Regulatory Class - Oct 10 Flashcards
Parts of a 510(k)
Cover Sheet (FDA Form 3514) Cover Letter Table of Contents User Fee Information Certification of Compliance with ClinicalTrials.gov (FDA Form 3674) Statement of Substantial Equivalence Labeling Advertising and Promotional Material Comparative Information Biocompatability Assessment Truthful and Accurate Statement Clinical Data Shelf Life (and Sterilization) Indication for Use Form Financial Certification and/or Disclosure Device Description Executive Summary Performance Testing Software Electromagnetic Compatibility (EMC) and Electrical Safety
Parts of a PMA
Premarket Review Submission Cover Sheet (FDA Form 3514) Medical Device User Fee Cover Sheet Certification of Compliance with ClinicalTrials.gov (FDA Form 3674) Applicant name and addresss Table of Content Summary Section Description of Device Performance Standards Nonclinical Technical Data Clinical Technical Data Justification for Single Investigator (if applicable) Bibliography Device Sample Proposed Labeling Environmental Assessment or Exclusion Financial Certification and/or Disclosure
Parts of PMA section: Summary Section
Indications for Use Device description Alternative practices and procedures Marketing history Summary of studies
Parts of PMA section: Description of device
Device
Functional Components
Properties relevant to diagnosis, treatment, cure or mitigation of disease
Methods, facilities, and controls
Quality System Regulations (QSR)
Device GMPs
Apply to device development and manufacturing process (Class II and III)
Apply to manufacturing (Class I)
Does not apply to research devices
Goal is to create a self-correcting system that reliably produces robust device designs and production methods, ensuring they perform consistent with their intended use
QSR: Management Responsibility
Establish quality policy (ensure it’s understood, implemented, and maintained)
Ensure adequate organizational structure
Appoint management representative to ensure quality system maintained and report to executive management (quality system audits)
Establish quality plan and quality system procedures
Management review QSR and oversee SOPs
QSR: Personnel Requirements
Sufficient personnel (education, background, training and experience) Identify training needs Personnel trained to adequately perform their assigned responsibilities Training should be documented
SOPs should identify training methods and policies
QSR: Design Controls
Establish plan describing design and development activities and define responsibility for implementation (review, update, and approve as design/development progress)
Procedures required to ensure specified design requirements are met
Applies to Class II and III devices and some Class I
QSR: Document Controls
Procedures required to control documents (New procedures and/or documents must be reviewed/approved
Approval must be documented
Documents available at all relevant locations
Changes to documents must be reviewed/approved
Obsolete documents removed to prevent unintended use
New documents or SOPs need way to determine which is the official document (usually special ink or signature)
QSR: Document Controls: Change records must include:
Description of change Identification of affected documents Signature/date of approval Effective date (When document is released to personnel)
QSR: Purchasing Controls
All received products and services meet requirements
Applies to suppliers, contractors and consultants (make sure they are qualified)
Must evaluate suppliers; Define control over product, services, suppliers; Maintain records of acceptable suppliers
Maintain purchasing documents, including agreement that suppliers notify manufacturer of product/service changes
QSR: Identification and Traceability
Procedures for identifying product at all stages: receipt, production, distribution, installation (to prevent mix-ups)
Procedures for identifying finished devices or appropriate components by control number of unit, lot or batch (to facilitate corrective action; ex. surgical implants)
QSR: Production and Process Controls
Ensure that devices conform to specification
Procedures for changes to specification, methods, processes or procedures (Changes approved, verified, validated prior to implementation and documented)
Environmental control (temperature, humidity)
Personnel (health, cleanliness, clothing)
Contamination control (equipment and product)
Buildings (suitable design and sufficient space)
Equipment (specified requirements, appropriate for use, maintained, inspected, adjusted)
Automated Processes (validate computer software for its intended use)
QSR: Inspection, measuring and test equipment
Suitable for intended purposes and capable of producing valid results
Need procedures for: calibration, inspection, maintenance
QSR: Process Validation
Establishing by objective evidence that a process consistently produces a result meeting predetermined specification
DOne if process cannot be fully verified by inspection and testing (ex, if testing would destroy product)
Performed by qualified personnel
All procedures and validation records maintained
QSR: Acceptance activities
Need procedures and records for:
Receiving - acceptance (inspection, testing, verification) of incoming product
In-process - ensure in-process product controlled until inspection, test, or verification activities are completed
