PART 1: LEARNING OBJECTIVES AND FRAMEWORK

Week 4 Focus: Two Parallel Regulatory Pathways

By the end of Week 4, you will be able to:

IND Pathway (21 CFR Part 312):

• Distinguish when an IND application is required vs. exempt
• Identify required components of FDA Form 1571 (IND Application)
• Compare sponsor vs. investigator responsibilities in drug development
• Calculate safety reporting timelines (7-day vs. 15-day vs. annual)
• Apply FDA-1572 requirements for investigators
• Determine clinical hold triggers and responses

IDE Pathway (21 CFR Part 812):

• Distinguish IDE application requirements from IND requirements
• Identify IDE submission components and format requirements
• Compare device-specific sponsor obligations (manufacturing, tracking, quality)
• Understand IDE review committee vs. IRB coordination
• Calculate IDE safety reporting timelines
• Distinguish device-specific accountability requirements

Comparative Understanding:

• Map regulatory differences between 21 CFR 312 and 812
• Identify when product classification drives pathway selection
• Synthesize sponsor/investigator responsibilities across both pathways
• Apply ICH E6(R3) principles to both drug and device contexts

PART 2: REGULATORY FRAMEWORK OVERVIEW

21 CFR Part 312: IND Applications and Drug Development

Purpose and Scope (312.1)

• Governs investigational new drugs—any drug not approved for marketing
• Applies when conducting clinical investigations of unapproved drugs
• Applies to approved drugs being studied for new indications
• Requires FDA notification prior to human testing

Key Definition: IND An application submitted to FDA requesting authorization to conduct a clinical investigation of a drug. Covers all investigational uses including:

• Unapproved drugs
• Approved drugs in new therapeutic indications
• Approved drugs in new patient populations
• Approved drugs via new routes of administration

When IND Is NOT Required (312.20 - IND Exemptions)

• Pharmacy compounding for individual patient
• Educational seminars on approved drugs
• Approved drug in FDA-approved manner/indication
• Certain marketed biologics
• Emergency use of unapproved drugs (with FDA notification)
• Phase 1 studies exemption (limited circumstances)

21 CFR Part 812: IDE and Device Development

Purpose and Scope (812.1)

• Governs investigational device exemptions
• Permits marketing/distribution of investigational devices for purposes of investigation without meeting all device approval requirements
• Requires IDE application prior to human testing of non-approved/non-cleared devices
• Covers all unapproved/uncleared medical devices

Key Definition: IDE An application to FDA for investigational use of a device that is not approved or cleared for commercial distribution. IDE permits:

• Investigational use by qualified physicians
• Investigation in clinical settings meeting defined requirements
• Exemption from certain premarket approval requirements during investigation

Device Classification Context IDE requirements vary based on device risk classification:

• Class I (Low Risk): Some exemptions may apply; shorter review timelines
• Class II (Moderate Risk): Standard IDE requirements; 30-day FDA review
• Class III (High Risk): Standard IDE requirements; extensive review; potential PMA track

PART 3: IND APPLICATION REQUIREMENTS - 21 CFR 312

FDA Form 1571: IND Application Components

Required Elements of IND (312.23)

1. Cover Sheet (IND-1571)

• Sponsor name, address, contact information
• Investigator information (names, qualifications, contact)
• Drug name, pharmacological class, chemical name
• Proposed clinical indication
• Routing designation (standard vs. expedited)

2. Table of Contents

• Lists all sections and exhibits
• Page numbers for easy navigation

3. Introductory Statement and General Investigational Plan (312.23(a))

• Rationale for development and public health significance
• Phase(s) of investigation proposed
• Estimated duration of investigation
• General approach to safety monitoring

4. Previous Human Experience and Comparative Literature (312.23(b))

• Summary of all previous investigations
• Complete pharmacology, toxicology, and previous human experience data
• Chemical and pharmaceutical characteristics
• Known hazards and safety concerns

5. Chemistry, Manufacturing, and Controls (CMC) Information (312.23(c))

• Drug substance characterization
• Synthesis and manufacture procedures
• Analytical methods for identification, assay, impurities
• Stability data (storage conditions, shelf-life)
• Container/closure system
• Environmental assessment or categorical exclusion

6. Pharmacology and Toxicology (312.23(d))

• Animal pharmacology data relevant to proposed clinical indication
• Toxicology data from appropriate animal studies
• Hazard assessment summary
• Integration of nonclinical and clinical data

7. Previous Human Experience (312.23(b))

• Prior IND applications and their fates
• Published literature on the drug
• Clinical experience in other countries
• Summary of safety and efficacy findings

8. Clinical Protocol(s) and Investigator's Brochure (312.23(e))

• Complete investigator's brochure (Investigator's Brochure = FDA Form 1572 equivalent detailed)
• Protocol(s) for planned clinical investigation(s)
• Protocol amendments if multiple studies proposed

9. Chemistry and Related Information for Drug Substance and Product (312.23(f))

• Complete characterization of drug as proposed for human use
• Specifications and acceptance criteria
• Analytical procedures and validation

10. Safety Reports and Updated Information (312.23(g))

• Initial safety information
• Commitment to submit safety updates
• Commitment to notify FDA of changes

11. Case Report Forms (CRFs) (312.23(h))

• Representative CRFs for planned investigations
• Shows data collection approach

12. Literature References (312.23(i))

• All citations supporting submitted information

Timeline for IND Review

30-Day Rule (312.21)

