Introduction to US FDACDRH Regulations, PMA

Do-Hyun Kim, Ph.D, Ph.D

CEO, BT Solutions, Inc. South Korea

CEO, Solutions 4BT, LLC, USA

The Transformation of Medical Device Industry for Thailand 4.0: Software Validation for Medical Devices

Novotel Bangkok Sukhumvit 20, 5th floor, Room Benjasiri 1-2

January 17, 2017, 3:45 pm – 5:00 pm

Classification

• Class I – Lowest Risk An example of a Class I device is a manual toothbrush. Class I devices are subject to general controls.

• Class II – Moderate Risk Examples of Class II devices are male condoms and non-invasive blood pressure monitors. Class II devices are subject to general controls and special controls.

• Class III – Highest Risk An example of Class III device is a heart valve. Class III devices are subject to general controls and premarket approval.

After Classification – Premarket Submission• Premarket notification [510(k)]

• For Class I devices exempt from [510(k)] the submission of a [510(k)] and marketing clearance from FDA is not required.

• If your Class I (or certain class II) device is exempt, subject to the limitations on exemptions, from the 510(k) process, this will be stated in the classification regulation.

• However, other General Controls such as registration and listing, labeling, and good manufacturing practices (GMP) may apply.

• PMA

Premarket Approval (PMA)

• Original PMA

• Licensing Agreement PMA

• Modular PMA

• Some single use devices – Premarket Report (PMR)

• Supplements• Panel-track supplement: significant change

• 180-day supplement: significant change in material, software, etc

• Real-time supplement: minor change in software, sterilization, etc

• 30-day notice: change in manufacturing procedure, etc

PMA (1): Traditional (Original) PMA

• A PMA application involves many volumes of material to be submitted to FDA.• Device description and intended use

• Nonclinical and clinical studies

• Case report forms

• Manufacturing methods

• Labeling, etc.

• In the traditional PMA method, the complete PMA application is submitted to FDA at once. This method is generally used if the device has already undergone clinical testing and has been approved in a country with established medical device regulations.

PMA (2): Modular PMA

• In a Modular PMA the complete contents of a PMA are broken down into well-delineated components (or module) and each component is submitted to FDA as soon as the applicant has completed the module, compiling a complete PMA over time.

• The PMA is viewed as a compilation of sections or "modules," such as preclinical, clinical, manufacturing, that together become a complete application. This method is recommended for products that are in early stages of clinical study.

• The process begins with a PMA Shell which lays out the plan for submission of the modules. The review team will work with applicants to develop a customized shell for each specific product that includes module contents and suggested timelines. It is developed individually with the manufacturer for a specific device.

PMA(3): Premarket Report

• A Premarket Report (PMR) is a marketing application for Class III reprocessed single use devices (SUDs) that otherwise would have required a pre-market approval application.

• Among other information, a PMR must include validation data regarding cleaning, sterilization, and functional performance of the reprocessed device to ensure it is substantially equivalent to a legally marketed device.

PMA(4): Licensing Agreement PMA

• A licensing agreement PMA involves a PMA applicant (licensor) entering into a licensing agreement with another party (licensee) to provide that party with permission to reference the data in its PMA.

• The licensee, after submitting the licensing agreement PMA to FDA, may request FDA to approve its own device, by referencing all the information that was used as a basis for approval of the licensor’s device.

• Upon receiving FDA’s approval, the licensee assumes all the responsibilities of a PMA applicant, including the manufacture and distribution of a device that is identical to the licensor’s. In addition, following approval of the licensing agreement, licensees may choose to make changes to their product. As for all PMA applicants, such changes may require the submission of a PMA supplement.

PMA(5): Panel-track supplements

• Supplement to an approved premarket application or premarket report under section 515 that requests a significant change in design or performance of the device, or a new indication for use of the device, and for which substantial clinical data are necessary to provide a reasonable assurance of safety and effectiveness.

