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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 [email protected] 202.661.7888. Agenda.

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Pamela furman forrest esq partner king spalding llp pforrest@kslaw com 202 661 7888

Basic Principles of FDA Medical Device Regulation and How FDA Might Have Handled the Recent PIP CrisisBritish Institute of International and Comparative LawJune 10, 2013

Pamela Furman Forrest, Esq.Partner, King & Spalding [email protected]


Agenda
Agenda FDA Might Have Handled the Recent PIP Crisis

  • Overview of FDA Medical Device Regulation

  • FDA Premarket Regulatory Scheme

  • How the Recent PIP Crisis Might Have Been Handled in the U.S.


Overview of fda medical device regulation
Overview of FDA Medical Device Regulation FDA Might Have Handled the Recent PIP Crisis


Definition of device
Definition of “Device” FDA Might Have Handled the Recent PIP Crisis

  • In general, a medical “device” is an instrument, apparatus, implement, machine, contrivance, implant, invitro reagent, or other similar or related article, including any component, part, or accessory:

    • 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

  • The definition of “device” is interpreted broadly by FDA


General principles
General Principles FDA Might Have Handled the Recent PIP Crisis

  • FDA imposes premarket and postmarket requirements on medical devices

  • 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


Risk based classification scheme
Risk-Based Classification Scheme FDA Might Have Handled the Recent PIP Crisis

  • Class I -- “Low risk”

    • Examples: orthopedic blade, tongue depressor

    • Typically exempt from premarket review requirements

    • Subject to postmarket “general controls.” See 21 U.S.C. § 360c(a)(1)(A)

  • Class II – “Moderate Risk”

    • Examples: powered wheelchair, endoscope

    • 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”

    • Examples: breast implants, coronary stents

    • Typically subject to premarket approval (PMA) and postmarket “general controls.” (See 21 U.S.C. § 360c(a)(1)(C))

    • Potentially subject to additional conditions of approval


Premarket controls
Premarket Controls FDA Might Have Handled the Recent PIP Crisis


Two main premarket pathways
Two Main Premarket Pathways FDA Might Have Handled the Recent PIP Crisis

  • Premarket notification (510(k))

  • Premarket approval (PMA)


Postmarket controls
Postmarket Controls FDA Might Have Handled the Recent PIP Crisis


Registration and listing
Registration and Listing FDA Might Have Handled the Recent PIP Crisis

  • 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


Quality system regulation
Quality System Regulation FDA Might Have Handled the Recent PIP Crisis

  • 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


Medical device reporting
Medical Device Reporting FDA Might Have Handled the Recent PIP Crisis

  • 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


Reports of corrections and removals
Reports of Corrections and Removals FDA Might Have Handled the Recent PIP Crisis

  • 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)


Labeling
Labeling FDA Might Have Handled the Recent PIP Crisis

  • “Labeling”: All written, printed, or graphic matter (21 U.S.C. § 321(m))

    • Upon an article or container OR

    • Accompanying such article

  • By statute, labeling cannot be “false or misleading”

  • All labeling claims must be:

    • 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


Consequences of noncompliance
Consequences of Noncompliance FDA Might Have Handled the Recent PIP Crisis

  • 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))


How fda learns of noncompliances
How FDA Learns of Noncompliances FDA Might Have Handled the Recent PIP Crisis

  • Inspections

  • Trade Complaints

  • “Surfing” the web


Consequences of noncompliance1
Consequences of Noncompliance FDA Might Have Handled the Recent PIP Crisis

  • FDA’s main statutory enforcement tools:

    • 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


Fda premarket regulatory scheme
FDA PREMARKET REGULATORY SCHEME FDA Might Have Handled the Recent PIP Crisis


510 k pathway
510(k) Pathway FDA Might Have Handled the Recent PIP Crisis


Overview
Overview FDA Might Have Handled the Recent PIP Crisis

  • 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

  • Substantial Equivalence means the device to be marketed has:

    • The same intended use as all of its predicates and

    • 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)


When 510 k clearance is required
When 510(k) Clearance is Required FDA Might Have Handled the Recent PIP Crisis

  • Introduction of a device subject to the 510(k) requirement (i.e., a Class I or Class II reserved device)

  • A change/modification to an already marketed device that could significantly affect its safety or effectiveness

  • A major change or modification to the device’s intended use


Traditional 510 k submissions
Traditional 510(k) Submissions FDA Might Have Handled the Recent PIP Crisis

  • User fee

    • 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)

    • Device description

    • Substantial equivalence discussion

      • Comparison table

      • Narrative comparison


Key elements of a traditional 510 k cont d
Key Elements of a Traditional 510(k) (cont.’d) FDA Might Have Handled the Recent PIP Crisis