• IND is deemed "approved" for Phase 1 study 30 days after submission if FDA does not place on Clinical Hold
• FDA may place on Clinical Hold if safety/scientific deficiencies identified
• Sponsor may commence Phase 1 after 30 days unless notified of Clinical Hold
• Critical: Clinical Hold prevents initiation of study despite lapse of 30-day period

Clinical Holds (312.42)

• FDA may place IND on hold if study poses unreasonable risks
• Circumstances include:
  • Deficient IND (incomplete information)
  • Unreasonable risks based on submitted data
  • Investigator safety violations or regulatory violations
  • Safety monitoring deficiencies
  • Drug quality issues (CMC deficiencies)
  • Sponsor failure to respond to FDA requests

Response to Clinical Hold (312.42(b))

• Sponsor receives written notice of deficiency from FDA
• Sponsor may revise IND and resubmit
• FDA provides recommendations for addressing deficiencies
• Resubmission triggers new 30-day period

IND Amendments and Updates (312.39)

Types of IND Changes Requiring Submission

1. IND Amendment (New Study Phase)

• When adding new Phase 1, 2, or 3 study
• Submit protocol and supportive information
• 30-day review period applies

2. Supplemental IND

• When adding new indication
• When changing drug manufacturer
• When changing drug formulation (significant changes)
• 30-day review period typically applies

3. Protocol Amendment

• Changes to active study(ies)
• Requires IRB review first
• Safety changes expedited by FDA

4. Toxicology/Safety Updates (312.23(g))

• New safety information
• Literature updates relevant to safety
• Must report within 15 calendar days of learning of new adverse events

IND Safety Reporting Timelines (Critical for Exam)

7-Day Reports (312.32(c)(1)) Serious, unexpected adverse events occurring during clinical investigation

Requirements:

• Must be reported within 7 calendar days of investigator learning of event
• Telephone report to FDA acceptable initially
• Written follow-up required within 7 days
• Covers: Death, life-threatening adverse events, hospitalization, disability, birth defects
• Unexpected: Not consistent with Investigator's Brochure

15-Day Reports (312.32(c)(2)) Adverse events reportable but not meeting 7-day criteria

Requirements:

• Report within 15 calendar days of sponsor learning
• Written report format
• Includes: Unexpected non-serious adverse events, suspected deaths not meeting 7-day criteria

Annual (IND Annual Report - 312.32(c)(3))

• Due within 60 days of IND anniversary date
• Comprehensive safety summary
• List of all adverse events (serious, unexpected, routine)
• Analysis of adverse event patterns
• Update on CMC, toxicology, literature

PART 4: IDE APPLICATION REQUIREMENTS - 21 CFR 812

IDE Application Components (812.20)

Submission Format and Content

1. Cover Page

• Applicant name, address, contact
• Device name, intended use, classification
• Indication for use
• Track assignment (PMA vs. 510(k) track or HDE track)

2. IDE Application Form (FDA Form 1571 - for IDE)

• Investigator information
• Study protocol summary
• Manufacturing and quality controls overview

3. Study Protocol (812.20(a)) Comprehensive document including:

• Investigational plan
• Study objectives and endpoints
• Subject selection criteria (inclusion/exclusion)
• Study design and methodology
• Monitoring for safety and effectiveness
• Statistical considerations
• Data analysis plan
• Duration of investigation

4. Investigator's Qualifications (812.20(b)(1))

• Curriculum vitae of principal investigator
• Evidence of qualifications to conduct device studies
• Institutional affiliation and access to facilities
• Financial disclosure (Form FDA 3454 or 3455)

5. Institutional Review Board Information (812.20(b)(2))

• IRB name and contact information
• IRB approved protocol (attached or reference number)
• IRB approval letter
• Committee roster documentation

6. Device Description (812.20(b)(3))

• Complete device specification
• Device drawings/diagrams
• Manufacturing and quality control procedures
• Sterility assurance (if applicable)
• Biocompatibility data
• Performance standards compliance

7. Clinical Background and Rationale (812.20(b)(4))

• Literature review supporting clinical use
• Nonclinical test data
• Prior clinical experience with device or similar devices
• Comparison to predicate devices (for 510(k) track)
• Risk analysis and mitigation strategies

8. Case Report Form (CRF) (812.20(b)(5))

• Representative CRF template
• Data collection procedures
• Subject identification codes
• Data quality assurance measures

9. Consent Form and Related Materials (812.20(b)(6))

• IRB-approved informed consent form
• Information sheet for subjects if separate
• Recruitment materials (if applicable)

10. Literature References (812.20(b)(7))

• Complete citations supporting safety/effectiveness
• Pre-clinical testing reports
• Bench testing results

11. Quality Overall Summary (812.20(b)(8))

• Device specifications verification
• Manufacturing procedures
• Quality control procedures
• Sterility assurance (if applicable)
• Risk analysis and control measures

Pre-IDE Meeting Procedures (812.20(c))

What Is a Pre-IDE Meeting?

