FDA

20
Jan
2024
21 CFR Part 860: Medical Device Classification

21 CFR Part 860: Medical Device Classification

Three Classes of Regulatory Control

The FDA classifies devices into one of three classes based on their risk and regulatory oversight.

Class Risk Level Controls Examples
I Low General Bandages, tongue depressors, dental floss
II Moderate Special + General, premarket notification and clearance Pregnancy tests, blood glucose meters, infusion pumps
III High General, premarket approval Implants, pacemakers, artificial heart valves, companion diagnostics
  • general controls include registration, listing, labeling, good manufacturing practices, and adverse event reporting.
  • special controls include performance standards, postmarket surveillance, patient registries, special labeling, or guidance documents.

Classification Panel

A classification panel is an advisory committee of experts that makes recommendations to the FDA on the classification and reclassification of devices. The FDA has 16 classification panels, each covering a major medical specialty or device type such as Anesthesiology, Cardiovascular, and Pathology.

To simplify regulations for special controls, devices are grouped into generic types of devices, which have similar features and require similar regulatory controls to ensure their safety and effectiveness. Classification panels help the FDA develop a classification regulation for each type of device (see 21 CFR parts 862 through 892). A panel may also recommend whether a class I or II device should be exempt from some or all general or special controls.

Factors that Determine Classification

The FDA classifies a device based on the following factors:

  • Intended users: The persons who will use the device
  • Indications and conditions of use: How, when, and where the device will be used, including labeling and advertising
  • Technological characteristics: The design, material, and performance of the device
  • Benefit-risk profile: The potential benefits and harms of using the device
  • Regulatory necessity: The level of regulation needed to ensure safety and effectiveness
  • Regulatory alternatives: The existing options for regulating the device
  • Reliability: The consistency and accuracy of the device
  • Novelty: The degree of innovation and uniqueness of the device
  • Availability of alternatives: The presence or absence of other devices that serve the same or similar purposes
  • Public health need: The importance and urgency of addressing the medical problem that the device aims to solve
  • Health care system impact: The effect of the device on the cost, quality, and accessibility of health care

Evidence for Classification

For devices that require premarket approval or clearance, the FDA requires valid scientific evidence of safety and effectiveness to classify the device. This includes:

  • Well-controlled investigations: Studies that follow rigorous scientific principles and use appropriate control groups and methods
    • Objectives and methods: The study plan and report should clearly state the goals, the selection and assignment of subjects, the observation and measurement methods, and the comparison and analysis of results.
    • Control groups: The study should use a suitable control group that minimizes bias and allows quantitative evaluation. The study should explain the type and methods of the control group and the degree and methods of blinding, if any.
    • Test device standardization: The study should use a test device that is consistent in its composition, design, and performance to ensure the reliability of the results.
  • Partially controlled studies: Studies that use some but not all elements of well-controlled investigations
  • Uncontrolled studies: Studies and trials that do not use control groups but have other means of ensuring validity and reliability
  • Qualified case histories: Well-documented reports of clinical experience by experts
  • Significant human experience: Reports of widespread and consistent use of a marketed device
  • Nonclinical methods: Laboratory tests, animal studies, or analytical studies for in vitro diagnostic devices, when required, to assess the safety of the device

Note that isolated case reports, random experience, reports lacking details, and unsubstantiated opinions are NOT valid scientific evidence.

How the FDA Evaluates Evidence

The FDA evaluates the quality, quantity, relevance, and applicability of the evidence to the device and its intended use. The evidence must:

  • Demonstrate safety: Show that the device does not pose unreasonable risk of illness or injury for its intended uses and conditions of use, based on valid scientific evidence
  • Demonstrate effectiveness: A device is effective if it produces clinically significant results for most of the target population, under the intended uses and conditions of use, with proper instructions and warnings.
  • Provide directions and warnings: Include adequate instructions and cautions to prevent unsafe use of the device

When submitting evidence, the sponsor must:

  • Comply with any reports or information requests related to the classification of the device and its safety and effectiveness, including the reason, description, time, form, and manner of the report or information.
  • Incorporate by reference any required information that has been previously submitted to the relevant Center.

De Novo Classification

The de novo classification process is for novel devices that are not similar to any existing device or are automatically classified as Class III. The FDA can classify such devices as Class I or II based on their risk and regulation level.

The process begins with a De Novo request from the device sponsor, which includes the device description, proposed classification, benefits and risks summary, scientific evidence summary, and bibliography. The FDA will make a decision within 150 days, and may ask for more information, consult experts or panels, or inspect the device.

The sponsor can withdraw the request before the FDA issues an order, but will not get a refund of the de novo fee. The FDA will grant or decline the request based on the evidence and risk, and will issue an order, publish it in the Federal Register, and update the database. De Novo submissions are confidential until granted.

