Medical Device Development: Regulation and Law, 2009 Edition, is the 'must-have' resource for the novice or veteran medical device regulatory affairs professional. This practical reference provides the most comprehensive and updated analysis of US medical device and diagnostics development and approval requirements anywhere. This book also features in-depth analysis on how emerging developments and trends are reshaping medical device and combination product regulations in the US. The new edition of this popular and authoritative resource addresses the latest regulatory and legal developments that guide how medical devices are developed today:
- The Medical Device User Fee and Modernization Act of 2002, including user fees, third party inspections, reprocessed single use devices, and the establishment of the Office of Combination Products.
- The Food and Drug Administration Amendments Act of 2007, including unique device identifiers, ClinicalTrials.gov registration, pediatric device promotion, and postmarket surveillance and medical device reporting changes.
- The current and future landscape of electronic 510(k) and PMA submissions.
New chapters and features in the newly-released edition include:
- Medical Device Compliance and Postmarket Surveillance requirements.
- Quality System Regulation, including management controls, design controls, risk analysis and corrective and preventive action, and other QSR provisions.
- In Vitro Diagnostics, including IVD clinical studies, ASR regulation, LDTs, CLIA, and IUO/RUO requirements.
- Combination Products and Product Jurisdiction, including a description of FDA's jurisdictional decision-making for single entity products, the establishment of the Office of Combination Products and its jurisdiction and processes, with a detailed discussion of the new definition of the "primary mode of action."
- A glossary and comprehensive index of terms and concepts.
- The Medical Device User Fee and Modernization Act of 2002, including user fees, third party inspections, reprocessed single use devices, and the establishment of the Office of Combination Products.
- The Food and Drug Administration Amendments Act of 2007, including unique device identifiers, ClinicalTrials.gov registration, pediatric device promotion, and postmarket surveillance and medical device reporting changes.
- The current and future landscape of electronic 510(k) and PMA submissions.
New chapters and features in the newly-released edition include:
- Medical Device Compliance and Postmarket Surveillance requirements.
- Quality System Regulation, including management controls, design controls, risk analysis and corrective and preventive action, and other QSR provisions.
- In Vitro Diagnostics, including IVD clinical studies, ASR regulation, LDTs, CLIA, and IUO/RUO requirements.
- Combination Products and Product Jurisdiction, including a description of FDA's jurisdictional decision-making for single entity products, the establishment of the Office of Combination Products and its jurisdiction and processes, with a detailed discussion of the new definition of the "primary mode of action."
- A glossary and comprehensive index of terms and concepts.
Table of Contents
CHAPTER 1 THE FRAMEWORK FOR REGULATION OF MEDICAL DEVICES- The Impetus for Premarket Clearance of Medical Devices
- The Medical Device Amendments of 1976
- Definition of a Medical Device
- The Medical Device Reclassification Process
- The Classification System
- Class I: General Controls
- Class II: Performance Standards and Special Controls
- Class II: Performance Standards and Special Controls
- Classification of “Preamendment” Devices
- FDA’s Device Classification, 1973-1988
- Continuing Classification of Devices
- Marketing a Medical Device: Routes to Market
- 510(k) Notification Process
- PMA Process
- PDP Process
- Reclassification
- De Novo Review (Automatic Reclassification) Following a Not