• Optional meeting with FDA prior to IDE submission
• Sponsor requests meeting to clarify requirements
• FDA provides guidance on IDE submission content and format

Timing and Request Process

• Sponsor submits meeting request
• FDA responds within 21 days with meeting date/arrangements
• Meeting typically held within 75 days of request

Meeting Topics (Typical)

• Device classification confirmation
• Intended regulatory pathway (PMA vs. 510(k) track)
• IDE requirements and specific submission format
• Statistical considerations for study
• Safety monitoring and reporting requirements

IDE Approval Pathways (812.25, 812.26, 812.27)

Three Primary Pathways

1. Approved IDE (Formal Approval Process)

• FDA reviews IDE application
• 30-day review period
• FDA issues Acknowledgment Letter with conditions
• IDE approved if no major deficiencies
• Study may commence upon approval

2. PMA Track IDE

• Device intended for eventual PMA submission
• IDE data will support PMA application
• FDA reviews for PMA-phase appropriateness
• Study must generate data supportive of future PMA
• Longer review period (may require advisory committee)

3. 510(k) Track IDE

• Device intended for eventual 510(k) submission
• IDE data will support 510(k) predicate comparison
• Predicate device identification required
• Shorter review typically (30 days)
• Less extensive IDE approval process

4. Humanitarian Device Exemption (HDE) Track IDE (Investigational)

• Similar to IDE but for humanitarian devices
• More limited subject exposure
• Alternative pathways for rare disease/conditions

Device-Specific Sponsor Responsibilities

1. Device Manufacturing and Quality (812.3(b), 812.20(a))

• Maintain written manufacturing procedures
• Implement quality control procedures
• Ensure device meets specifications throughout study
• Document manufacturing history
• Maintain master production schedule

2. Device Tracking (812.3(c), 812.60)

• Track all investigational devices throughout study
• Maintain records of device location
• Implement device accountability measures
• Ensure device retrieval at end of study or if recalled
• Maintain tracking records for inspection

3. Manufacturing Quality Overview (812.75)

• Sponsor certifies device quality
• Provides device master specification
• Supplies test data demonstrating conformity
• Maintains Quality System Documentation

4. Device Labeling (812.3(d))

• Label must state: "CAUTION: Investigational Device. Federal law restricts this device to investigational use"
• Ensure labeling not misleading
• Include proper instructions for use
• Provide investigator instructions clearly

PART 5: SPONSOR RESPONSIBILITIES COMPARISON

IND Sponsor Responsibilities (21 CFR 312.50-312.80)

Core Obligations

1. Regulatory Submissions and Communication (312.50)

• Submit IND application and all amendments to FDA
• Maintain communication with FDA
• Respond to FDA requests within specified timeframes
• Update FDA on study progress annually
• Notify FDA of clinical hold responses

2. Safety Monitoring and Reporting (312.32)

• Establish adverse event monitoring system
• Implement safety tracking procedures
• Report serious adverse events to FDA within 7 days
• Report other adverse events within 15 days
• Provide annual safety summaries

3. Protocol Review and Approval (312.30)

• Ensure all protocols submitted to IRB before initiation
• Ensure written IRB approval obtained
• Ensure protocols include informed consent procedures
• Modify protocols only after IRB review
• Maintain documentation of IRB actions

4. Investigator Selection and Oversight (312.52)

• Ensure investigator qualifications documented
• Provide current resume/CV for each investigator
• Ensure investigator submits FDA Form 1572
• Monitor investigator performance
• Ensure investigator compliance with protocol and regulations
• Terminate investigator if non-compliance identified

5. Drug Supply Management (312.50(a))

• Ensure adequate, appropriate, and properly labeled drug supply
• Maintain inventory records
• Ensure stability data current
• Control access to investigational drug
• Implement accountability system for drug distribution

6. Case Report Form (CRF) Management (312.50(a))

• Develop clear, comprehensive CRF
• Ensure investigator training on CRF completion
• Review CRF data for completeness and accuracy
• Query investigators regarding missing/inconsistent data
• Archive complete CRF records

7. Record Retention (312.57 and 312.58)

• Duration: Retain IND records for minimum 2 years after marketing approval or clinical hold
• If no marketing approval: Retain for minimum of 1 year after termination of investigation
• Records include: IND application, protocols, safety reports, correspondence, CRFs, lab data
• Location: Records must be maintained at sponsor's principal place of business or data archive

8. CRO Delegation and Oversight (312.50(b))

• May delegate functions to CRO (Contract Research Organization)
• Sponsor retains ultimate responsibility for accuracy and integrity of data
• CRO must maintain records as if sponsor
• Sponsor remains liable for CRO violations
• Written agreements specify roles and responsibilities
• Regular audits of CRO performance required

9. Quality Assurance and Regulatory Compliance (312.75)

• Implement QA procedures for all aspects of investigation
• Regular monitoring of investigator conduct
• Regular review of safety data
• Compliance with current GCP (ICH E6(R3))
• Regular communication with IRB on safety issues

IDE Sponsor Responsibilities (21 CFR 812.3, 812.50)

Core Obligations - Device-Specific

1. IDE Submission and FDA Communication (812.3(a), 812.50)

• Submit IDE application per 812.20
• Respond to FDA IDE Advisory Committee meetings if requested
• Submit IDE amendments for protocol changes
• Notify FDA of safety issues
• Maintain correspondence with FDA IDE reviewer

2. Device Manufacturing Control (812.75, 812.3(b))

• Establish manufacturing control procedures
• Implement Quality System (QS) requirements applicable to investigation
• Maintain device specifications and performance standards
• Control changes to device or manufacturing process
• Implement process validation
• Control device labeling and packaging
• Maintain manufacturing records throughout investigation

3. Device Tracking (812.60 - Critical IDE Requirement)

• Requirement: For devices with risk of serious harm if malfunctioning
• Implementation: Unique identifier for each device
• Tracking: Record of each device from manufacture through:
  • Investigator receipt
  • Subject implantation/use
  • Subject discharge from investigation
  • Device explanation/removal (if applicable)
  • Device return or destruction
• Records: Sponsor maintains master tracking log
• FDA Inspection: FDA may audit tracking records

