Basic Principles of FDA Medical Device
Regulation and How FDA Might Have
Handled the Recent PIP Crisis
British Institute of International and Comparative Law
June 10, 2013
Pamela Furman Forrest, Esq.
Partner, King & Spalding LLP
pforrest@kslaw.com
202.661.7888
Agenda
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Overview of FDA Medical Device Regulation
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FDA Premarket Regulatory Scheme
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How the Recent PIP Crisis Might Have Been Handled in the
U.S.
•2
Overview of FDA Medical Device
Regulation
•3
Definition of “Device”
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In general, a medical “device” is an instrument, apparatus,
implement, machine, contrivance, implant, in vitro reagent, or
other similar or related article, including any component, part, or
accessory:
―
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Intended for use in the diagnosis of disease or other conditions, or in the
cure, mitigation, treatment, or prevention of disease, in man or other
animals, or
Intended to affect the structure or function of the body of man or other
animals. See 21 U.S.C. § 321(h).
•
Product claims largely determine “device” status
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The definition of “device” is interpreted broadly by FDA
•4
General Principles
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FDA imposes premarket and postmarket requirements on medical
devices
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The extent of regulation depends upon the device’s perceived risk
•
In order to be lawfully marketed, a device must comply with
applicable premarket and postmarket requirements
•5
Risk-Based Classification Scheme
•
•
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Class I -- “Low risk”
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Examples: orthopedic blade, tongue depressor
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Typically exempt from premarket review requirements
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Subject to postmarket “general controls.” See 21 U.S.C. § 360c(a)(1)(A)
Class II – “Moderate Risk”
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Examples: powered wheelchair, endoscope
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Typically subject to premarket notification (510(k)), postmarket “general controls,” and potentially
“special controls.” See 21 U.S.C. § 360c(a)(1)(B)
Class III – “High Risk”
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Examples: breast implants, coronary stents
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Typically subject to premarket approval (PMA) and postmarket “general controls.” (See 21 U.S.C. §
360c(a)(1)(C))
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Potentially subject to additional conditions of approval
•6
Premarket Controls
•7
Two Main Premarket Pathways
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Premarket notification (510(k))
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Premarket approval (PMA)
•8
Postmarket Controls
•9
Registration and Listing
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Establishments “engaged in the manufacture, preparation,
propagation, compounding, assembly, or processing of a device”
intended for commercial distribution in the U.S. are required to
register with FDA
―
•
Registration puts firms on FDA’s “radar screen” for inspection
In general, these same establishments must file with FDA a list
of the devices they have placed in commercial distribution
―
Listing provides FDA with information about the types of devices being
manufactured
•10
Quality System Regulation
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The Quality System Regulation (QSR) forms the basis for
assuring that only products that meet company specifications
are released for distribution
•
The FDA uses compliance with the QSR to determine if a
company is in control of its manufacturing process
•
QSR requirements govern the methods used in, and the
facilities and controls used for, the design, manufacture,
packaging, labeling, storage, installation, and servicing of all
finished devices
•11
Medical Device Reporting
•
Medical Device Reports (“MDRs”) are intended to alert FDA to
devices that may have caused or contributed to death or serious
injury or that may eventually cause or contribute to a death or
serious injury due to a malfunction
•
MDR requirements apply to manufacturers, importers, and device
user facilities
•12
Reports of Corrections and Removals
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FDA has the authority to require manufacturers to recall devices, but
rarely uses it. See 21 C.F.R. Part 810. Rather, most recalls
(corrections and removals) are conducted voluntarily
•
Voluntary corrections to and removals of devices must be reported
to FDA when the action is taken to reduce a risk to health or to
remedy a violation of the Federal Food, Drug, and Cosmetic Act
caused by the device that may present a risk to health. (See 21
C.F.R. Part 806)
•13
Labeling
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“Labeling”: All written, printed, or graphic matter (21 U.S.C.