- Substantially Equivalent Determination
- General Principles of Market Clearance/Approval
- Reasonable Safety and Effectiveness
- Substantial Equivalence
- Considering Whether to File a 510(k) or PMA
- The Safe Medical Devices Act of 1990 and the Medical Device
- Amendments of 1992
- The SMDA
- User Reports
- Distributor Reports
- Device Tracking
- Substantial Equivalence to Preamendment Class III Devices
- Reclassification of Preamendment Class III Devices
- Transitional Devices
- Special Controls
- Performance Standards
- Reports of Removals and Corrections
- Recall Authority
- Temporary PMA Suspension
- Postmarketing Surveillance
- Use of Premarketing Approval Data
- Determining Substantial Equivalence
- Humanitarian Use Devices
- Office of International Relations
- Combination Products
- Civil Penalties
- Design Validation
- MDA 1992
- The Impact of the Food and Drug Administration Modernization Act of
- 1997 on the Approval Process
- Overriding Themes of the Legislation
- Investigational Device Exemptions
- Special Review for Certain Devices
- Expanding Humanitarian Use of Devices
- Device Standards
- Scope of Review; Collaborative Determinations of Device
- Data Requirements
- Premarket Notification
- Evaluation of Automatic Class III Designation
- Classification Panels
- Certainty of Review Time Frames; Collaborative Review Process
- Accreditation of Persons for Review of Premarket Notification
- Reports
- Device Tracking
- Postmarket Surveillance
- Practice of Medicine
- Use of Data Relating to Premarket Approval; Product Development
- Protocol
- Dissemination of Information on “Off-Label” Uses
- Mutual Recognition Agreements and Global Harmonization
- MDUFMA 2002
- User Fees
- Performance Goals
- Office of Combination Products
- Modular PMA Reviews
- Reprocessed Single Use Devices
- Inspections by Accredited Third Parties
- Manufacturer Identification
- The Food and Drug Administration Amendment Act of 2007
- User Fees
- MDUFMA 2007 Substantial Changes
- Pediatric Device Act
- Reagan-Udall and Advisory Panels
- Clinical Trial Registry
- CDRH Organizational Structure
- Office of the Center Director (OCD)
- Office of Device Evaluation (ODE)
- Office of Compliance (OC)
- Office of Management Operations (OMO)
- Office of Surveillance and Biometrics (OSB)
- Office of Science and Engineering Laboratories (OSEL)
- Office of Communication, Education, and Radiation Programs (OCER)
- Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
CHAPTER 2 THE 510(K) PREMARKET NOTIFIFICATION PROCESS
- Premarket Notification: The Original Intent
- When Is a 510(k) Required?
- Misbranded/Adulterated Devices
- Definition of “Commercial Distribution”
- Determination of Preamendment Status
- Exemptions from Premarket Notification
- Exemptions of Generic Types of Class I Devices
- Exemptions of Generic Types of Class II Devices
- Custom Devices
- Other Exempt Devices
- Radiological Health
- Determination of Substantial Equivalence
- Congress Defines “Substantial Equivalence”
- Data Requirements for Substantial Equivalence
- Guidance Documents
- Collaborative Determinations of Device Data Requirements
- Clinical Trials
- Biocompatibility Issues
- Preclinical Testing
- Device Standards
- Guidance on the Recognition and Use of Consensus Standards
- Determination of Intended Use: Implied Intended Use and General/
- Specific Intended Use
- Regulatory Strategy Considerations
- The Format and Content of a 510(k) Notice
- Abbreviated 510(k) Notices
- Basic Content Requirements and Format for Traditional and Abbreviated
- 510(k) Notices
- Elements of a 510(k) Notice
- Medical Device User Fee Cover Sheet (Form FDA 3601)
- CDRH Premarket Review Submission Cover Sheet
- Indications for Use Statement
- 510(k) Summary or 510(k) Statement
- The 510(k) Summary
- The 510(k) Statement
- Certification of the Truthfulness and Accuracy of the 510(k) Notice
- Class III Summary and Certification