Final acceptance - ensure each production lot or batch meets acceptance criteria
Finished devices quarantined and controlled until released
QSR: Acceptance records
Activities performed, dates, results
Signature of person(s) conduction acceptance activities
Equipment used
QSR: Acceptance Status
Conformance or nonconformance with acceptance criteria
Maintained throughout manufacturing, packaging, labeling, installation, and servicing
Ensure only product that has passed is distributed, used, or installed
QSR: Nonconforming Product
Establish procedures to control product that does not meet specifications; document evaluation and investigation of nonconforming product
Review and disposition of nonconforming product
Rework - including retesting and re-evaluation
QSR: Labeling and Packaging
Maintain procedures to ensure labeling integrity; document labeling inspection and release; Control labeling storage and operations to prevent mix-ups; Ensure packaging protects device from damage during processing, shipping, storage, and handling
QSR: Handling and Storage
Procedures to prevent mix-ups, damage, deterioration, contamination during handling
Procedures to control storage areas and stock rooms:
Prevent mix-ups, damage, deterioration, contamination
Ensure obsolete, rejected, deteriorated product is not used or distributed
Authorize product movement to/from storage areas and stock rooms
QSR Controls: Distribution and Installation
Procedures to ensure only devices approved for release are distributed; prevent expired or deteriorated devices from distribution; maintain records of initial consignee
Maintain installation instructions and test procedures; installer document inspection and test results that demonstrate proper installation
Device Master Record (DMR)
For each type of device
Procedures and specification for finished device: device, production process, packaging and labeling, installation, maintenance specification
Device History Record (DHR)
Production history of a finished device or production-run of devices
Manufacturing documentation, testing results, labeling documentation, release/approval documentation
Corrective and Preventative Action (CAPA)
Corrective action - correct product problem that has been identified
Preventative action - prevent a potential problem that could occur in the future
Data from: internal audits; incoming, in-process, and final QC testing; service and repair records; customer feedback
Verify and validate effectiveness of CAPA; need to complete testing periodically to confirm that preventative actions are successful
QSR: Complaint Files
Complaint - any written, electronic, or oral communication that alleges deficiencies in a device after it is released for distribution; deficiencies in: identity, quality, durability, reliability, safety, effectiveness, performance
Maintain procedures for receiving, reviewing, evaluating complaints; records of investigations, determine if reportable to FDA
QSR: Servicing
Procedures required
Service reports must be reviewed to determine whether event represents adverse event reportable to FDA
QSR: Statistical Techniques
Procedures for identifying valid statistical techniques for control of manufacturing processes and product characteristics
Sampling plans based on valid statistical rationale
QSR Records
Records must be maintained for time equivalent to design and expected life of device (a minimum of 2 years from date of release for commercial distribution)
Internal audit reports (management review, quality audit, supplier audit) are not subject to retention requirement
Not required to be provided to the FDA, but must certify that reviews and audits were performed
Medical Device Classification
Class I - lowest risk; general controls, may require only listing it with the FDA
Class II - moderate risk; general and special controls; most require 510(k)
Class III - highest risk; general controls; PMA
General Controls
Baseline requirements apply to all medical devices
Quality System Regulations: manufacturing (cGMPs) and recordkeeping
Establishment registration
Device listing
Reporting adverse events
Labeling, advertising, and promotional materials requirements
Special Controls
Performance standards - mandatory or voluntary
Specific FDA guidance documents
Special labeling requirements
Postmarketing surveillance
510(k) - Required for:
Significantly changed or modified in design, components, method of manufacture (could significantly affect safety or effectiveness)
Major change in intended use
Custom devices are exempt: must not be generally available for purchase, not advertised, only for a specific person and named in order by a physician
Substantially Equivalent (SE)
Must demonstrate substantial equivalence to predicate device (class I or II device, cleared thru 510(k), legally marketed in US)
SE in: Intended use; technological characteristics (not identical but no new questions of safety or effectiveness)
Specifically demonstrate SE with: intended use, design, materials in construction, biocompatability, performance, safety, labeling, standards
Traditional 510(k)
Most commonly used; device must not be a modification of manufacturer’s own cleared device
90 day review
513(g) Submission
Request for designation of device classification Company writes description of device and makes an argument for the class they think it is
Helpful with Class I devices, since they only need to be listed, to make sure not a Class II device requiring a premarket notification