4. Device-Specific Quality Monitoring (812.3(c))

• Monitor device performance during investigation
• Identify and track device malfunctions
• Assess device design changes if performance issues
• Control any manufacturing changes
• Monitor biocompatibility (if applicable)
• Implement supplier controls for device components

5. IRB Coordination and IDE Review Committee (812.3(d), 812.50(a)(1))

• Ensure IRB review before study initiation
• Maintain communication with IRB chair
• Provide IRB with safety reports promptly
• Coordinate with IDE Review Committee if applicable
• Ensure IRB maintains current IDE information

6. Investigator Selection and Oversight (812.50(a))

• Select qualified investigators
• Verify investigator qualifications
• Ensure investigator submits appropriate forms
• Monitor investigator performance and protocol compliance
• Provide investigator training on device
• Terminate investigator if safety violations
• Document investigator actions throughout study

7. Device Supply and Accountability (812.3(a), 812.50(a)(3))

• Ensure adequate device supply
• Properly label investigational devices
• Implement device accountability system
• Ensure investigator training on device use
• Retrieve unused devices at study end
• Document device disposition

8. Safety Reporting - Devices (812.46)

• Establish system for tracking adverse events
• Report unexpected adverse events to FDA
• Report to IRB within timeframes specified
• Implement corrective actions if safety issues
• Maintain safety log for FDA inspection

9. Record Retention - Devices (812.140)

• Duration: Minimum 2 years after marketing approval or study termination
• Content: IDE application, protocols, safety reports, tracking records, CRFs, device specs
• Location: At sponsor's location or archival facility
• Availability: Must be producible for FDA inspection within 48 hours

10. CRO Delegation for Devices (812.50(a))

• Similar to IND requirements
• CRO must maintain device tracking records
• CRO must comply with QS regulations
• CRO conducts device monitoring activities
• Sponsor performs regular audits of CRO performance
• Written agreement specifies responsibilities

PART 6: INVESTIGATOR RESPONSIBILITIES COMPARISON

IND Investigator Responsibilities (21 CFR 312.60-312.70)

FDA Form 1572: IND Investigator's Brochure

Purpose: Certifies investigator qualifications and commitment to conduct study per protocol and regulations

Required Information (312.23(a)(4) and 312.60)

• Name, address, contact information
• Qualifications: CV, training, experience
• Current curriculum vitae (at least 2 years of investigative background)
• IRB where research conducted
• Commitment to comply with protocol
• Commitment to comply with 21 CFR Part 312
• Commitment to comply with informed consent requirements
• Commitment to comply with IND safety monitoring
• List of concurrent investigations in which investigator participates

Core IND Investigator Obligations

1. Protocol Adherence (312.60)

• Conduct investigation per approved protocol
• Seek IRB modification for any protocol changes
• Document reasons for protocol deviations
• Cease investigational drug if unacceptable adverse events

2. Drug Accountability (312.62)

• Receive investigational drug only from authorized sponsor/CRO
• Use drug only for enrolled subjects
• Maintain records of drug receipt and dispensing
• Account for all drug inventory (used and unused)
• Return unused drug to sponsor at study completion
• Maintain drug storage logs (temperature, expiration)
• Ensure proper drug labeling and security

3. Adverse Event Reporting to Sponsor (312.64)

• Report serious adverse events to sponsor immediately or within 24 hours
• Report unexpected adverse events to sponsor within specific timeframe
• Provide written reports with all relevant clinical details
• Identify relationship between adverse event and investigational drug
• Update reports if additional information becomes available

4. Informed Consent (312.61)

• Obtain informed consent BEFORE subject enrollment
• Provide Institutional Review Board-approved consent form
• Ensure subject understands risks and benefits
• Document informed consent (signed consent form)
• Obtain additional consent if protocol modified
• Maintain subject's copy of consent form and investigator's copy in records

5. Case Report Form (CRF) Accuracy (312.62(b))

• Complete CRF entries clearly and accurately
• Use specified units and terminology
• Respond to sponsor queries about missing/inconsistent data
• Maintain source documentation supporting CRF entries
• Sign and date all CRF pages
• Maintain CRF records for minimum 2 years after study

6. Subject Safety Monitoring (312.60(b))

• Assess subject eligibility per protocol inclusion/exclusion criteria
• Monitor subjects during investigation
• Identify and report adverse events
• Implement stopping rules if applicable
• Withdraw subjects if safety concerns
• Maintain subject safety throughout study

7. Financial Disclosure (312.54)

• FDA Form 3454 or 3455 (Financial Disclosure Form)
• Disclose significant financial interests:
  • Compensation from sponsor >$25,000 in past 12 months
  • Equity interest in sponsor company
  • Royalty interests related to drug
  • Stock options in sponsor
• Submit form with IND application
• Update form if financial status changes
• Maintain records of disclosures

8. IRB Coordination (312.66)

• Notify IRB of adverse events per 21 CFR Part 56 requirements
• Notify IRB of protocol modifications
• Maintain communication with IRB chair
• Participate in IRB continuing reviews
• Cease research if IRB suspends approval

9. Record Retention (312.62(a) and 312.62(b))

• Maintain subject records documenting:
  • Informed consent
  • Protocol eligibility assessment
  • Baseline characteristics
  • All clinical observations
  • Adverse events
  • Drugs received and dispensed
  • Subject disposition
• Retention Period: Minimum 2 years after IND termination or 5 years after final adverse event report, whichever is later
• Availability: Must be available for FDA inspection