- Financial Certification or Disclosure Statement
- Declarations of Conformity and Summary Reports
- Executive Summary
- Device Description
- Substantial Equivalence Discussion
- Proposed Labeling
- Sterilization and Shelf Life
- Biocompatibility
- Software
- Electromagnetic Compatibility and Electrical Safety
- Performance Testing: Bench
- Performance Testing: Animal
- Performance Testing: Clinical
- Alternative Methods of Demonstrating Substantial Equivalence
- Special Requirements for Kit 510(k)s
- Bundling Multiple Devices or Indications in a Single Submission
- Special Requirements for Single-Use Devices
- FDA Review of 510(k) Notices
- CDRH’s Refuse to Accept 510(k) Notifications Policy
- Requests for Additional Information and Interactive Review
- Third-Party Review of 510(k)s
- Accreditation of Persons
- Third-Party Review Process
- Termination of Third-Party Review Authority
- The Advertising and Promotion of a Device Pending CDRH Clearance
- FDA Actions Regarding Premarket Notifications
- The Implications of a Finding of Substantial Equivalence
- The Implications of a Not Substantially Equivalent Finding
- Dispute Resolution
- Judicial Review of a Substantial Equivalence Determination
- 510(k) Notice Review Times
- Expedited Review
- Determining the Status of CDRH’s 510(k) Review
- Linking GMP Inspections to Product Clearances
CHAPTER 3 DEVICE MODIFIFI CATIONS REQUIRING A 510(K) NOTICE
- CDRH Policy on Device Modification
- The 510(k) Decision Flowchart
- Types of Device Modifications
- Design Creep/Changes
- Labeling Changes
- Technology/Manufacturing Changes
- Changes in a Device’s Control Mechanism
- Changes in a Device’s Operating Principle and Energy Source
- Changes in a Device’s Sterilization Method
- Changes in a Device’s Packaging
- Other Types of Changes
- Materials Changes
- Implantable Devices
- Non-Implantable Devices
- Changes to In Vitro Diagnostic Devices
- Changes to Wireless Telemetry Devices
- Changes to Recalled or Corrected Devices
- Impact of a Decision Not to File a New 510(k)
- The Special 510(k) Notice
CHAPTER 4 FDA REGULATION OF MEDICAL DEVICE SOFTWARE
- Stand-Alone Information Management Software Devices
- Software as a Component or Accessory
- Review of Software Premarket Submissions
- Reviewer Guidelines
- Establishing the Level of Concern
- Major
- Moderate
- Minor
- Documentation of the Level of Concern
- Software Description
- Device Hazard Analysis
- Software Requirements Specification (SRS)
- Traceability Analysis
- Verification, Validation, and Testing
- Results of Testing and Analysis
- Labeling
- Off-the-Shelf (OTS) Software
- Software Changes
- Telemedicine and PACS Devices
- Medical Device Software: The Future
CHAPTER 5 THE INVESTIGATIONAL DEVICE EXEMPTION APPLICATION:
- Overview of the IDE Process and Humanitarian
- Devices
- Responsibility for IDE Review
- Nonsignificant Risk Devices
- Exempted Investigations: Devices Exempted from IDE Requirements
- Preamendment Devices
- Substantially Equivalent Devices
- Diagnostic Devices
- Consumer Preference Testing
- Veterinary Use
- Laboratory Animal/Research Use
- Custom Device
- Determination of Investigational Device Risk
- Significant Risk (SR) vs. Non Significant Risk (NSR) Devices
- Selection of the IRB
- Planning for the IDE Application
- CDRH Guidances Applicable to IDEs
- The Pre-IDE Filing Meeting
- FDAMA Early Collaboration Meetings
- Agreement Meeting
- Determination Meeting
- Content of an IDE Application
- CDRH Review of the IDE Application
- CDRH’s Refuse to Accept Policy
- FDA Requests for Additional Information
- FDA Actions Regarding IDE Applications
- Confidentiality
- Reimbursement for Investigational Devices
- IDE Supplements
- IDE Applications for Feasibility Studies
- The Promotion and Commercialization of Investigational Devices
- Expanded Access to Investigational Devices
- Emergency Use
- Compassionate Use
- Treatment Use
- Continued Access