§ 321(m))
―
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Upon an article or container OR
Accompanying such article
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By statute, labeling cannot be “false or misleading”
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All labeling claims must be:
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Consistent with the product’s FDA-cleared or approved intended use
(i.e., “on-label”)
Provide fair balance (i.e., provide information about risk with equal
emphasis as information about benefits)
Have valid scientific support
•14
Consequences of Noncompliance
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Failure to comply with applicable FDA requirements typically
renders a device adulterated or misbranded. (21 U.S.C. §§ 351 &
352)
•
Marketing an adulterated or misbranded device is a “prohibited
act,” and can trigger FDA enforcement action. (21 U.S.C. §
331(a))
•15
How FDA Learns of Noncompliances
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Inspections
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Trade Complaints
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“Surfing” the web
•16
Consequences of Noncompliance
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FDA’s main statutory enforcement tools:
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Seizure (21 U.S.C. § 334)
Injunction (21 U.S.C. § 332)
Criminal prosecution (21 U.S.C. § 333; 18 U.S.C. § 3571)
Civil Penalties (21 U.S.C. § 333(g))
Issuance of a Warning Letter typically is the first step
•17
FDA PREMARKET REGULATORY
SCHEME
•18
510(k) Pathway
•19
Overview
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A 510(k) is a premarket submission made to FDA to demonstrate
that the device to be marketed is “substantially equivalent” to
another legally marketed device
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Substantial Equivalence means the device to be marketed has:
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The same intended use as all of its predicates and
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Similar technological characteristics as its predicate(s) or
Its technological differences
― Do not raise any new questions of safety or effectiveness; and
― Performance data demonstrate that the device is as safe and effective
as its predicate device(s)
―
•20
When 510(k) Clearance is Required
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Introduction of a device subject to the 510(k) requirement
(i.e., a Class I or Class II reserved device)
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A change/modification to an already marketed device that
could significantly affect its safety or effectiveness
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A major change or modification to the device’s intended use
•21
Traditional 510(k) Submissions
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User fee
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Standard fee is $4,960 for FY 2013
Small business (< $100 million) for FY 2013 is $2,480
Key elements of a traditional 510(k)
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Device description
Substantial equivalence discussion
― Comparison table
― Narrative comparison
•22
Key Elements of a Traditional 510(k)
(cont.’d)
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•
•
•
•
•
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Proposed labeling
Sterilization and shelf life information
Biocompatibility information
Electrical safety information
Bench testing summaries
Animal testing summaries
Clinical testing summaries
•23
Alternatives to Traditional 510(k)s
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Special 510(k)
―
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No changes to the device’s intended use/indications or fundamental
scientific technology
Change being made to the company’s own device
Does not include data
Abbreviated 510(k)
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Where FDA has issued an applicable device-specific guidance document;
recognized an applicable consensus standard; or identified another special
control
Must include a declaration of conformance to an FDA-recognized
consensus standard; and/or a summary report regarding how the guidance
document or other special control was used to address the risk
Does not include data
•24
FDA’s Decisions on a 510(k) Notice
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FDA actions on a 510(k) notice
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Finds the device to be substantially equivalent (“SE”), i.e., clears the
device, if it is at least as safe and effective as the predicate(s);
Requests additional information
Withdraws the 510(k) if the submitter does not respond to an FDA request
within the allotted time; or
Finds the device to be not substantially equivalent (“NSE”)
•25
510(k) Review Period
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90 days for traditional and abbreviated 510(k) notices
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30 days for a special 510(k) notice
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FDA can extend that period by requesting additional information
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When the sponsor of the 510(k) responds to FDA’s request for additional
information, the 90-day (traditional / abbreviated) or 30-day (special) review
period re-starts
•26
PREMARKET APPROVAL
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Overview
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Not a comparative submission
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The device must be safe and effective for its intended
use
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A PMA generally requires more information (especially
clinical data) and longer review time than a 510(k)
•28
Original PMA Submission
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User Fee
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$248,000 for FY 2013
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$62,000 for small businesses (<$100 million in gross sales or revenue)
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Fee waived for first PMA for a company with gross receipts or sales less
than $30 million
Key elements of an original PMA submission
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Device description
Detailed description of manufacturing processes
•29
Original PMA Submission (cont’d)
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Key elements of an original PMA submission (cont.’d)
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Nonclinical studies summaries
Clinical studies summaries
Clinical investigator financial certification or disclosure
Proposed device labeling
•30
PMA Review Process