IDE Investigator Responsibilities (21 CFR 812.100-812.140)

IDE Investigator Obligations - Device-Specific

Core Differences from IND Investigator Role

1. Device Accountability (812.100(a))

• Receive device only from sponsor
• Use device only for enrolled subjects
• Maintain device inventory records
• Track device receipt, implantation/use, and disposition
• Account for all devices (used and implanted or explanted)
• Return unused devices to sponsor
• Maintain device records including serial numbers
• Document device performance during investigation

2. Informed Consent (812.100(b))

• Obtain informed consent before subject enrollment
• Provide IRB-approved informed consent form
• Ensure subject understands device risks and benefits
• Document informed consent with signed form
• Maintain consent documentation in subject records
• Re-consent subjects if protocol modifications affect risks

3. Subject Safety Assessment (812.100(c))

• Assess subject eligibility per protocol criteria
• Monitor subject response to device
• Identify device malfunctions or performance issues
• Report device problems to sponsor immediately
• Withdraw subjects if device safety issues
• Maintain subject safety logs

4. Adverse Event Reporting - Devices (812.100(d))

• Report device-related adverse events to sponsor
• Report device malfunctions (even if no adverse event)
• Report expected vs. unexpected events
• Use specified device adverse event categories:
  • Death related to device
  • Serious injury/illness related to device
  • Device malfunction that could cause serious injury
  • Expected performance issue vs. unexpected failure
• Timeline: Serious events within 24 hours; other events within specified timeframe

5. Case Report Form (CRF) Completion (812.100(e))

• Complete CRF with accurate device performance data
• Document device identification and serial number
• Record implantation/use details
• Describe device performance observations
• Document any device modifications or adjustments
• Maintain CRF consistency with subject records

6. Financial Disclosure (812.100(f))

• Complete financial disclosure form
• Disclose significant financial interest in sponsor
• Update form if financial status changes
• Forms filed with IDE sponsor

7. IRB Coordination for Devices (812.100(g))

• Notify IRB of adverse events per 21 CFR Part 56
• Notify IRB of device malfunctions
• Participate in IRB continuing reviews
• Cease research if IRB suspends approval
• Communicate with IDE Review Committee (if applicable)

8. Subject Records (812.100(h))

• Maintain subject records documenting:
  • Informed consent
  • Device receipt and implantation/use
  • Device serial number
  • Subject assessment data
  • Adverse events and device performance
  • Subject follow-up observations
  • Device removal or return
• Retention: Per sponsor records requirements (typically 2 years post-study)

9. Accountability and Record Review (812.100(i))

• Allow sponsor access to subject records for monitoring
• Cooperate with sponsor data audits
• Maintain records available for FDA inspection
• Provide accurate, timely information to sponsor

PART 7: SAFETY REPORTING TIMELINES - THE CRITICAL COMPARISON

IND Safety Reporting Timeline Reference (312.32)

Serious Unexpected Adverse Events: 7-Day Reports

Definition Criteria (Must Meet ALL)

1. Serious: Causes death, life-threatening condition, hospitalization, persistent/permanent disability, or congenital anomaly
2. Unexpected: Not consistent with Investigator's Brochure description
3. Possibly Related: Reasonable possibility that event caused by investigational drug

Timeline:

• FDA notification within 7 calendar days of sponsor awareness
• Initial report by telephone acceptable
• Written follow-up within 7 days of initial report

Content Requirements

• Investigator name
• Subject identifier
• Event description and dates
• Assessment of drug relationship
• Previous similar events
• Regulatory actions taken (e.g., dose reduction, subject withdrawal)
• Updated risk/benefit assessment

Route

• FDA Division responsible for IND review
• Emergency contact numbers provided in IND approval letter

Other Adverse Events: 15-Day Reports

Definition Criteria

1. Unexpected adverse events (serious or non-serious)
2. Serious adverse events considered possibly related but expected
3. Any adverse event pattern suggesting new risk

Timeline

• FDA notification within 15 calendar days of sponsor awareness
• Written report format
• Can be cumulative (multiple events in one report)

Content Requirements

• Subject information
• Event descriptions and timing
• Drug relationship assessment
• Previously reported similar events
• Current safety monitoring status
• Recommendation for protocol continuation or modification

Annual IND Safety Report (312.32(c)(3))

Timing: Due within 60 calendar days of IND anniversary

Content Requirements

• Comprehensive adverse event summary
• Listing of all adverse events (serious, unexpected, routine)
• Comparative analysis: observed vs. expected event rates
• Safety data from new animal/laboratory studies
• Literature citations of new safety information
• CMC changes and updated stability data
• Regulatory actions or clinical holds
• Estimated completion timeline
• Updated risk/benefit assessment

IDE Safety Reporting Timeline Reference (812.46)

Serious Adverse Event (SAE) Reports

Definition Criteria for IDE

• Death of a subject regardless of relationship to device
• Serious injury or illness related to device
• Device malfunction that could cause serious injury if device failed

Unexpected SAE Timeline

• Sponsor reports to FDA within 10 business days of learning
• Written report required
• Telephone pre-notification acceptable for emergency situations

Expected SAE Timeline

• Sponsor reports to FDA within 15 calendar days
• Written report documenting expectedness rationale
• Included in cumulative safety report

Device Malfunction Reports

Definition: Device failure that:

• Does not result in adverse event BUT
• Could cause serious injury if repeated or if failure occurs in different manner