60 Day review
Special 510(k)
Modification of manufacturer’s own device
No new indication for use; No change to fundamental scientific technology (Modification to operating principles or mechanism of action)
Requires design controls and risk analysis
Cannot file until all design controls are in place
30 Day Review
De Novo 510(k)
Low risk Class III products that are NSE to predicate device
Within 30 days after receiving a NSE determination, sponsor may request a risk-based classification determination
510(k) Cover Letter
Type of submission, device name, submitter, contact person name, title, and phone number, preference for continued confidentiality, class, FDA review panel, product code
Indications for Use Statement
Specific indications, clinical settings, target population, anatomical sites
Must be consistent with labeling, advertising and instructions for use
Will be available on FDA’s website within 30 days of SE letter
510(k) Summary or Statement
Brief summary of the device and safety and effectiveness information that forms the basis for SE determination
If you don’t provide the summary, you must submit a statement saying you have 30 days to redact the whole 510(k) submission when a request is made in writing
510(k): Truthful and Accurate Statement
Signed and dated by a responsible person at the sponsor (not a consultant)
Judicial action can be taken if false or misleading info is submitted
Usually, Director or VP of Quality or Regulatory department sign the truthful or accurate statement
510(k): Declarations of Conformity and Summary Reports
to standards, quality, or guidance documents
For abbreviated 510(k) submission: info regarding conformity to any standards, summary reports recommended in any relevant device-specific guidance
For Special 510(k): info regarding design control activities
510(k): Executive Summary
Concise description of the device (indications for use and technology)
Device comparison table
Concise summary of performance testing
510(k): Device Description
Operating principles, photos, engineering drawings, diagrams, schematics
Performance specifications and device design requirements
Identify all models, accessories, or components included in the submission
List all patient contacting components and respective materials
Very detailed
510(k): Substantial Equivalence Discussion
Detailed comparison with the predicate device sufficient to demonstrate substantial equivalence (indications for use, technology, and performance specifications)
510(k): Proposed Labeling
Packaging, stickers, operator’s manual, instructions for use, patient brochures, promotional materials
promotional materials and patient brochures are not likely to be included as they aren’t typically made until device is marketed
510(k): Sterilization and Shelf-life
Accelerated aging data; real-time studies, validation
510(k): Biocompatibility assessment
if device includes patient-contacting materials
difference requirements for devices that contact the surface of the body versus invasive contact or implantables
Know short-term and long-term or specific toxic effect and effects on reproduction
Can pass on the bioavailability assessment, if the exact same materials are used in the predicate device
510(k): EMC and Electrical Safety
if the device includes an electric component, evaluate device’s EMC
Emission (interference with electronic products)
Immunity (interference with device performance created by emissions from other electronic products)
510(k): Performance Testing (Bench and Animal Studies)
List specific tests conducted Describe each test protocol-objective, test articles used, test methods and procedures, study endpoint and criteria for assessment Summarize the results Describe analysis Discuss conclusions
Can be extensive if no clinical trial data; should compare to predicate device, standards, or guidelines if possible
510(k): Performance Testing (Clinical)
FDA considers alternatives to clinical studies if supported by adequate scientific rationale
Provide the clinical protocol - objective of the test, test methods and procedures, study endpoints (safety and effectiveness), statistical methodology
Discuss study results, analyses performed and conclusions
IRB and informed consent apply. If study is significan risk, must use an IDE
Abbreviated 510(k)
Relies on guidance documents, performance standards to demonstrate substantial equivalence
Submission must include Declaration of Conformance to FDA-recognized performance standards
Typically less info, specific data not required if providing summary of conformance to special controls (guidance, standards)
90 Day Review
FDA Review of 510(k)
FDA acknowledges receipt of 510(k) and assigns a ‘k number’ to use for all future correspondence
‘K number’ - first 2 digits are year submitted
May request additional info, which can reset the review clock, sponsor must respond in 30 days or the FDA considers the 510(k) withdrawn (can ask the FDA for an extensions, up to 2)
Does not approve, but clears device for marketing
FDA acknowledges that devices are or are not substantially equivalent to legally marketed product; does not determine if devices are safe or effective
PMAs: Used for
Devices that are not substantially equivalent o any advice cleared through 510(k)
Also, Class III devices that support or sustain human life; substantial importance in preventing impairment of human health; present potential unreasonable risk of illness or injury
