Regulatory Frameworks, Sponsor and Investigator Responsibilities for Clinical Research Professionals

Summary

This comprehensive study guide provides clinical research professionals transitioning from implementation science to IND/IDE regulatory frameworks with a complete examination of 21 CFR Part 312 (Investigational New Drug Applications) and 21 CFR Part 812 (Investigational Device Exemptions). The FDA regulates investigational drugs and devices through parallel but distinct regulatory pathways—INDs for pharmaceutical products and IDEs for medical devices—each with specific sponsor and investigator responsibilities that form the backbone of compliant clinical research. Understanding these frameworks is critical for the SOCRA CCRP exam, where 25-30% of regulatory questions focus on IND/IDE requirements, safety reporting timelines, and responsibility attribution.

The regulations establish a three-tier protection system. For drugs, all investigational use requires an IND that becomes effective 30 days after FDA receipt unless placed on clinical hold. For devices, the system is risk-based: exempt studies require no IDE, non-significant risk (NSR) devices need only IRB approval, while significant risk (SR) devices require both FDA and IRB approval before initiation. This fundamental difference—FDA review for all drugs versus risk-stratified device review—drives distinct procedural requirements throughout the investigation lifecycle.

Key distinctions critical for exam success include: sponsor responsibilities cannot be delegated despite CRO transfer (ultimate accountability remains), investigator obligations are formalized through FDA Form 1572 for INDs versus investigator agreements for IDEs, safety reporting uses calendar days for INDs (7-day and 15-day reports) versus working days for IDEs (10-working-day reports), and record retention requires maintaining documentation for 2 years after marketing approval or investigation discontinuation. This guide provides regulatory citation-level detail, decision trees, practice questions, and exam strategies to master these complex requirements.

Section 1: IND Regulatory Framework (21 CFR Part 312)

1.1 Purpose and Scope of 21 CFR Part 312

The Investigational New Drug (IND) regulations in 21 CFR Part 312 govern the introduction of investigational drugs into interstate commerce and establish requirements for conducting clinical investigations. An IND application is required before an investigational drug can be shipped across state lines or administered to human subjects for research purposes (with specific exemptions detailed in §312.2(b)).

Key Regulatory Principle: The IND becomes effective 30 days after FDA receipt unless FDA places the investigation on clinical hold. This "30-day rule" allows FDA to review sponsor submissions for safety concerns, protocol deficiencies, or inadequate investigator qualifications before human subject exposure begins.

1.2 IND Application Requirements (21 CFR 312.23)

Complete IND Application Content

A complete IND application must contain the following components in the order specified:

1. Cover Sheet (Form FDA-1571) The IND Application Cover Sheet serves as the primary submission document and includes:

2. Table of Contents Detailed index of all materials included in the IND submission

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

Introductory Statement Components:

General Investigational Plan:

4. Investigator's Brochure (§312.23(a)(5))

Required contents per §312.55:

The Investigator's Brochure must be updated with new and significant information as it becomes available.

5. Clinical Protocol (§312.23(a)(6))

For Phase 1 Investigations:

For Phase 2 and Phase 3: Detailed protocol or protocol outline including:

(a) Study Objectives and Purpose

(b) Investigator Data

(c) Patient Selection Criteria

(d) Study Design

(e) Clinical Procedures

(f) Investigational Product Information

(g) Directions for Reconstitution (if applicable)

(h) Drug Accountability Procedures

(i) Protocol Modifications

(j) Adverse Event Definitions and Reporting Procedures

(k) Statistical Considerations

6. Chemistry, Manufacturing, and Controls (CMC) Information (§312.23(a)(7))

Drug Substance:

Drug Product:

Placebo (if used):

Labeling:

Environmental Analysis:

Phase-Specific CMC Requirements: The amount and detail of CMC information varies by development phase:

7. Pharmacology and Toxicology Information (§312.23(a)(8))

Pharmacology:

Toxicology:

GLP Compliance: Statement that nonclinical laboratory studies were conducted in compliance with 21 CFR Part 58 (Good Laboratory Practice), or if not, explanation of reason for noncompliance.