- Investigator-Sponsor Studies
- Humanitarian Devices
- Summary
CHAPTER 6 MEDICAL DEVICE CLINICAL STUDIES
- History of Medical Device Clinical Studies
- Clinical Trial Design Considerations
- Number of Clinical Investigations Required for Approval
- Developing Protocols
- Study Hypothesis
- Control Group
- Eligibility Criteria
- Assignment of Intervention
- Sample Size
- Endpoints
- Blinding (Masking)
- Comparability of Patients in Study Groups
- Other Design Considerations
- Study Data Analysis
- Study Conduct
- Good Clinical Practices
- Clinical Trials, FDAMA, and FDAAA
- FDAMA and Alternative Study Designs
- Least Burdensome Mandate and PMAs
- Least Burdensome Mandate and 510(k)s
- Clinical Trial Registry
- Responsibilities of Clinical Trial Sponsors, Investigators,
- Monitoring Groups, IRBs, and Other Study Units
- Sponsor Obligations
- Requirements for an NSR Device
- Requirements Prior to Clinical Trial
- Requirements during a Clinical Trial
- Requirements after Clinical Phase
- Recordkeeping Requirements
- Reporting Requirements
- Investigator Obligations
- Requirements Prior to Clinical Trial
- Requirements during a Clinical Trial
- Requirements after Clinical Phase
- Recordkeeping Requirements
- Reporting Requirements
- Adverse Event Reporting
- Financial Disclosure by Clinical Investigators
- The Monitoring of Clinical Studies
- Qualifications of a Study Monitor
- Monitoring Procedures
- Result of Monitoring or Failure to Monitor
- IRB Obligations
- Membership
- Functions and Operations
- Informed Consent
- Continuing Review
- Suspension of Approval
- Other Study Units
- International Clinical Studies
- Data from International Feasibility Studies
- International and U.S. Data
- Reliance on International Data as the Sole Basis for Approval
CHAPTER 7 THE PREMARKET APPROVAL APPLICATION
- Medical Devices Subject to the PMA Process
- Early Collaboration Meetings under FDAMA
- Structure of the PMA Application
- Administrative Documents
- Section 1: General Information
- Section 2: Table of Contents
- Section 3: Summary of Safety and Effectiveness Data
- Section 4: Device Description and Manufacturing
- Device Description
- Manufacturing
- Section 5: Performance Standards
- Section 6: Technical Data
- Preclinical Studies
- Clinical Studies
- Section 7: Justification for One Investigator
- Section 8: Bibliography, References, and Other Reports
- Section 9: Samples
- Section 10: Labeling
- Section 11: Environmental Assessment
- Section 12: Financial Certification or Disclosure Statement
- Common Flaws in Drafting PMAs
- Biostatistical Methodologies and Analyses Supporting PMA Approval
- Statistical and Data Presentation
- Common Deficiencies
- Patient Accountability
- Protocol Not Followed
- Hypothesis Test Not Stated or Performed
- Insufficient Justification for Pooling
- Potential Bias Not Evaluated
- Sample Size Not Justified
- The Modular PMA Review
CHAPTER 8 REVIEW OF A PREMARKET APPROVAL APPLICATION
- Overview of the PMA Review Process
- The Filing Decision
- Expedited Review of PMAs
- FDA Review of the PMA Application
- The Day-100 Meeting and Other Mid-Review Communications
- A Modular Approach to PMA Review
- The Panel Review Process
- Advisory Panel Member Selection
- Advisory Panel Procedures
- Preparing for Advisory Panel Presentations
- Providing New Information during the PMA Review Process:
- Amendments to Pending PMAs
- PMA Amendments and Resubmitted PMAs
- Voluntary Withdrawal of a PMA
- FDA Action on a PMA
- PMA Submission and Approval Times
- PMA Confidentiality during the Review Process
- Conditions of PMA Approval: Quality System Regulation (QSR)
- Inspections and Bioresearch Monitoring
- QSR Inspections
- Bioresearch Monitoring Inspections
- Postapproval Requirements
- Postmarket Surveillance Studies
- Withdrawal of a PMA Approval
- Change of PMA Ownership
CHAPTER 9 PMA SUPPLEMENTS
- When is a PMAS Necessary and What Type Should be Submitted?