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Acceptance and filing review
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Review to determine whether the PMA is administratively complete
Must be conducted within 45 days of receipt of the PMA
Substantive review
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Review of performance, animal, clinical, and manufacturing information
Typically conducted by a scientific team of reviewers
180 day review time
FDA may request additional information
•31
PMA Review Process
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Advisory Committee (Panel) review
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FDA may refer a PMA for review by a panel of experts for various reasons
― Occurs during the review period, typically after FDA has completed its
substantive review
Panel review is conducted via a public meeting
Panel submits a final report to FDA that includes the Committee's
recommendation and the basis for such recommendation on the PMA
― Panel recommendation is not binding on the Agency, but FDA typically
follows the panel recommendation
•32
PMA Review Process
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Pre-approval Bioresearch Monitoring (BiMo) inspection
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Inspection of clinical trial sites and the study sponsor to assure accuracy of
clinical data
Pre-approval manufacturing inspection
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Inspection of manufacturing facilities to assure compliance with FDA
requirements
•33
FDA’s Decision
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Approval Order
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Decision that the device is safe and effective and the device may be
legally marketed in the U.S. subject to the conditions in the approval order
Approvable Letter
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FDA believes the device can be approved if specific minor additional
information, e.g., labeling changes, are provided
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Not approvable letter
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Generally, additional information is needed to demonstrate the safety and
effectiveness of the device
Order denying approval
•34
Changes to a PMA Device
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Regulations (21 C.F.R. § 814.39) require that manufacturers submit
and receive approval for a PMA supplement before making a change
affecting the safety or effectiveness of the device:
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New intended use;
Labeling changes;
Different manufacturing facility;
Changes in sterilization procedures;
Changes in packaging;
Changes in performance or design specifications, circuits, components,
ingredients, principle of operation, or physical design; and/or
Extension of expiration date based on a new protocol/procedure.
In general, all changes made to a PMA approved device must, in
some way, be reported to FDA
•35
Why the 510(k) Route is Generally
Preferred
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Approximately 10% of 510(k) notices include clinical data; almost
all PMAs include clinical data
Generally, the 510(k) path is a quicker route to market than the PMA
path even if the 510(k) contains clinical data
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Shorter submissions
Shorter FDA review periods (90 days v. 180 days)
FDA Advisory Panel review generally not required
•36
How FDA Might Have Handled the
Recent PIP Crisis
•37
Bottom Line
•
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The manufacturer reportedly began manufacturing breast
implants with a non-medical grade silicone gel
This sort of deliberate, impermissible act is difficult for
even the most stringent regulatory system to prevent
•38
FDA Warning Letter and Import
Detention
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In June 2000, FDA issued a Warning Letter to PIP regarding its
manufacturing process for saline breast implants, which cited
multiple Quality System violations including:
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Failure to maintain procedures for verifying and validating device design
Failure to maintain procedures for implementing corrective and preventive
actions
Failure to maintain procedures for changes to a specification, method, process,
or procedure
Failure to submit MDR reports
Failure to establish procedures for identifying training needs
FDA placed an import detention on PIP saline implants pending
correction of the violations cited in the Warning Letter
•39
FDA Advisory Panel Recommendation
Against Approval of PIP PMA
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PIP silicone breast implants were never sold in the U.S.
PIP saline breast implants were sold in the U.S. from 1996-2000
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In 2000, an FDA Advisory Panel voted unanimously to recommend that PIP’s
PMA for saline breast implants not be approved
The Advisory Panel felt that PIP’s preclinical and clinical data were
inadequate
•40
Premarket Controls That Might Have Kept
PIP Silicone Implants Off the Market
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FDA concerns regarding PIP’s proposed clinical trials might have
led to disapproval of PIP’s Investigational Device Exemption (IDE)
application
Bioresearch Monitoring (BiMo) inspection might have raised
concerns about PIP’s clinical study-related practices
PIP might have failed to satisfactorily respond to FDA’s deficiency
letters during the PMA review process
FDA might have found violative practices during its pre-approval
QSR inspection of PIP
•41
Postmarket Enforcement Tools That Might
Have Been Used Against PIP
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FDA inspection – routine and/or for cause
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Often leads to 483, Untitled Letter, Warning Letter, and/or import detention
(for foreign manufacturers)
Seizure
Injunction
Civil Penalties
Initiation of criminal proceedings
•42
Postmarket Tools (cont’d)
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Cease Distribution and Notification (CD&N) Order
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Mandatory Recall
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Requires a firm to immediately cease distribution of a device, notify health
professionals and device user facilities of the Order, and instruct them to cease
use of the device
There must be a “reasonable probability that a device . . . would cause serious,
adverse health consequences or death”
FDA can amend a CD&N order to require a recall
Repair, Replacement, or Refund Order
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Among other things, device must “present an unreasonable risk of substantial
harm to public health”
•43
Thank you! Questions?
•44