Reclassification

Reclassification is changing the class of a device. A reclassification petition from an interested person or a device manufacturer or importer contains the type, action, basis, reasons, and data for reclassification. The classification panel will recommend the appropriate class before the FDA or the Commissioner issues an order to reclassify the device. There are five types of reclassification processes, depending on the situation and the law. They are:

  • Based on new or existing information on its safety and effectiveness.
  • Based on new performance standard or information, requiring premarket approval for a Class I or II device.
  • Requiring premarket approval for a Class III device subject to premarket notification.
  • Reclassifying a device without a predicate device (De Novo request).
  • Reclassifying a product that was a drug or biological product before 1976. Each process starts with a petition or notification from the FDA, with panel consultation and public comment.
Posted by IVD Enthusiast in IVDs
13
Jan
2024
21 CFR Part 830: Unique Device Identification

21 CFR Part 830: Unique Device Identification

The FDA requires certain medical devices to have a unique device identifier (UDI) that can be used to identify and track them throughout their distribution and use. A UDI is a code that consists of two parts: a device identifier (DI) and a production identifier (PI). The DI identifies the specific version or model of a device, and the PI identifies the unit of device production, such as the lot or batch number, the serial number, the expiration date, or the date of manufacture. The UDI must be displayed on the device label and package, and in some cases, on the device itself. The purpose is to improve patient safety by making device recalls and postmarket surveillance easier.

UDI Applies to Only a Subset of Devices

The UDI system applies to a subset of devices that are classified by the FDA according to their risk level (see 21 CFR Part 821 for the list of devices and compliance dates).

Issuing UDIs

The UDI must be issued by an FDA-accredited issuing agency, such as GS1, and conform to international standards for data structure and character set. The UDI must use only one DI per version or model of a device, and must not reuse a DI that has been previously assigned to another device.

Global Unique Device Identification Database (GUDID)

The FDA also maintains a Global Unique Device Identification Database (GUDID) that stores the UDI and other information about each device. The GUDID allows the public and health care professionals to access information about medical devices. The labeler of a device, which is usually the manufacturer, is responsible for electronically submitting the UDI and other information to the GUDID no later than the date the label is placed on the device, or the date the device is released for commercial distribution. The labeler must also update the GUDID if any information changes, or if a new DI is required for a device.

The information that must be submitted to the GUDID for each version or model of a device includes:

  • The labeler’s name and contact information, and the name of the issuing agency
  • The DI, and any previous DI that was assigned to the device
  • The device name, and the version or model number
  • Any applicable statements that indicate if the device is sterile, has a permanent marking of the DI, contains natural rubber latex, has safety issues if exposed to magnetic resonance, or has multiple sizes
  • The type of PI that is displayed on the device label
  • The premarket submission number, if any, that was assigned by the FDA
  • The FDA listing number that identifies the device
  • The Global Medical Device Nomenclature (GMDN) term or code that describes the device
  • The number of devices contained in each package

The FDA may grant a waiver or an exception from the UDI requirements for certain devices, or allow voluntary submission of UDI information for devices that are not subject to the requirements.

Significant Changes to Devices Require a New UDI

A new DI is required for a device if there is a change in the device’s specifications, performance, size, or composition that could affect its safety or effectiveness, or if there is a change in the device’s package or labeling. The labeler must notify the FDA of any changes that require a new DI, and update the GUDID accordingly.

Corrections to UDI Data

The FDA may review the GUDID data and request corrections or explanations from the labeler if the data is incorrect or misleading. The FDA may also delete or modify the data if necessary.

Records

The labeler must keep records of all UDIs and the relationship of prior and current DIs for each device, and retain the records for three years after the device is no longer marketed. The FDA may inspect the records and request copies as part of its regulatory oversight.

Posted by IVD Enthusiast in IVDs
02
Dec
2023
21 CFR Part 812: Investigational Devices

21 CFR Part 812: Investigational Devices

Investigating A Medical Device

Consider this Catch-22:

  • You can’t distribute a medical device before getting FDA approval.
  • You can’t get FDA approval without evidence the medical device works.
  • You can’t get evidence a device works without using the medical device.

The FDA solved this problem with 21 CFR Part 812, which allows an exemption to distribute a device for a clinical trial to investigate it (i.e. ‘investigational device exemption’ or ‘IDE’).

21 CFR Part 812 takes a risk-based approach to IDEs, as well as the procedures for obtaining IRB and FDA approval, and the responsibilities of sponsors and investigators who conduct device studies.  It also addresses how investigational devices must be labeled.

Risk-Categories of Investigational Devices

The FDA classifies investigational devices into three categories based on the level of risk they pose to human subjects:

  • exempt,
  • non-significant risk (NSR), and
  • significant risk (SR).

The risk category determines the type and extent of regulatory oversight required for the device study.

