overview of premarket approval (pma) program
DESCRIPTION
What is PMA? Premarket Approval (PMA) A regulatory pathway to market Class III (highest-risk) medical devices Application requires FDA scientific, regulatory review & quality system review. Approval requires reasonable assurance of safety and effectiveness based on intended use Typically requires clinical data Requires payment of User FeeTRANSCRIPT
Overview of Premarket Approval (PMA) Program
Roy Baby, Investigator US Food & Drug Administration 4040 N
Central Expressway, Dallas, TX What is PMA? Premarket Approval
(PMA)
A regulatory pathway to market Class III
(highest-risk)medicaldevices Application requires FDA scientific,
regulatory review& qualitysystem review. Approval requires
reasonable assurance of safety and effectivenessbased on intended
use Typically requires clinical data Requires payment of User Fee
FY16 User Fees (in US Dollars)
Application Type Standard Small Business PMA 261,388 65,347 180 Day
Supplement 39,208 9,802 Real Time Supplement 18,297 4,574 PMA
Annual Report 9,149 2,287 Legal Framework: Law &
Regulations
Section 515, Food, Drug and Cosmetic Act (FD&C Act) Part 814,
Title 21Code of Federal Regulations (CFR) Section 501(f), FD&C
Act Class III device that fails to meet PMA requirements considered
adulterated! Class III: Highest Tier of Scientific Review
In comparison to the 510(k) / premarket notification regulatory
process, PMA devices are stand-alone applications and not based on
substantial equivalence to a predicate device. Typically, a
multidisciplinary Review Team conducts the evaluation. Regulatory
review times generally follow longer timelines. Reference: MDUFA
III Performance Goals Summary of Safety and Effectiveness Data
(SSED) explains the basis of the approval decision. Examples of
devices requiring PMA approval prior to marketing
Intraocular Lens Deep Brain Stimulator for OCD Cervical Disc
Replacement Gastric Band Implantable Cardioverter Defibrillator
(ICD) Glucose Monitoring System FDA Review: Safety and
Effectiveness
Valid scientific evidence Well-controlled clinical investigations
or other objective information Not opinions, random reports or
un-interpretable data Considerations Risks and benefits for
indicated patient population Conditions of device use Device
safety, performance and reliability Safety as defined in 21 CFR
860.7(d)1
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. Safety as
defined in 21 CFR 860.7(d)1 Effectiveness as defined in 21 CFR
860.7(e)1
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. Effectiveness as defined in
21 CFR 860.7(e)1 Clinical Studies Clinical studies on human
subjects that are conducted within the United States and U.S.
territories must comply with medical devicesGood Clinical Practices
regulations. These regulations include: Investigation Device
Exemption (IDE), 21 CFR 812, Protection of Human Subjects, 21 CFR
50, and Institutional Review Boards, 21 CFR 56 Clinical
Investigators Financial Disclosure, 21 CFR 54 Design Controls
(QSR), 21 CFR 820 subpart C Regulations apply to the manufacturers,
sponsors, clinical investigators, institutional review boards, and
the medical device Acceptance of Foreign Clinical Studies
If conducting an IDE study outside the US in support of a PMA, then
it will be beneficial to have foreign sites follow the samestudy
protocol. If the study in the foreign site is not under an IDE, the
study must be in accordance with the Declaration of Helsinki and
the laws/regulations of that country whichever offered greater
human subjects protection. Potential challenges: Different patient
demographics Differences in practice of medicine/standard of care
Lack of robust clinical protocol/patient follow-up Guidance for
Industry - Acceptance of Foreign Clinical Studies Pre-Submission
Sponsors who seek approval based solely on foreign data are
encouraged to meet early with FDA officials pre-IDE meeting prior
to submission of the IDE application pre-PMA meeting prior to
submission of the PMA application Provides the opportunity for the
sponsor to obtain FDA feedback prior to intended submission of an
investigational device exemption or marketing application Draft
Guidance for Industry and FDA Staff Medical Devices: The
Pre-Submission Program and Meetings with FDA Staff PMA Review
Process: Filing a PMA
Within 45 days receipt of PMA, FDA will notify the applicant
whether theapplication has been filed. Meets minimum threshold of
acceptability, i.e., application is sufficientlycomplete to begin
in-depth review. Information required by the FD&C Act, PMA
regulations, 21 CFR 814,and Refuse to File Policy Checklist for
Filing Decision for PMAs.Guidance for Industry and FDA Staff:
Premarket Approval ApplicationFiling Review430.htm PMA Review
Process: In-depthScientific, Regulatory, Quality System
Review
Multidisciplinary and team-based review Communicates deficiencies
to sponsor eitherinteractively or in major deficiency letter (puts
PMAon hold) Internal meetings Filing meeting Team meetings PMA
Guidance Documents e.g. Filing Review Statistical Checklist Others
Interactive Review with Sponsor PMA Review Process (Very Simplified
Block Diagram)
Application Not File File Pre-PMA Submission Meeting FDA &
Sponsor Filing Meeting No Yes Interactive Substantive Review
Major/Minor Deficiency Day-100 Meeting Major Deficiency Letter
Advisory Panel Review recommendations may be needed to address new
safety and effectiveness questions Labeling Review with
Manufacturer FDA/CDRH Decision Letter Approval Package: Approval
Order, SSED, Final Draft Labeling PMA Review Determinations
Approval: Device can be marketed Letter of Approval (may include
conditions of approval such as annual reports, restricted users,
etc.) Approvable: Specific deficiencies Manufacturing deficiencies
Labeling changes Agreement on conditions of approval Not
Approvable: Identify steps needed to make PMA approvable, such as
new data Resets review clock Post Approval Study (PAS)
FDA has authority to require sponsor to perform PAS at the timeof
PMA approval to help ensure continued safety and effectiveness (or
continuedprobable benefit, in the case of an HDE) of the approved
