors Who Know
Cardiovascular Devices
For successful CV device trials, sponsors need
to have strategic partners with knowledge of the
therapeutic area. A CRO with first-hand regulatory and trial knowledge can ensure that sponsors
select experienced, certified vendors for the trial
conduct, data analyses and marketing approval
A CRO with first-hand regulatory and
trial knowledge can ensure that sponsors
select experienced, certified vendors for
the trial conduct, data analyses and
marketing approval submissions.
submissions. For example, sponsors should expect
CROs to make recommendations not just for
sites and investigators but also for core laboratories, DSMBs and CECs. The CRO’s own team
should also have established skills in the appropriate therapeutic settings, such as cardiac
catheterization laboratories. Such practice-based knowledge helps clinical research associates
(CRA) understand many aspects of the procedure, ranging from how a catheter works to
typical time constraints in treating a patient within a window of a cardiac event. Applying such
experience can subsequently help a CRA address protocol deviations and non-compliance
at the time of the intervention. Novella Clinical has found that for trial sites outside the US,
cardiac-experienced CRAs may be expected to play a broader role, including helping investigators with ethics committee reviews.
14
WHO Top 10 Causes of Death, accessed at http://www.who.int/mediacentre/factsheets/fs310/en/index.html
Feb. 6, 2014.
ii
Research and Markets. Global Cardiac Medical Devices - An Analytical Report, 2009-2015. April 2013. Accessed
at http://www.researchandmarkets.com/research/2kcqmn/global_cardiac Jan. 30, 2014.
iii
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Feb. 6, 2014.
iv
CDC FASTSTATS, accessed at http://www.cdc.gov/nchs/fastats/deaths.htm Feb. 6, 2014.
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Circulation. 2014;129:e28-e292; originally published online December 18, 2013. Accessed at
http://circ.ahajournals.org/content/129/3/e28.full.pdf+htm lon Feb. 22, 2014.
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AHA, “Cardiovascular Disease and Diabetes,” Jan. 31, 2013. Accessed at http://www.heart.org/HEARTORG/
Conditions/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp Feb. 8, 2014.
vii
Research and Markets. Global Cardiac Medical Devices - An Analytical Report, 2009-2015. April 2013. Accessed
at http://www.researchandmarkets.com/research/2kcqmn/global_cardiac Jan. 30, 2014.
viii
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Industry,” February 2011. Accessed at http://www.bcg.com/documents/file72060.pdf Feb. 11 2014.
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Boston Consulting Group, “Competitiveness and Regulation: The FDA and the Future of America’s Biomedical
Industry,” February 2011. Accessed at http://www.bcg.com/documents/file72060.pdf Feb. 11 2014.
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The FDA, “Medical Devices, PMA Clinical Studies, Research conducted outside the United States,” Posted March 1,
2013. Accessed at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
PremarketSubmissions/PremarketApprovalPMA/ucm050419.htm March 4, 2014.
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the Time of Premarket Approval,” JAMA. 2012;308(17):1740-1742 Accessed at http://jama.jamanetwork.com/
article.aspx?articleid=1389607#ref-jld120026-3 Feb. 11, 2014.
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Chen, C.E., et. al. “Inclusion of Comparative Effectiveness Data in High-Risk Cardiovascular Device Studies at
the Time of Premarket Approval,” JAMA. 2012;308(17):1740-1742 Accessed at http://jama.jamanetwork.com/
article.aspx?articleid=1389607#ref-jld120026-3 Feb. 11, 2014.
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www.iom.edu/Reports/2009/ComparativeEffectivenessResearchPriorities.aspx Feb. 11, 2014.
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“2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management
of Patients With Atrial Fibrillation,” 2011. Accessed at http://www.utmb.edu/internalmedicine/pdf/cardiology/
Atrial_fibrillation_updated_guidelines.pdf Feb. 8, 2014.
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Dhruva, S. et. al., “Strength of Study Evidence Examined by the The FDA in Premarket Approval of Cardiovascular Devices,” JAMA. 2009;302(24):2679-2685/ Accessed at http://jama.jamanetwork.com/article.
aspx?doi=10.1001/jama.2009.1899 Feb. 10, 2014.
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Science%20and%20Quality/Guidelines/Clinical_Documents/UniversalDefMI.ashx,” Feb. 8, 2014 , page 14.
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Milan Experience. “JACC June 2010. Vol 3. Issue 6. Accessed at http://interventions.onlinejacc.org/article.
aspx?articleid=1111698 Feb. 8, 2014.
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i
15
A Novella Clinical White Paper
About Novella Clinical
Novella Clinical, a Quintiles company, is a full-service clinical research organization specializing
in medical device and diagnostic clinical trials. Our medical device division is comprised of
clinical trial specialists across all functional areas. With particular expertise in cardiovascular
device trials, Novella Clinical has specific cardiovascular teams and processes that include
board-certified cardiologists and a network of cardiovascular experienced CRAs. Our cardiovascular portfolio focuses specifically on interventional medical devices, and our experience
includes ablation devices (endovascular and epicardial), cardiac leads, embolic protection
devices, implantable cardioverter defibrillators, stents, stent grafts, pacemakers, valves and
ventricular assist devices as well as the evaluation of new diagnostics, such as imaging
technologies and screening tests.
Novella Clinical has preferred-vendor status with top medical device companies due to our
outstanding operational execution, quality management program including ISO 9001:2008
certification, and superior client satisfaction ratings.
Headquartered in Research Triangle Park, NC, and Stevenage, UK, Novella Clinical provides
the experience and insight to bring devices and diagnostics to market on time and on budget.
For more information, visit novellaclinical.com/mdd or contact us at 866-303-4966.
You see beyond the clinical trial. Your goal is to
ultimately give people a better quality of life and
more time to enjoy those special little moments.
Novella Clinical is proud to be a part of your mission.
Moving Potential. Forward.
Novella Clinical’s Global Headquarters: 1700 Perimeter Park Drive, Morrisville, NC 27560 | Phone: 919-484-1921
European Operations: Richmond House, Walkern Road, Stevenage, Hertfordshire SG1 3QP | Phone: +44 (0)1438 221122

Best Practices for Interventional Cardiovascular

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