- Traditional PMA
- Panel-Track Supplement
- 180-Day Supplement
- Real-Time Supplement
- Special PMA Supplement—Changes Being Effected
- The 30-Day Notice and 135-Day Supplement
- The 30-Day Supplement
- PMA Supplement—Manufacturing Site Change
- Periodic Reports (“Annual Reports”)
- The PMA Supplement Application
- Review of the PMA Supplements
- PMA Supplement Strategies
CHAPTER 10 MEDICAL DEVICE RECLASSIFIFICATION
- Reclassifi cation Standard
- The Statutory Framework
- Reclassifi cation Based on New Information
- Reclassifi cation Based on FDA’s Requirement for Performance
- Standards/Premarket Approval
- Reclassifi cation of New Devices
- Reclassifi cation of Transitional Devices Under the 1976 Amendments
- The Reclassifi cation of Preamendment Class III Devices
- Data Requirements for the Reclassifi cation Petition
- FDA’s Reclassifi cation Record, 1976-2008
- Contact Lenses
- Sutures
- Drionic Device
- Inductive Nasal Device
- Magnetic Resonance Imaging
- Ophthalmic Nd:Yag Lasers
- Automated Differential Cell Counter
- Obstetrics and Gynecology Devices
- Endosseous Dental Implants
- Pedicle Screw Spinal Systems
- Bone Sonometers
- Cutaneous Electrodes
- Intervertebral Body Fusion Devices
- Absorbable Hemostatic Agent and Dressings
- De Novo Classifi cation
- Infl uenza A IVD and Cancer Molecular Expression Test
- Conclusion
CHAPTER 11 THE REGULATION OF IN VITRO DIAGNOSTICS
- FDA Regulation of IVDs
- CBER Regulation of IVDs
- CDRH Regulation of IVDs
- Labeling of IVDs
- RUO and IUO Devices
- Labeling of Cleared/Approved IVDs
- Clinical Investigations Involving IVDs
- IVD Exemption from IDE Regulation
- IRB and Informed Consent Requirements
- Analytical Studies and Reagent Characterization
- Reagent Characterization & Interference Studies
- Performance Characteristics Testing
- Analytical Sensitivity or Limit of Detection Studies
- Precision or Reproducibility Studies
- Accuracy Studies
- Linearity Studies
- Special Topics
- Analyte Specifi c Reagents, General Purpose Reagents, and Laboratory
- Developed Tests
- IVD Automation
- CLIA Categorization and Waivers
- Personalized Medicine and Companion Diagnostics
CHAPTER 12 THE QUALITY SYSTEM REGULATION
- Scope of the QSR
- Management Responsibility
- Quality Policy
- Organization
- Management Representative
- Management Review
- Quality Planning
- Quality Procedures
- Quality Audits
- Personnel (and Training)
- Design Controls
- Design and Development Planning
- Design Inputs
- Design Outputs
- Design Verifi cation and Validation
- Design Review
- Design Transfer
- Recordkeeping
- Purchasing Controls
- Supplier Evaluation
- Supplier Control
- Recordkeeping
- Purchasing Data
- Incoming Inspection Activities
- Production and Process Controls
- Production and Process Changes
- Environmental Control
- Personnel
- Contamination Control
- Buildings
- Equipment
- Automated Processes
- Process Validation
- Monitoring
- Receiving, In-Process, and Finished Device Acceptance
- Incoming Acceptance Activities
- In-Process Acceptance Activities
- Final Acceptance Activities
- Recordkeeping Requirements
- Nonconforming Product
- Corrective and Preventive Action (CAPA)
- Device Recordkeeping
- Device Master Record
- Device History Record
- Complaint Handling
- Servicing
- Statistical Techniques
- Conclusion
CHAPTER 13 COMPLIANCE
- Establishment Registration and Device Listing
- Initial Registration and Listing
- Annual Certifi cation
- User Fees
- Updating Information
- Foreign Facilities