8. Previous Human Experience (§312.23(a)(9))

9. Additional Information (§312.23(a)(10))

10. Relevant Information Any other relevant information FDA may request

1.3 FDA Form 1571: IND Application Cover Sheet

Form FDA-1571 is the required cover sheet for all IND submissions including initial applications, amendments, safety reports, and annual reports. Every submission under an IND must be accompanied by a completed Form 1571.

Section-by-Section Breakdown:

Item 1: Name of sponsor (person or entity responsible for IND)

Item 2: Date of submission

Item 3: Address of sponsor (street, city, state, ZIP, country, telephone)

Item 4: Person(s) responsible for monitoring conduct and progress of investigations (name, title, address, telephone)

Item 5: Person(s) responsible for review and evaluation of safety information (name, title, address, telephone)

Item 6: Name and address of contract research organization (if applicable)

Item 7: IND number (if previously assigned; leave blank for new IND)

Item 8: Name of drug (generic and trade name if available)

Item 9: Drug indication(s) being investigated

Item 10: Phase(s) of clinical investigation to be conducted (check all that apply):

Item 11: List of contents of submission (check all that apply):

Item 12-17: Contents of application or submission detailed

Item 18: Sponsor commitments (signature line)

By signing, sponsor commits to:

  1. Not begin clinical investigations until 30 days after FDA receipt (unless notified FDA authorization earlier)
  2. Not begin or continue clinical investigations if clinical hold ordered
  3. IRB review and approval will be obtained per 21 CFR Part 56
  4. Informed consent will be obtained per 21 CFR Part 50
  5. Notify FDA immediately of any serious and unexpected adverse experiences per 21 CFR 312.32
  6. Comply with all other IND requirements per 21 CFR Part 312

Item 19: Signature of sponsor or authorized representative

Item 20: Date signed

EXAM CRITICAL: Form 1571 is required for EVERY submission under an IND, not just the initial application. Common exam question: "What form accompanies an IND safety report?" Answer: Form FDA-1571.

1.4 FDA Form 1572: Statement of Investigator

Form FDA-1572 is the legally binding commitment from the investigator to conduct the clinical investigation according to GCP, applicable regulations, and the signed agreement. This form creates enforceable obligations between the investigator and FDA.

Complete Form 1572 Breakdown:

Section 1: Investigator Information

Section 2: Education, Training, and Experience Investigator must provide curriculum vitae or equivalent showing:

Section 3: Clinical Study

Section 4: Research Facility(ies)

Section 5: Clinical Laboratory Facilities

Section 6: Institutional Review Board (IRB)

Section 7: Subinvestigators

Section 8: Commitments - THE "9 COMMANDMENTS" OF FORM 1572 [CRITICAL FOR EXAM - MEMORIZE]

By signing, investigator commits to:

Commitment 1: Conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.

Commitment 2: Personally conduct or supervise the described investigation(s).

Commitment 3: Inform any potential subjects that the drugs are being used for investigational purposes and that informed consent will be obtained as required under 21 CFR Part 50 and IRB review and approval per 21 CFR Part 56.

Commitment 4: Report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.

Commitment 5: Have read and understood the information in the investigator's brochure, including the potential risks and side effects of the drug.

Commitment 6: Ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

Commitment 7: Maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.

Commitment 8: Ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. Also, I will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

Commitment 9: Comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.

Section 9: Signature and Date

EXAM STRATEGIES FOR FORM 1572:

  1. 9 commitments are highly testable - know them all
  2. "Immediate hazard" exception appears in Commitments 1 and 8 - can deviate from protocol and make changes without prior IRB approval when necessary to eliminate apparent immediate hazards
  3. Subinvestigator changes do NOT require new Form 1572 - update and communicate to sponsor
  4. When new 1572 required: New protocol, new IND, new investigator site
  5. Investigator Brochure (Commitment 5) - must read and understand BEFORE signing 1572

1.5 IND Amendments (21 CFR 312.30)

Sponsors must submit amendments to keep IND current and notify FDA of significant changes. Three types of amendments exist, each with specific requirements and timelines.