Exempt devices are those that do not require an IDE from the FDA, because they meet one of the following criteria:

  • They are legally marketed devices that are used in accordance with their approved labeling
  • They are diagnostic devices with little or no risk to subjects (see 21 CFR 809.10(c))
  • Testing is not to determine safety or effectiveness of device, and does not put subjects at risk
  • They are custom devices not intended for general distribution.

Significant Risk (SR) devices are those that:

  • Are implants
  • Support or sustain human life
  • Are of substantial importance to diagnose, cure, mitigate, or treat disease, or otherwise prevent impairment of human health
  • Present a potential for serious risk to the health, safety, or welfare of a subject

Non-Significant Risk (NSR) devices are everything else.

Actions Required Based on Risk

Exempt devices

The sponsor does not need to submit an IDE application to the FDA, but must:

  • Obtain approval from an IRB before initiating the study
  • Label the device as investigational
  • Obtain informed consent from subjects

NSR devices

The sponsor does not need to submit an IDE application to the FDA, but must. The sponsor must do everything required for an exempt device AND also comply with the abbreviated requirements in 21 CFR 812.2(b), which include:

  • Conduct the study per the approved protocol
  • Monitor the study and ensure that any unanticipated adverse device effects are reported to the FDA and the IRB
  • Maintain certain records and reports (see 21 CFR 812.140(b)(4) and (5))

SR devices

The sponsor must submit an IDE application to the FDA and obtain approval from both the FDA and an IRB before initiating the study. The sponsor must also comply with the full requirements in 21 CFR Part 812, which include everything for exempt and NSR devices AND:

  • Conduct the study in per any conditions of approval imposed by the FDA or the IRB
  • Maintaining all records and reports as required by 21 CFR Part 812.  NOTE: There are considerably more records and reports needed for SR devices.

IRB approval process for device studies

The Institutional Review Board (IRB) is an ethics committee responsible for reviewing and approving human studies to ensure that they are ethically sound and protect the rights and welfare of human subjects. The IRB must follow the general requirements in 21 CFR Part 56 (IRB), as well as the specific requirements in 21 CFR Part 812 for device studies.

The IRB must review and approve:

  • The research protocol
  • The informed consent document
  • The investigational device brochure (if any)
  • The investigator’s qualifications
  • The site where the study will be conducted
  • Any other relevant information

The IRB must also determine whether the device is NSR or SR based on the information provided by the sponsor. If the IRB disagrees with the sponsor’s initial NSR determination, it must notify the sponsor and the FDA within five working days.

FDA approval process for device studies

The FDA is responsible for reviewing and approving IDE applications for SR devices to ensure that they are scientifically valid and protect public health. The FDA will follow the general requirements in 21 CFR Part 50 (Protection of Human Subjects), as well as the specific requirements in 21 CFR Part 812 for IDE applications.

The FDA will review and approve:

  • The research protocol
  • The risk analysis
  • The device description
  • The manufacturing information
  • The preclinical and clinical data (if any)
  • The investigator’s qualifications
  • The informed consent document
  • The investigational device brochure (if any)
  • Any other relevant information

The FDA will also determine whether the device is SR or NSR based on the information provided by the sponsor. If the FDA disagrees with the sponsor’s initial SR determination, it must notify the sponsor and the IRB within 30 days.

Sponsor Responsibilities

The sponsor is the person or entity who initiates a device study, or who assumes responsibility for a study initiated by another person or entity. The sponsor is typically the manufacturer of the device, a clinical investigator, an academic institution, or a contract research organization.

The sponsor must:

  • Obtain an IDE from the FDA (if required) and an approval from an IRB before initiating a device study
  • Select qualified investigators and provide them with the necessary information and training to conduct the study
  • Provide the investigators with the investigational devices and ensure that they are properly labeled, stored, distributed, and accounted for
  • Obtain agreements from the investigators to comply with the protocol, the IDE regulations, and any other applicable regulations
  • Monitor the progress and conduct of the study and ensure that any problems or deviations are corrected or reported
  • Report any unanticipated adverse device effects, withdrawals of IRB or FDA approval, progress reports, final reports, and any other information as required by 21 CFR Part 812
  • Maintain records and reports as required by 21 CFR Part 812

Investigator responsibilities

The investigator is the person who actually conducts a device study, or who supervises the conduct of a device study by other persons under his or her direction. The investigator may be a physician, a nurse, a technician, or any other person qualified by training and experience to conduct the study.