PMAdevice. The CDRH Post-Approval Studies Program encompasses
design, tracking, oversight, and review responsibilities for
studiesmandated as a condition of approval. Changes Requiring a PMA
Supplement
Changes affecting safety and effectiveness of the PMA-approved
device.Examples of changes, but not limited to the following: New
indication for use Labeling changes Use of different facility or
establishment to manufacture, process, sterilize of package the
device Changes in sterilization procedures, packaging Changes in
performance or design specifications, circuits, components,
principles of operation 180-day Supplements Examples
Addition of a new diameter or lengthsizes to a vascular stent
Change in software for an excimerlaser system A new mechanism of
action for avascular stent delivery system Down-sized or
less-featured modelbased on the identical platform of afamily of
pulse generators. Typical supplements for significant changes to:
Design Materials Labeling Specifications Software May go to
advisory panel Real-Time Supplements
Real-time Review (does not need to be face to face) Minor device
change Change must be expected for the device type Supported by
well-characterized non-clinical data Review involves a single
scientific discipline Requires agreement between FDA and sponsor
that real-time review is appropriate Sponsor submits request prior
to submitting supplement Usually within 30 days Questions and
concerns about device changes FDA provides feedback Official
response letter to be sent later Guidance for Industry and FDA
Staff: Real-Time Premarket Approval Application (PMA) Supplements
New manufacturing specification Extension of shelf-life New
packaging configuration Panel-Track Supplements
Significant changes to: Indications for use Device design or
performance Substantial clinical data to provide a reasonable
assurance of safety and effectiveness. Examples Expansion of
indications for ventricular assist device (VAD) from
bridge-to-transport to destination therapy Change in indications
for vascular stent from use in coronary arteries to use in renal
arteries New graft material for an aortic aneurysm endovascular
graft 30-Day Notice & 135 PMA Supplement
Modifications tomanufacturing process 135-Day Supplement required
if the 30-Day Notice is inadequate Guidance for Industry and FDA
Staff - 30-Day Notices, 135-Day Premarket Approval (PMA)
Supplements and 75-Day Humanitarian Device Exemption (HDE)
Supplements for Manufacturing Method or Process Changes Automating
a previously manual process New manufacturing equipment New
sterilization process Special PMA Supplement
Special PMA Supplement -- Changes Being Effected Changes that
enhance the safety of device Can be implemented prior to FDA
approval 30-day review New quality assurance step New warnings to
labeling Expedited Reviews Device intended to treat or diagnose a
life-threatening or irreversibly debilitating disease or condition,
and No approved alternative treatment or means of diagnosis May
offer significant advances over alternatives Breakthrough
technology Availability is in best interest of patients Expedited
application receives priority review Not always a faster review
time Guidance for Industry and FDA Staff: Expedited Review of
Premarket Submissions for Devices PMA Supplement vs.
Amendment
PMA supplement (e.g., P130001/S001; P130001/S002) required for a
change affecting the safety or effectiveness of the device for
which the applicant has an approved PMA A PMA amendment(e.g.,
P130001/A1, A2, etc. or P130001/S001/A1, etc.) all additional
submissions to a PMA or PMA supplement before approval of the PMA
or PMA supplement OR all additional correspondence after PMA or PMA
supplement approval Note: Additional information provided to FDA
for PMA supplement under review are amendments to a supplement. HUD
and HDE An HUD (Humanitarian Use Device) is a device that is
intended to benefit patients by treating or diagnosing a disease or
condition that affects or is manifested in fewer than 4,000
individuals annually in the United States. An HDE (Humanitarian
Device Exemption) is a marketing application submitted to FDA in
order to obtain approval of an HUD. similar in both form and
content to (PMA) application, but is exempt from the effectiveness
requirements of a PMA. Label as Humanitarian Use Device (HUD) -
Effectiveness for the specific indication has not been demonstrated
HDE Requirements An incentive for development of devices intended
for treatment or diagnosis, in small populations where otherwise a
device manufacturers R&D costs could exceed market returns Must
contain sufficient information for FDA to determine that the device
does not pose an unreasonable or significant risk of illness or
injury, i.e., safety and probable benefit outweighs the risk Must
demonstrate no comparable devices are available to treat or
diagnose the disease or condition, via 510(k) or PMA Only used in
facilities with established IRB Summary The PMA program is a
regulatory pathway to market Class III devices, the most stringent
requirements for medical devices. FDA review generally begins with
administrative and limited review, followed by in-depth scientific,
regulatory and Quality System review, if determined suitable for
filing. PMA data must demonstrate reasonable assurance of Safety
and Effectiveness, typically with clinical data. Applicant must
receive the FDA PMA approval letter prior to introduction of the
device into the U.S. interstate commerce. Selected References
Premarket Approval Application Filing Review
Refuse to File Policy Checklist for Filing Decision for PMAs
Guidance on PMA Interactive Procedures for Day 100-Meetings and
Subsequent Deficiencies Discuss review status of PMA Panel Review
of Premarket Approval Applications #P91-2 (blue book memo) Guidance
for Panel Review Industry Education Resources Three Resources
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Device Advice Text-Based Education comprehensive regulatory
information on premarket and postmarket topics Division of Industry
and Consumer Education (DICE) Contact DICE if you have a question
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