Timeline

• 5 calendar days from discovery if malfunction could contribute to serious injury
• 15 calendar days for other malfunctions
• Written report required

Content

• Device identification and serial number
• Description of malfunction
• Explanation of potential consequences
• Corrective actions taken
• Subject outcome

IDE Periodic Safety Reports

Timing: As specified in approved IDE protocol or FDA request

Typical Frequency

• Quarterly for high-risk devices
• Semi-annually or annually for lower-risk devices
• More frequent if safety issues identified

Content

• Summary of adverse events (serious and non-serious)
• Device malfunction summary
• Device performance analysis
• Updated safety assessment
• Comparison to predicate device safety data (if applicable)
• Regulatory actions taken

IDE Annual Report (812.46(c)(2))

Timing: Within 60 calendar days of IDE anniversary

Content

• Complete list of adverse events
• Comparative analysis: observed vs. expected
• Device performance data
• Manufacturing quality issues (if any)
• Regulatory actions
• Study completion status
• Updated risk/benefit assessment

PART 8: INVESTIGATOR OBLIGATIONS FORMS AND REQUIREMENTS

FDA Form 1572 (IND) - Detailed Requirements

Section 1: Investigator Information

• Name, title, institution
• Address and contact information
• Professional license/certification numbers

Section 2: Qualifications

• Education: Degrees, institutions, dates
• Training: Postdoctoral training, clinical fellowship
• Professional Experience: Years in current position, research experience
• Concurrent research activities: List of other studies investigator conducting

Section 3: Commitment Statements (Mandatory Certifications)

Investigator attests to:

1. "I will conduct the investigation according to the protocol and will perform only those procedures described in the protocol."
2. "I will not deviate from the protocol without IRB approval except when necessary to protect the health and safety of subjects."
3. "I have the qualifications to conduct the investigation described in the protocol."
4. "I will ensure informed consent is obtained from subjects."
5. "I will report adverse events according to FDA and IND requirements."
6. "I will maintain accurate case report forms and records."
7. "I will comply with 21 CFR Part 312."

Section 4: Commitment to IRB Review

• IRB name and address where protocol will be reviewed
• Commitment to notify IRB of protocol modifications
• Commitment to cease research if IRB suspends approval

Section 5: Financial Disclosure

• Certification of submitted FDA Form 3454 or 3455
• Disclosure of financial interests in sponsor company
• Affirmation that no undisclosed conflicts exist

Section 6: Curriculum Vitae Attachment

• Summary document (minimum 2 years of investigative background)
• Education and training
• Professional experience
• Publications in relevant field
• Professional certifications

IDE Investigator Obligations (Alternative to 1572)

IDE Studies Do Not Use FDA 1572 - Instead:

IDE Investigator Forms (812.100)

• Curriculum vitae (similar format to 1572 CV requirements)
• Statement of qualifications specific to device investigation
• Commitment to protocol adherence
• Commitment to regulatory compliance
• Financial disclosure form

Key Differences from IND 1572

• More emphasis on device-specific expertise
• Manufacturing quality understanding (for implantable devices)
• Device performance monitoring skills
• Less emphasis on pharmacology background
• More emphasis on clinical device handling

PART 9: IRB COORDINATION AND DEVICE-SPECIFIC OVERSIGHT

IRB Requirements for IND (21 CFR 56 Context - From Uploaded Materials)

IRB Approval Requirements (56.111) From your uploaded 21 CFR 56 materials, IRBs must find:

• Risks minimized through sound research design
• Informed consent appropriately sought
• Selection of subjects equitable
• Informed consent documentation adequate
• Monitoring for safety adequate
• Risk/benefit ratio acceptable
• Privacy/confidentiality protected

For IND Studies Specifically

• IRB reviews protocol per above criteria
• IRB reviews Investigator's Brochure
• IRB approves informed consent form
• IRB conducts continuing reviews at least annually
• IRB maintains documentation of approvals and modifications

IDE Review Committee and Device-Specific Oversight (812.21 - 812.27)

IDE Review Committee (Not IRB)

Composition (812.21)

• IDE Review Committee established by IDE sponsor
• Members selected based on device risk and expertise
• Typically includes:
  • Clinicians with device expertise
  • Biomedical engineers
  • Manufacturing specialists
  • Clinical safety experts
  • Statistical specialists

Function (812.21(a), 812.21(b))

• Review device design specifications
• Assess manufacturing quality controls
• Review device performance monitoring procedures
• Assess adequacy of safety monitoring
• Review adverse event tracking procedures
• Ensure device tracking compliance
• Oversee device accountability throughout study

Relationship to IRB (812.25(c))

• IDE Review Committee reviews device technical aspects
• IRB reviews human subject protection aspects (per 21 CFR 56)
• Both committees must approve IDE study before initiation
• IDE Review Committee and IRB may coordinate on overlapping issues

IDE Review Committee vs. IRB - Clear Delineation

PART 10: ICH E6(R3) ENHANCED SPONSOR OVERSIGHT

New Requirements Effective December 2024 (Affects Both IND and IDE)

1. Quality Assurance Enhancement (QA/QC Oversight)

• Sponsor implements enhanced quality oversight for both drug manufacturing and device manufacturing
• Risk-based approach: More oversight for higher-risk products
• Regular audits of manufacturing facilities
• Quarterly quality reviews instead of annual for high-risk drugs/devices