  • Proposed labeling

  • Sterilization and shelf life information

  • Biocompatibility information

  • Electrical safety information

  • Bench testing summaries

  • Animal testing summaries

  • Clinical testing summaries


Alternatives to traditional 510 k s
Alternatives to Traditional 510(k)s FDA Might Have Handled the Recent PIP Crisis

  • Special 510(k)

    • 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)

    • 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


Fda s decisions on a 510 k notice
FDA’s Decisions on a 510(k) Notice FDA Might Have Handled the Recent PIP Crisis

  • FDA actions on a 510(k) notice

    • 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”)


510 k review period
510(k) Review Period FDA Might Have Handled the Recent PIP Crisis

  • 90 days for traditional and abbreviated 510(k) notices

  • 30 days for a special 510(k) notice

  • FDA can extend that period by requesting additional information

    • 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


Premarket approval
PREMARKET APPROVAL FDA Might Have Handled the Recent PIP Crisis


Overview1
Overview FDA Might Have Handled the Recent PIP Crisis

  • Not a comparative submission

  • The device must be safe and effective for its intended use

  • A PMA generally requires more information (especially clinical data) and longer review time than a 510(k)


Original pma submission
Original PMA Submission FDA Might Have Handled the Recent PIP Crisis

  • User Fee

    • $248,000 for FY 2013

    • $62,000 for small businesses (<$100 million in gross sales or revenue)

    • Fee waived for first PMA for a company with gross receipts or sales less than $30 million

  • Key elements of an original PMA submission

    • Device description

    • Detailed description of manufacturing processes


Original pma submission cont d
Original PMA Submission (cont’d) FDA Might Have Handled the Recent PIP Crisis

  • Key elements of an original PMA submission (cont.’d)

    • Nonclinical studies summaries

    • Clinical studies summaries

    • Clinical investigator financial certification or disclosure

    • Proposed device labeling


Pma review process
PMA Review Process FDA Might Have Handled the Recent PIP Crisis

  • Acceptance and filing review

    • Review to determine whether the PMA is administratively complete

    • Must be conducted within 45 days of receipt of the PMA

  • Substantive review

    • 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


Pma review process1
PMA Review Process FDA Might Have Handled the Recent PIP Crisis

  • Advisory Committee (Panel) review

    • 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


Pma review process2
PMA Review Process FDA Might Have Handled the Recent PIP Crisis

  • Pre-approval Bioresearch Monitoring (BiMo) inspection

    • Inspection of clinical trial sites and the study sponsor to assure accuracy of clinical data

  • Pre-approval manufacturing inspection

    • Inspection of manufacturing facilities to assure compliance with FDA requirements


Fda s decision
FDA’s Decision FDA Might Have Handled the Recent PIP Crisis

  • Approval Order

    • 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

    • FDA believes the device can be approved if specific minor additional information, e.g., labeling changes, are provided

  • Not approvable letter

    • Generally, additional information is needed to demonstrate the safety and effectiveness of the device

  • Order denying approval


Changes to a pma device
Changes to a PMA Device FDA Might Have Handled the Recent PIP Crisis

  • 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:

    • 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


Why the 510 k route is generally preferred
Why the 510(k) Route is Generally Preferred FDA Might Have Handled the Recent PIP Crisis

  • 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

    • Shorter submissions

    • Shorter FDA review periods (90 days v. 180 days)

    • FDA Advisory Panel review generally not required


How fda might have handled the recent pip crisis
How FDA Might Have Handled the Recent PIP Crisis FDA Might Have Handled the Recent PIP Crisis


Bottom line
Bottom Line FDA Might Have Handled the Recent PIP Crisis

  • 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


Fda warning letter and import detention
FDA Warning Letter and Import Detention FDA Might Have Handled the Recent PIP Crisis

  • 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:

    • 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


Fda advisory panel recommendation against approval of pip pma
FDA Advisory Panel Recommendation Against Approval of PIP PMA

  • PIP silicone breast implants were never sold in the U.S.

  • PIP saline breast implants were sold in the U.S. from 1996-2000

    • 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


Premarket controls that might have kept pip silicone implants off the market
Premarket Controls That Might Have Kept PIP Silicone Implants Off the Market

  • 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


Postmarket enforcement tools that might have been used against pip
Postmarket Enforcement Tools That Might Have Been Used Against PIP

  • FDA inspection – routine and/or for cause

    • Often leads to 483, Untitled Letter, Warning Letter, and/or import detention (for foreign manufacturers)

  • Seizure

  • Injunction

  • Civil Penalties

  • Initiation of criminal proceedings


Postmarket tools cont d
Postmarket Tools (cont’d) Against PIP

  • Cease Distribution and Notification (CD&N) Order

    • 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”

  • Mandatory Recall

    • FDA can amend a CD&N order to require a recall

  • Repair, Replacement, or Refund Order

    • Among other things, device must “present an unreasonable risk of substantial harm to public health”



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