Protocol Amendments (§312.30(b))

Definition: Changes to previously submitted protocols or addition of new protocols.

Types:

New Protocol

Changes to Protocol Must submit protocol amendment describing:

Study Initiation Timeline:

EXAM CRITICAL: Cannot begin new protocol until BOTH FDA (30 days or authorization) AND IRB approval obtained.

Information Amendments (§312.30(c))

Definition: Essential information about IND updated but not falling under protocol or IND safety report.

Examples include:

Timeline: Submit as soon as available; implementation varies by type of change

New Investigator (§312.30(d))

Required Information:

  1. Form FDA-1572 signed by new investigator
  2. Updated investigator's brochure (if revised)
  3. Protocol being studied by investigator (if not previously submitted)
  4. All information required per §312.53(c):
    • Curriculum vitae
    • Protocol outline (Phase 1) or detailed protocol (Phase 2/3)
    • Financial disclosure information

Timeline:

1.6 IND Safety Reporting Requirements (21 CFR 312.32)

[This section covered extensively in Safety Reporting section - cross-reference to Section 5]

Key Points for IND Framework:

1.7 Annual Reports (21 CFR 312.33)

Due Date: Within 60 days of the anniversary date that IND went into effect

Required Contents:

1. Individual Study Information

2. Summary of IND Safety Reports

3. Subject Deaths

4. Dropouts Due to Adverse Events

5. Summary of Serious Adverse Events

6. Data from Controlled Trials

7. Preclinical Studies

8. Manufacturing and Microbiological

9. General Investigational Plan

10. Investigator's Brochure Revisions

11. Phase 1 Protocol Modifications

12. Foreign Marketing Developments

13. Log of Outstanding Business

14. Log of Amendments

EXAM TIP: Annual reports are due 60 days after IND anniversary - frequently tested timeline

1.8 Clinical Hold (21 CFR 312.42)

Definition: An order issued by FDA to sponsor to delay proposed clinical investigation or suspend ongoing investigation.

When FDA May Issue Clinical Hold:

For Phase 1 (§312.42(b)(1)):

  1. Human subjects exposed to unreasonable and significant risk of illness or injury
  2. Clinical investigators are not qualified by training and experience for investigation
  3. Investigator's brochure is misleading, erroneous, or materially incomplete
  4. IND does not contain sufficient information required per Part 312 to assess risks to subjects
  5. For Phase 1 studies in life-threatening conditions, clinical hold may not be based solely on exclusion of reproductive-potential subjects if acceptable contraception/pregnancy testing

For Phase 2 or 3 (§312.42(b)(2)): All Phase 1 grounds PLUS: 6. Plan or protocol clearly deficient in design to meet stated objectives 7. Insufficient information to assess risks or to prepare investigator's brochure 8. Insufficient drug characterization or preclinical testing for Phase 2/3 9. For Phase 2/3 in life-threatening conditions, same reproductive-potential provisions as Phase 1

For All Phases (§312.42(b)(3)): Clinical hold if IND for combination therapy does not:

Clinical Hold Procedures:

Timeline for FDA Notification:

Sponsor Response:

Lifting Clinical Hold:

Study Resumption:

EXAM SCENARIO: "FDA issues clinical hold on Day 1 of IND review. On Day 10, sponsor provides additional information addressing concerns. When may sponsor begin study?" Answer: When FDA lifts clinical hold AND IRB approval maintained - not automatic after 30 days when hold in place.

1.9 IND Exemptions (21 CFR 312.2(b))

Studies Exempt from IND Requirements:

1. Clinical investigations of lawfully marketed drugs Criteria (ALL must be met):

Exam Example: Study comparing two FDA-approved diabetes medications at approved doses for approved indication = IND exempt if criteria met

2. Bioavailability/Bioequivalence Studies Criteria:

3. In Vitro Diagnostic Biological Products Under specific conditions per 21 CFR 809.10(c)

4. Placebos When investigation doesn't otherwise require IND

5. Studies Not Intended for FDA Submission If ALL criteria met:

Common Exam Pitfalls:

1.10 IND Sponsor Responsibilities Summary

[Covered extensively in Section 3 - cross-reference]