PMA(6): 180-day supplements

• Supplement to an approved premarket application or premarket report under section 515 that is not a panel-track supplement and requests a significant change in components, materials, design, specification, software, color additives, or labeling.

PMA(7): Real-time supplements

• Supplement to an approved premarket application or premarket report under section 515 that requests a minor change to the device, such as a minor change to the design of the device, software, sterilization, or labeling, and for which the applicant has requested and the agency has granted a meeting or similar forum to jointly review and determine the status of the supplement.

PMA(8): 30-Day Notices

• A notice under section 515(d)(6) that is limited to a request to make modifications to manufacturing procedures or methods of manufacture affecting the safety and effectiveness of the device.

• Product can be distributed after 30 days of notification, unless it is determined inappropriate in 30days

• Where FDA finds such notice inadequate, FDA will inform the applicant that a 135-day PMA supplement or 75-day HDE supplement must be submitted

PMA(9): Periodic (annual) reports

• Under section 212 of FDAAA, PMA applicants are subject to an “annual fee for periodic reporting concerning a class III device.

Changes without a PMA Supplement

• (1) the change does not affect the device's safety or effectiveness

• (2) the change is reported to FDA in a postapproval periodic report (annual report) required as a condition of approval of the device, e.g., an editorial change in labeling which does not affect the safety or effectiveness of the device.

• Trivial changes, such as changes in the color of a label, would not have to be included in the postapproval periodic report

Product Development Protocol (PDP)

• Clinical evaluation of a device and the development of necessary information for marketing approval are merged into one regulatory mechanism.

• Ideal candidates for the PDP process are those devices in which the technology is well established in industry.

• The PDP allows a sponsor to come to early agreement with FDA as to what would be done to demonstrate the safety and effectiveness of a new device. Early interaction in the development cycle of a device allows a sponsor to address the concerns of the FDA before expensive and time consuming resources are expended.

• A PDP that has been declared completed by FDA is considered to have an approved PMA (§814.19).

HDE• An Humanitarian Use Device (HUD) is a device that is i

ntended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.

• To obtain approval for an HUD, an humanitarian device exemption (HDE) application is submitted to FDA. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA.

• The application, however, must contain sufficient information for 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.

• Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.

IDE: Investigational Device Exemption

• Clinical evaluation of devices that have not been cleared for marketing requires:

• an investigational plan approved by an institutional review board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA;

• informed consent from all patients;

• labeling stating that the device is for investigational use only;

• monitoring of the study and;

• required records and reports.

Foreign companies/studies

• Can a foreign company submit an IDE/Is a U.S. Sponsor required?• A foreign company cannot sponsor an IDE; the company must have a U.S. agent who a

cts as the sponsor (see 21 CFR 812.18(a)). The U.S. agent must fulfill all the responsibilities of a sponsor identified in the IDE regulations.

• Do clinical studies have to be conducted in the U.S. / Will foreign studies be accepted?

FDA will accept a foreign clinical study involving a medical device not conducted under an IDE only if the study conforms to whichever of the following provides greater protection of the human subjects:• the ethical principles contained in the 1983 version of the Declaration of Helsinki, or• the laws and regulations of the country in which the research was conducted.• When foreign clinical data is used to support a marketing application, the applicant sh

ould ensure that the foreign data are applicable to the U.S. population and U.S. medical practice, that the clinical investigators have recognized competence, and that FDA can validate the data through an on-site inspection or other appropriate means, if necessary.

513(g)

• For devices that are innovative, it can sometime difficult to find an exact predicate device using the FDA classification database. In this case, you can submit a 513(g) “Request for Information” to the FDA. The 513(g) submission should outline the characteristics of your device and include rationale on why you believe it falls into a specific class.

Post-Market Regulations

• MDR (medical device reporting)

• Mandatory Medical Device Reporting:

• The Medical Device Reporting (MDR) regulation (21 CFR 803) contains mandatory requirements for manufacturers, importers, and device user facilities to report certain device-related adverse events and product problems to the FDA.