- Misbranding by Reference to Establishment Registration
- Medical Device Reporting
- Manufacturers and MDR Reporting Requirements
- Device Manufacturers and MDR-Reportable Events
- Time and Knowledge Requirements
- Importers and MDR Reporting Requirements
- Importers and MDR-Reportable Events
- Time and Knowledge Requirements
- User Facilities and MDR Reporting Requirements
- MDR-Reportable Events
- Time and Knowledge Requirements
- Sentinel Reporting System
- The Practical Application of the MDR
- Internal MDR Procedures
- Recordkeeping Requirements
- How and Where to File
- When Not to File
- Enforcement Actions
- Recall Policy, Procedures, and Industry Responsibilities— Reports of
- Corrections and Removals
- Voluntary Recalls
- Health Hazard Evaluations
- Recall Strategy
- Recall Classifi cation
- FDA Notice under Part 7
- Recall Communications
- Recall Status Reports
- Recall Termination
- Reporting to FDA under Part 806
- Reportability of Recalls that Occur Exclusively Outside of the U.S
- FDA Mandated Recalls
- Strategy for Compliance with Order
- Termination of Order
- Advertising and Promotion
- Regulatory Authority
- Labels, Labeling, and Intended Use
- Labels
- Labeling
- Prescription Devices
- Restricted Devices
- Intended Use and Indications for Use
- Adulteration and Misbranding Provisions Applicable to Advertising,
- Labeling, and Promotion
- Misbranding
- Misbranding and Adulteration for Lack of Clearance or Approval
- False and Misleading Statements
- General Versus Specifi c Claims
- Regulatory Status
- Comparative Claims
- Off-Label Promotion
- Off-Label Device Promotion Precedent from Drug Regulation
- Dissemination of Off-Label Scientifi c and Medical Information
- Enforcement Provisions
- Inspections
- Warning Letters and Untitled Letters
- Administrative Detention
- Recalls (Voluntary and Mandatory) I
- Application Integrity Policy (AIP)
- Injunctions, Preliminary Injunctions, and Consent Decrees
- Refusing Requests for Premarket Approval (PMA) of New Products/
- PMA Suspensions
- Civil Penalties
- Combined Civil and Criminal Actions
- Conclusion
CHAPTER 14 MEDICAL DEVICE EXPORTS AND IMPORTS
- Export of Legally Marketed Devices
- Export of Unapproved or Uncleared Devices
- Exporting Uncleared Devices Due to Lack of 510(k) Marketing
- Clearance—Section 801(e)(1)
- Exporting Medical Devices via Section 801(e)(2)
- Exporting Medical Devices via Section 802
- Exporting for Investigational Use
- Exporting for Marketing or in Anticipation of Foreign Market
- Approval
- Importing for Export
- Certifi cates of Exportability
- Certifi cates to Foreign Governments
- Certifi cates of Exportability
- Importation of Medical Devices
- Entry Requirements
- FDA Regulatory Requirements Applicable to Initial Importers
- Inter-Agency Guidance on Good Importer Practices
CHAPTER 15 PRODUCT JURISDICTION AND THE REGULATION OF
- Combination Products
- Introduction
- Combination Products
- Determining Primary Jurisdiction for a Combination Product
- FDA Intercenter Agreements
- Request for Primary Jurisdiction Designation
- Strategies for Combination Product Approval
- Single Entity Products
- Good Manufacturing Practices for Combination and Single Entity
- Products
- Conclusion
CHAPTER 16 WORKING WELL WITH FDA
- Frequent Communication
- Internal Planning for the Product Submission
- Meeting with CDRH
- Review Status Reports
- Disagreements between CDRH and the Sponsor
- Truthful and Accurate Communication
- Strategies for Successful Product Submissions
- Glossary
- Index