Six Core Responsibilities (§312.50):

  1. Select qualified investigators
  2. Provide investigators necessary information
  3. Ensure proper monitoring
  4. Ensure investigations conducted per plan and protocols
  5. Maintain effective IND
  6. Ensure FDA and investigators promptly informed of significant new adverse effects or risks

Section 2: IDE Regulatory Framework (21 CFR Part 812)

[Drawing extensively from IDE Framework Researcher findings]

2.1 Purpose and Scope of 21 CFR Part 812

Purpose (§812.1):

Applicability (§812.2(a)): Applies to ALL clinical investigations of devices to determine safety and effectiveness (with exceptions in §812.2(c))

Key Distinction from IND: IDE regulations establish risk-based three-tier system:

  1. Exempt: No IDE required
  2. Non-Significant Risk (NSR): Abbreviated IDE (IRB approval only)
  3. Significant Risk (SR): Full IDE (FDA + IRB approval)

2.2 IDE Exemptions (21 CFR 812.2(c))

Seven Categories of Exempt Investigations:

1. Legally Marketed Devices

2. Diagnostic Devices (§812.2(c)(3)) Must meet ALL FOUR criteria:

a) Noninvasive (§812.3(k)):

b) No significant risk from invasive sampling: Significant risk procedures include:

c) Does not introduce energy:

d) Not used as sole diagnostic:

Must comply with labeling requirements in §809.10(c)

3. Consumer Preference Testing

4. Veterinary Use Devices intended solely for veterinary use

5. Animal Research

6. Custom Devices (§812.3(b))

7. Transitional Devices Specific devices subject to separate regulations

IMPORTANT: Exempt studies are NOT exempt from:

2.3 Significant Risk vs. Non-Significant Risk Determinations (21 CFR 812.3(m), 812.66)

Significant Risk Device Definition (§812.3(m))

An investigational device that:

  1. Is intended as an implant AND presents potential for serious risk; OR
  2. Is purported/represented for use supporting or sustaining human life AND presents potential for serious risk; OR
  3. Is for use of substantial importance in diagnosing, curing, mitigating, or treating disease AND presents potential for serious risk; OR
  4. Otherwise presents potential for serious risk to health, safety, or welfare of subject

Key Concept - "Serious Risk": Studies where potential harm could:

Non-Significant Risk Device: Any device that does NOT meet SR definition (determined by exclusion)

Risk Determination Process (§812.66)

1. Sponsor's Initial Determination:

2. IRB Review:

3. FDA as Final Arbiter:

If IRB Disagrees with Sponsor's NSR Assessment (§812.66):

Examples of NSR Devices (from FDA Guidance)

Examples of SR Devices (from FDA Guidance)

EXAM CRITICAL: Risk determination based on PROPOSED USE, not device alone. A pacemaker modification is SR even if it poses less/slightly greater risk than commercial model because any pacemaker presents serious risk potential.

2.4 Abbreviated IDE Requirements for NSR Devices (21 CFR 812.2(b))

NSR Device Studies - "Abbreviated Requirements":

NSR investigations are considered to have approved IDE applications UNLESS FDA specifically notifies sponsor otherwise.

Requirements for NSR Studies:

1. Labeling (§812.5): "CAUTION—Investigational device. Limited by Federal (or United States) law to investigational use"

2. IRB Approval (§812.2(b)(1)(ii)):

3. Informed Consent (§812.2(b)(1)(iii)):

4. Monitoring (§812.2(b)(1)(iv)): Comply with §812.46 monitoring requirements

5. Records (§812.2(b)(1)(v)): Maintain records per §812.140(b)(4) and (5)

6. Reports (§812.2(b)(1)(v)):

7. Investigator Records/Reports (§812.2(b)(1)(vi)):

8. Promotion Prohibition (§812.2(b)(1)(vii)): Comply with §812.7 prohibitions against promotion

Key Difference: NSR studies do NOT require FDA approval before beginning - IRB approval sufficient

2.5 IDE Application Requirements (21 CFR 812.20)

Required for SR Device Investigations

General Principle: Sponsor must demonstrate: