Medical Device Development: Regulation and Law, All New Edition!

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