• Manufacturers: Manufacturers are required to report to the FDA when they learn that any of their devices may have caused or contributed to a death or serious injury.

• Importers: Importers are required to report to the FDA and the manufacturer when they learn that one of their devices may have caused or contributed to a death or serious injury. The importer must report only to the manufacturer if their imported devices have malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

Other Post-Market Regulations

• Recalls

• Corrections

• Removals

PMA EXAMPLE

Original PMA

• Assume a CGM (continuous glucose monitor)

• Does not replace traditional glucose meter, but used as a supplementary

• A sensor implanted/attached to patient body continuously monitor the glucose level and transmits data to the console

• Only for 18-years gold and more

Submission (1)

• Cover letter

• Table of contents

• Mandatory• User fee cover sheet

• CDRH submission form

• PMA review checklist

• Certification of compliance with requirements of clinicaltrials.gov data bank

• Certification: Financial disclosure

Submission (2)

• Technical review documents• Device description• Safety and effectiveness• Environmental analysis• Risk management• Biocompatibility & sterilization• Software review (>10,000 pages)• Performance test• Packaging, shelf life, and storage testing• Human factors and usability testing• Manufacturing description (>10,000 pages)• Clinical trial data• Labeling

User fee cover sheet

User fee cover sheet - online

CDRH Submission form

PMA review checklist

Certification of compliance with requirements of clinicaltrials.gov data bank

Certification: Financial disclosure

Technical review: Device description

• Device generic name

• Device trade name and model number

• Company name and corresponding personnel

• Manufacturing facility

• Details• Shape, color, material, hardware, etc• Components (if such exist)• User’s manual• Principle of operation• Scientific papers

Safety and effectiveness

• Indication for use

• Caution for use

• Warnings• Only trained operator may install the device

• Multiple complexity patient warning

• Calibration needs

• Pediatric usage

• Physical damage to the device

Effects to environment

• Electromagnetic compatibility: IEC 60601-1-2

• Mechanical shock

• Material hazard• Toxicity of the material

• Pollution during manufacturing

Risk management

• ISO 14971: Medical devices – Application of risk management to medical devices

• IEC 60601-1: Medical electrical equipment-general requirements for basic safety and essential performance

• ISO 16269-6: Statistical interpretation of data

Biocompatibility & sterilization

• Biocompatibility• Direct contact with patients• Cytotoxicity• Irritation• Toxicity• Genotoxicity• Chronic toxicity

• Sterilization• ISO 11137-1• ISO 11137-2• Bioburden recovery method

Performance test

• Test mechanical change during cleaning procedure

• Mechanical strength test for each part

• Test assembly of each part

• Test of mechanical working condition

• Test of operation due to environment (temperature, humidity, etc)

• Test of electrical performance

• Test of performance for system

Packaging, shelf life, and storage testing

• Packaging• Sealing

• Change in shape

• Contamination

• Shock, environmental effect

• Shelf life

• Storage

Human factors and usability testing

• Human factors: Mater of how to design the product according to each users ability, limit, etc• Minimizing error

• Usability testing: user-interface design validation

• FDA guidance: Applying human factors and usability engineering to optimize medical device design

Manufacturing description (>5,000 pages)• GMP

• ISO 10993-x: Biological evaluation of medical devices

• ISO 11137-x: Sterilization of healthcare products

• ISO 11607-x: Packaging for terminally sterilized medical devices

• ISO 14644-x: Cleanrooms and associated controlled environments

Clinical trial data

• Sample size = >200

• Ethinicity

• Test period per person- 7 to 10 days

• Comparison to existing device• Hyperglycemia: 20% error, 80-90% range

• Hypoglycemia: 20% error, 70-80% range

• Safety issue: none

Labeling

• ISO 15223: Medical devices – symbols to be used with medical device labels, labelling and information to be supplied

CGM- software review

• Will be covered tomorrow

Thank you