2. Risk-Based Monitoring Approach

• Adaptive monitoring plans that adjust based on ongoing safety data
• For IND: More frequent safety reviews if adverse event rate increasing
• For IDE: Enhanced device performance monitoring if malfunction patterns emerge
• Sponsor may reduce monitoring frequency if safety profile stable and well-characterized

3. Enhanced Safety Reporting

• Sponsors expected to implement automated adverse event tracking systems
• Real-time dashboard monitoring for both drug and device safety
• Predictive analytics for emerging safety signals
• More frequent communication with FDA for emerging issues (not waiting for standard reporting timelines)

4. Investigator Training and Oversight

• Enhanced investigator training requirements
• Documentation of investigator competency
• Regular interaction between sponsor and investigator (not just at routine visits)
• Escalated oversight for new or underperforming investigators

5. Data Integrity and Records Management

• Enhanced requirements for electronic data capture
• Audit trail requirements for all CRF modifications
• Cybersecurity requirements for data systems
• Enhanced archival and records management

6. Sponsor-IRB/IDE Review Committee Communication

• More frequent communication on emerging safety issues
• Proactive reporting of safety signals (not waiting for reporting deadlines)
• Collaborative approach to risk assessment and management

PART 11: KEY REGULATORY CITATIONS REFERENCE

IND Regulations (21 CFR Part 312) - Quick Reference

Application and Exemptions

• 312.20 - When IND not required
• 312.21 - IND Application required; 30-day review rule
• 312.23 - Content of IND application

Safety Reporting

• 312.32(c) - IND safety reporting timelines (7-day, 15-day, annual)
• 312.42 - Clinical holds and response procedures

Sponsor Responsibilities

• 312.50 - Sponsor general responsibilities
• 312.52 - Investigator selection and oversight
• 312.57-312.58 - Record retention (2 years post-approval or 1 year post-termination)
• 312.75 - Quality Assurance requirements

Investigator Responsibilities

• 312.60 - Investigator responsibilities and protocols
• 312.62 - Drug accountability and CRF accuracy
• 312.64 - Investigator reporting of adverse events
• 312.66 - IRB coordination

Forms

• FDA 1571 - IND Application Cover Sheet
• FDA 1572 - Investigator's Brochure

IDE Regulations (21 CFR Part 812) - Quick Reference

Application Requirements

• 812.1 - Scope and applicability
• 812.20 - IDE application content
• 812.21 - IDE Review Committee formation
• 812.25-812.27 - IDE approval and conditional approval

Sponsor Responsibilities

• 812.3 - Sponsor general responsibilities
• 812.50 - Specific sponsor obligations
• 812.60 - Device tracking requirements
• 812.75 - Manufacturing controls and quality
• 812.140 - Record retention (2 years post-study or as required)

Investigator Responsibilities

• 812.100 - Investigator responsibilities and obligations
• 812.110 - IRB review and coordination (cross-reference to 21 CFR 56)

Safety Reporting

• 812.46 - IDE safety reporting requirements and timelines

Forms

• FDA 3454/3455 - Financial Disclosure
• Device-specific forms as required by IDE sponsor

PART 12: STUDY TOOLS AND QUICK REFERENCE

The "IND vs. IDE" Quick Decision Tree

Is the Product Being Investigated FDA-Regulated?
├─ NO → Neither IND nor IDE required; check other regulations
└─ YES → Continue

Is it a DRUG (including biologics, vaccines)?
├─ YES → Continue to IND pathway
│   ├─ Is drug approved for marketed use in proposed indication/population?
│   │   ├─ YES → Is protocol using approved use? 
│   │   │   ├─ YES → IND may not be required (check exemptions at 312.20)
│   │   │   └─ NO → IND Required
│   │   └─ NO → IND Required
│   └─ Submit FDA 1571 and FDA 1572 (investigator)
│
└─ Is it a MEDICAL DEVICE?
    └─ YES → Continue to IDE pathway
        ├─ Is device approved (PMA) or cleared (510(k))?
        │   ├─ YES → Is protocol using approved/cleared device?
        │   │   ├─ YES → IDE may not be required
        │   │   └─ NO → IDE Required
        │   └─ NO → IDE Required
        └─ Submit IDE application and device-specific forms

Timeline Calculation Practice Framework

IND 7-Day Report Timeline

• Start Point: Sponsor becomes aware of serious, unexpected adverse event
• Day 0 = Day event reported to sponsor
• Deadline: 7 calendar days from Day 0
• Method: Telephone + written follow-up acceptable
• Failure to report: Potential clinical hold

IND 15-Day Report Timeline

• Start Point: Sponsor becomes aware of other reportable adverse event
• Deadline: 15 calendar days from date of sponsor awareness
• Method: Written report only
• Cumulative: Can report multiple events in single submission

IDE UADE 10 Business Day Report Timeline

• Start Point: Sponsor becomes aware of serious unexpected adverse event
• Deadline: 10 business days from date of sponsor awareness
• Note: Business days = Mon-Fri (excludes federal holidays)

IDE 5 business Day Report Timeline

• IRB Termination
• FDA Termination
• Emergency Use
• Failure to Consent

Key Definitions Checklist

IND Key Terms

• Clinical Hold: FDA prohibition on initiating/continuing clinical investigation
• Serious Adverse Event: Death, life-threatening, hospitalization, disability, birth defect
• Unexpected Adverse Event: Not consistent with Investigator's Brochure
• Investigator's Brochure: Summary of pharmacology, toxicology, and prior human experience
• CRF: Case Report Form for subject data collection

IDE Key Terms

• Device Malfunction: Device failure with potential for serious injury
• Investigational Device: Device not approved/cleared for commercial distribution
• Device Tracking: Record of device from manufacture through study completion
• Serious Adverse Event: Related to device, causing death/serious injury/illness
• Predicate Device: Approved/cleared device used for 510(k) comparison

PART 13: COMMON EXAM SCENARIOS AND PITFALLS

Scenario 1: The Clinical Hold Confusion

Exam Question: "A sponsor receives an adverse event report and submits a 15-day safety report to FDA. The FDA reviews the report and determines the IND should be on clinical hold. When does the clinical hold take effect?"