Must demonstrate safety and effectiveness
PMA: Summary Section
Indications for use
Device description: function, scientific concepts that form the basis for the devices, and significant physical and performance characteristics
Alternative practices and procedures: for diagnosing, treating, preventing, curing, or mitigating the disease or condition
Marketing history (foreign and US): lit all countries where device has been marketed or withdrawn because of safety or effectiveness; Most are first marketed in Europe
Summary of studies: results of technical data (nonclinical and clinical studies); Objective of each study, experimental design, how data were collected and analyzed, brief description of findings and conclusions
Discuss how the data constitutes valid scientific evidence and a determination of safety and effectiveness for its intended use
PMA: Description of Device
Device (including pictorial representations)
Functional components or ingredients
Properties of the device relevant to the diagnosis, treatment, prevention, cure, or mitigation of a disease or condition
Principles of operation of the device
Methods, facilities, and controls used in manufacture, processing, packaging, storage, and installation of the device (consistent with cGMPs)
PMA: Performance standards
Justify any deviations from performance standards or voluntary standards
PMA: Technical Data - nonclinical
Results of the nonclinical laboratory studies
Statement that each study was conducted in compliance with GLPs or justification for noncompliance
PMA: Technical Data - clinical
Results of human clinical studies including:
protocols, number of investigators and subjects, inclusion/exclusion criteria, demographics, safety and effectiveness data, patient discontinuation, device failures and replacements, tabulations of data and copies of CRFs for each subject who died or who did not complete the investigation, statistical analyses
Statement that each study was conducted in compliance with IRB, informed consent, and IDE requirements or justification
Foreign Clinical Data
Must be conducted in accordance with Declaration of Helsinki and local requirements
Applicable to US patient population
Standard of care and medical practice similar to US
Competent investigators
Data and source documentation available for audit by FDA
PMA: Justification for Single Investigator
Data sufficient to demonstrate safety and effectiveness and ensure reproducibility of test results
PMA: Bibliography
Al published reports (adverse or supportive) that concern safety and effectiveness
Other data, info, or reports relevant too safety and effectiveness
PMA: Proposed Labeling
Instructions for use, advertising, package labels
PMA: Environmental assessment or exclusion
Not usually required if the device is of the same type and for the same use as a previously approved device
Modular PMA
Contents broken down into well-delineated components and each module is submitted to FDA as soon as it is completed (manufacturing, software validation, preclinical, clinical, labeling)
Recommended for products in early stages of clinical study but when device design is not likely to change
Shell-outline of PMA and plan for submission of the modules (developed individually with the manufacturer for a specific device)
FDA reviews each module separately - 90 day review
When final module is submitted, PMA is filed - 180 day review
PMA Amendments
Any new safety and effectiveness information learned about the device
From ongoing or completed studies that may affect safety and effectiveness or statements of contraindications, warnings, precautions, and AEs in draft labeling
Submitted 3 months after the filing date, or following the receipt of an approvable letter
FDA Review of PMA
Filing PMA occurs within 45 days after a PMA is received by the FDA
Date of filing starts the 180 Day review period
Timeframe not typically extended without major amendment
Within 100 days of filing, sponsor can meet with FDA to discuss the PMA
Reasons FDA may refuse to file PMA
PMA is incomplete Justification for omission of required info is inadequate 510(k) processing for the same device Contains a false statement Financial disclosure is missing
Advisory Panels
Generally used with all PMAs for the first of a kin device; devices raises questions that FDA has not addressed previously
Includes 1 nonvoting industry rep and 1 nonvoting consumer rep
Hold public meeting to discuss findings, review parts of the PMA, panel recommendation are not binding
Quality System Inspection
Scheduled following FDA determination that PMA design and manufacturing sections demonstrate compliance
Assess manufacturer’s ability to manufacture device; consistent with PMA; compliance with QSR
Bioresearch Monitoring (BIMO) Inspection
Clinical sites, sponsor, CROs, IRBs
Site selection based on: contribution to pivotal data, history of compliance, safety issues identified in PMA, concerns raised by reviewers
Response to PMA
Approval order - FDA approves the application on the basis of draft final labeling, (copy of final printed labeling must be submitted to FDA before marketing)
Approvable letter: specific additional info must be submitted or specific conditions are agreed to by the applicant; letter describes the requirement for approval
Not approvable letter: significant deficiencies in the application
Denying Approval
