IRB PRESENTATION
REGULATORY PATHWAYS
HDE – PMA
William Hellenbrand MD
Director – Pediatric Cardiology
Columbia University College of Physicians & Surgeons
Morgan Stanley Children’s Hospital of New York-Presbyterian
DISCLOSURE
• Medtronic
– Investigator
– Consultant
– Proctor
REGULATORY PATHWAYS
• Paucity of high level evidence for therapy in
congenital heart disease(CHD)
– Reviewed 3317 articles over 3 year period(20042007) related to therapy for CHD
– Surgery (49%), Catheter Interventions (23%),
medications (9%)…
– Case reports & series (52%), non randomized controlled series (45%), RCT (3%)
– Over a 10 year period there were 213 RCTs in
pediatric cardiology, 3263 in neonatology & 5394
in adult ischemic heart disease
Senthilnathan, Selvi ; Postgraduate course in Pediatric Cardiovascular Disease; F
REGULATORY PATHWAYS
 Randomization:
 Reduces the likelihood of patient selection bias
 Enhances likelihood that comparable groups of
subjects are actually compared
 Supports use of common statistical tests
Randomization is the gold standard for evaluating new
Device and Drug therapies
Zuckerman TCT 2005
ADVANTAGES OF MULTICENTER TRIALS
• No single center has the resources to
answer a question
• Collaboration will speed the resolution
of the research question
• Collaboration will resolve the question
more authoritatively
REGULATORY PATHWAYS
• Barriers to randomized multi-center
trials
– Congenital cardiovascular diseases are
rare and diverse disorders
– Randomization is difficult
– Proper endpoints are difficult
– Lack of clinical equipoise
– Lack of equal maturity of the techniques
being compared
RANDOMIZATION IS DIFFICULT
• Many medical devices are already approved
and available
• Off label use is not regulated as the IRB does
not require informed consent if we promise
not to collect data or learn anything about
the procedure
• We have to have informed consent if we
randomize and perform the procedure in only
half the patients instead of all of them
RANDOMIZATION IS DIFFICULT
• Due to all of these issues and patient
knowledge from physicians and
especially the internet; patient entry
into these clinical trials may preclude
adequate patient numbers
ENDPOINTS ARE DIFFICULT
• They must be important
– The FDA traditionally interested in
mortality(do you live longer) or feel better
(symptoms)
• They must be achievable
– Outcomes must be measurable in a
reasonable time frame or have surrogate
markers that accurately predict outcome
ENDPOINTS ARE DIFFICULT
• Patients are not likely to die (30% of the
population and 2% of the deaths)
• Symptoms are difficult to quantify
• Patients are a moving target as they
grow and develop
HDE VS PMA
• How does the FDA view these two
different regulatory pathways and the
need for multi-center randomized trials
in a population of diverse disorders
and a small number of patients
HDE
• The regulation provides for the FDA submission of a humanitarian
device exemption (HDE) application, which is similar in both form
and content to a premarket approval (PMA) application. However,
unlike a PMA application, an HDE application is not required to
contain the results of scientifically valid clinical investigations
demonstrating that the device is effective for its intended purpose.
The HDE application must, however, contain sufficient information
for the FDA to determine that the device does not pose an
unreasonable or significant risk of illness or injury, and that the
probable benefit to health outweighs the risk of injury or illness from
its use; taking into account the probable risks and benefits of
currently available devices or alternative forms of treatment.
Additionally, the HDE applicant must demonstrate that no
comparable devices are available to treat or diagnose the disease or
condition, and that the device could not otherwise be brought to
market unless it is granted HUD status.
OFF LABEL USE OF AN
APPROVED DEVICE
• Off-Label Use of a Humanitarian Use
Device in Emergency or Compassionate
Situations: It is recognized that there may
be circumstances in which “off-label” use
of a HUD may be necessary to save the
life or protect the well-being of a given
patient. Under either of these situations,
the involved physician and manufacturer
of the device should, on a case-by-case:
MELODY® - TPV
INDICATIONS & INTENDED PERFORMANCE
Indications
• RVOT conduit regurgitation
• RVOT conduit stenosis
Intended Performance
• Restore pulmonary valve
competence
• Relieve conduit stenosis without
inducing regurgitation
Prolong
conduit life
MELODY® - TPV
• RVOT conduits used to palliate complex congenital
heart defects
• RVOT conduit dysfunction is common
 Functional lifespan of RVOT conduits limited due
to progressive regurgitation & stenosis
• Current options for management
– Medical management
– Surgical pulmonary valve replacement
– Transcatheter management
MELODY® - TPV
MELODY® - TPV
OFF LABEL USE
• Why is there a difference in off label
use of a PMA vs an HDE approved
device
• With a PMA approved device it is not
regulated by the FDA or the IRB and left
to clinical judgment