Common Student Error: "The clinical hold takes effect on day 15 when the sponsor's report deadline passes."

Correct Answer: "The clinical hold takes effect when FDA issues the written clinical hold notification to the sponsor, not based on the safety report deadline. FDA has independent authority to place an IND on clinical hold at any time if safety/scientific deficiencies identified. The 30-day rule means studies can proceed after 30 days UNLESS FDA places on hold; the hold can occur before, during, or after the 30-day period."

Regulatory Citation: 21 CFR 312.42

Scenario 2: IND vs. IDE Form Confusion

Exam Question: "An IDE investigator is enrolling subjects in a device study. Which form must be submitted to FDA?"

Common Student Error: "FDA Form 1572 (Investigator's Brochure)"

Correct Answer: "IDE studies do NOT use FDA 1572. Instead, investigator submits curriculum vitae and qualifications statement directly to sponsor. FDA 1572 is drug-specific (IND). For IDE, the sponsor includes investigator qualifications in the IDE application."

Key Learning: Forms are pathway-specific. Don't mix IND and IDE paperwork.

Scenario 3: Device Tracking Requirement Scope

Exam Question: "A sponsor is conducting an IDE for a non-implantable cardiac monitoring device. Is device tracking required?"

Common Student Error: "Device tracking is required for all IDE investigations."

Correct Answer: "Device tracking is required ONLY for devices with potential risk of serious harm if malfunctioning (21 CFR 812.60). For non-implantable diagnostic devices with low malfunction risk, tracking may not be required. However, sponsor must still maintain inventory and accountability records."

Regulatory Citation: 21 CFR 812.60

Scenario 4: Safety Reporting Timeline Trap

Exam Question: "A sponsor learns of a serious adverse event on Wednesday. When is the 7-day report deadline?"

Correct Calculation:

• Day 0 (Wednesday) = day sponsor learned of event
• Days 1-7 counting forward: Thu, Fri, Sat, Sun, Mon, Tue, Wed
• Deadline: Next Wednesday (7 calendar days)

Common Student Error: "Deadline is the following Tuesday" (counting only 5 business days)

Key Learning: IND timelines use calendar days, not business days. IDE uses business days for 3-day reports.

PART 14: QUICK REFERENCE TABLES

Sponsor Responsibility Comparison: IND vs. IDE

Investigator Responsibility Comparison: IND vs. IDE

Safety Reporting Timeline Comparison: IND vs. IDE

1. SUSAR (Suspected Adverse Reaction): An adverse event that is (1) Serious, (2) Unexpected (not in the Investigator's Brochure), and (3) has a reasonable possibility of being caused by the drug ($21\text{ CFR }312.32$).
2. UADE (Unanticipated Adverse Device Effect): Any serious adverse effect on health or safety, life-threatening problem, or death caused by or associated with a device, if that effect was (1) not previously identified in nature, severity, or degree of incidence in the investigational plan or application, or (2) not anticipated in light of the known characteristics of the device ($21\text{ CFR }812.3(\text{s})$).

PART 15: EXAM READINESS CHECKLIST

By the end of Week 4, you should:

IND Knowledge (21 CFR 312)

• Identify when IND application required vs. exempt
• List FDA 1571 application components (12 sections)
• Explain 30-day rule and clinical hold authority
• Calculate 7-day, 15-day, and annual report timelines
• Distinguish sponsor vs. investigator responsibilities
• Complete FDA 1572 requirements from memory
• Identify IND safety reporting criteria (serious, unexpected, possibly related)

IDE Knowledge (21 CFR 812)

• Identify IDE submission components
• Explain IDE Review Committee vs. IRB roles
• Describe device tracking requirements
• Calculate IDE safety reporting timelines
• Compare device-specific vs. drug-specific sponsor obligations
• Identify device-specific investigator obligations
• Explain manufacturing quality oversight for devices

Comparative Understanding

• Map regulatory pathway selection (drug vs. device)
• Distinguish timeline calculations between pathways
• Explain form and documentation differences
• Apply ICH E6(R3) principles to both pathways
• Identify when clinical hold vs. IDE suspension applies

Conclusion: Bridge to Domain 1 Cumulative Review

Week 4 completes your Domain 1 foundational knowledge (Weeks 2-4):

Domain 1 Cumulative Assessment (Week 5):

• 100 questions spanning all three weeks
• Mix of IND and IDE scenarios
• High-yield safety reporting calculations
• Sponsor/investigator responsibility sorting
• Clinical hold and IDE suspension application

Preparation Strategy:

• Use Week 4 flashcards for daily review
• Practice timeline calculations until automatic
• Study comparison tables (IND vs. IDE) for pattern recognition
• Annotate 21 CFR 312 and 812 with highlighter system
• Discuss confusing scenarios in office hours

End of Comprehensive Learning Materials

Next Steps: Review Week 4 presentation slides, complete interactive activities, take Weekly Quiz #3, and practice timeline calculations.