The investigator must:

  • Obtain approval from an IRB before initiating a device study
  • Obtain informed consent from each subject before enrolling them in the study
  • Conduct the study per the approved protocol and any conditions of approval imposed by the IRB or the FDA
  • Use the investigational device only for the purposes and in the manner specified in the protocol
  • Control the investigational device and ensuring that it is not used for any other purpose or by any other person
  • Report any unanticipated adverse device effects, deviations from the protocol, changes in the study status, and any other information as required by 21 CFR Part 812
  • Maintain records and reports as required by 21 CFR Part 812

Device labeling requirements for investigational devices

The labeling of investigational devices is regulated by 21 CFR Part 812 to ensure that they are clearly identified as such and that they provide adequate information for their safe and effective use.

The labeling of investigational devices must:

  • Bear the statement “CAUTION — Investigational device. Limited by Federal (or United States) law to investigational use.”
  • Identify the device, the name and address of the manufacturer or sponsor, and any relevant information such as expiration date, lot number, serial number, etc.
  • Provide directions for use, warnings, precautions, potential adverse effects, contraindications, and any other information necessary for the protection of subjects
  • Not contain any false or misleading statements or claims about the safety or effectiveness of the device.
Posted by IVD Enthusiast in IVDs, LDTs
01
Oct
2023
Proposed rule for LDTs – The Turf War Escalates

Proposed rule for LDTs – The Turf War Escalates

The FDA has published a proposed rule to amend 21 CFR Part 809 (in vitro diagnostic) regulations to state that laboratory developed tests (LDTs) are in vitro diagnostic products (IVDs) designed, manufactured and used within a single clinical laboratory, and need to follow the same rules as other medical devices.

What you should know:

  • The FDA believes LDTs are IVDs and it’s going to regulate them as such.  This is a point that should come as no surprise as the FDA has made it ad nauseum for going on 20 years now.  The FDA’s oft-repeated line is that in the almost 50 years since the 1976 Medical Device Amendments, it has simply been practicing ‘enforcement discretion’.  In other word’s it has simply decided not to do anything about the thousands of labs not following the IVD regulations, but always maintaining they could if they felt it was needed.
  • The FDA has a long (unsuccessful) history of trying to start enforcing IVD rules for LDTs. It started 20+ years ago.  Jeffery Gibbs provides a comprehensive review of this in LDTs: The Saga Continues. The whole thing reads like two neighbors arguing over a property line.  Industry, and especially academic medical centers have fought the enforcement tooth and nail. The latest failure to get the VALID act through Congress appears to have been the FDA’s last straw.
  • The FDA expects a legal battle. Using the ‘rule-making process’, to call LDTs as IVDs effectively bypasses Congress and goes straight into the process to simply update the regulation (21 CFR Part 809). It’s the equivalent of saying the property line is ten feet over and simply starting the process to move the fence. Since the VALID act went to Congress in the first place, that would seem to imply the FDA knows Congressional action was needed to change the regulation.  The challenge of FDA’s  legal authority is bound to be a great show. Bring the popcorn.
  • Exemptions and Exceptions.  The rule provides a smorgasbord of labs and tests that may be exempt (e.g. blood typing, forensics), might have less stringent rules (academic labs, low revenue labs, tests approved by New York or the VHA), or that might get additional transition time.  It asks for feedback from the public on all of these possibilities, in what will almost certainly be a very long comment review process.
  • Benefits & Costs. Per the FDA, the rule is aimed at helping to ensure the safety and effectiveness of LDTs and improving innovation. Most of the 83 page document in the Federal Register are devoted to why the FDA believes LDTs are unsafe. Sure, improving patient safety is great. But labs are nervously eyeing the price tag.  The FDA outlines benefits ($86B/year) and costs of the rule (5.8B to labs, plus 500M to FDA that will be passed off to labs as user fees).  It’s anyone’s guess what magic hat the FDA pulled those estimates from.  The Pew Trust researched the topic in 2021 and concluded it was ‘difficult to know precisely how many LDTs are on the market, or to accurately estimate the volume of tests that are run using LDTs [but] they are clearly common, and many labs rely on them in some capacity.”
  • Timeline. As you might expect, the FDA’s plan is to phase in the new approach. See graphic below.  Year one starts with adverse event reporting and the ability to recall IVDs.  Year two will require registration and listing.  Year three will bring QMS requirements (design and manufacturing controls, CAPAs, complaints, etc under 21 CFR Part 820) which by that time might actually be updated to align with ISO 13485.  Lastly, year 3.5 and 4 will mark deadlines for FDA application for Class III PMA and Class I/II de novos or 510Ks.
  • What Does the Future Hold?  Considering the concerns that the FDA can’t even handle its current workload with IVDs, no doubt these cut-offs will be followed with a lengthy period of years in which the absolutely overloaded FDA will wade through a backfill funded by astronomical user fees that will still not cover the work that needs to be done as inexperienced labs take on their first FDA applications.  If you are a lab with one or more LDTs, the future holds much uncertainty.  If you are a regulatory affairs professional in the IVD industry, expect job security and a raise.

 

Posted by IVD Enthusiast in IVDs, LDTs