SOCRA Notes.docx

**Code of Federal Regulations** **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_** **Part 11 -- Electronic Records; Electronic Signatures** - **[Closed system:]** environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system - **[Open system:]** environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **Part 50 -- Protection of Human Subjects** - **[Subpart B -- 50.20: General requirements for informed consent]** - Except as specified in 50.23 and 50.24, investigators must obtain legally effective informed consent from human subjects or their authorized representatives before involving them in research. - Consent must be sought under conditions that allow the subject or representative enough time to decide about participation and reduce the risk of coercion or undue influence. - The information provided must be in language that is understandable to the subject or representative. - Informed consent cannot contain exculpatory language that waives or appears to waive the subject\'s legal rights, nor can it release the investigator, sponsor, institution, or agents from liability for negligence. - **[Subpart B -- 50.23: Exception from general requirements ]** - **Informed Consent Feasibility:** - Informed consent is considered feasible unless both the investigator and a non-participating physician certify in writing that: - The subject faces a life-threatening situation requiring the test article. - Informed consent cannot be obtained due to communication issues or inability to obtain legally effective consent. - There is insufficient time to obtain consent from the subject's legal representative. - No alternative therapy exists with equal or greater effectiveness. - **Immediate Use and Review:** - If the investigator believes immediate use of the test article is necessary and the required certification is not possible beforehand, the investigator's decisions must be reviewed by a non-participating physician within 5 working days after use. - **Documentation Submission:** - Documentation required under these provisions must be submitted to the Institutional Review Board (IRB) within 5 working days after using the test article. - **Presidential Waiver for Military:** - The President can waive informed consent requirements for investigational new drugs for military members under specific conditions: - The waiver must be based on a written determination that obtaining consent is not feasible, against the member's best interests, or contrary to national security. - The Secretary of Defense must request the waiver and provide detailed documentation, including evidence of drug safety, lack of alternatives, and potential risks. - IRB Requirements for Military Protocols: - **The IRB reviewing the military protocol must:** - Include non-affiliated members. - Approve information sheets and dissemination plans. - Review and approve the informed consent form if applicable. - **FDA and DOD Responsibilities:** - DOD must submit IRB meeting summaries to the FDA and ensure adherence to FDA regulations. - DOD must also provide public notice, track investigational drugs, and offer training to medical personnel. - **Informed Consent for Diagnostic Devices:** - Informed consent for investigational in vitro diagnostic devices used in emergencies is deemed feasible unless: - The subject is in a life-threatening situation. - Informed consent cannot be obtained due to the nature of the emergency. - There are no approved alternative diagnostic methods. - **Emergency Use and Reporting:** - If emergency use occurs, the investigator's decisions must be reviewed by a non-participating physician within 5 working days. - The investigator must report the use and certification to the IRB and FDA within 5 working days. - **Disclosure and IRB Responsibilities for Diagnostic Devices:** - The investigator must disclose the device\'s investigational status and performance characteristics. - The IRB must ensure adequate information is provided to the subject and oversee compliance with informed consent requirements. - **State Law Consistency:** - No state or local law may impose additional informed consent requirements for diagnostic devices used in emergencies beyond those stipulated by federal regulations. - **[Subpart B -- 50.24: Exception from informed consent requirements for emergency research ]** - **IRB Approval Without Informed Consent:** - **The IRB can approve emergency research without informed consent if:** - Subjects face a life-threatening situation with unproven or unsatisfactory treatments, and valid scientific evidence is needed. - [Obtaining consent is not feasible due to:] - Subjects' medical conditions, - Need for immediate intervention, - Inability to identify eligible subjects prospectively. - [Research offers direct benefits to subjects because:] - Subjects are in life-threatening conditions, - Preclinical studies support potential benefits, - Risks are reasonable relative to standard therapy and the intervention. - Research cannot be practically conducted without the waiver. - The investigational plan includes efforts to contact legally authorized representatives within a defined therapeutic window and to summarize these efforts to the IRB. - The IRB has reviewed and approved informed consent procedures and documents for use when feasible. - [Additional protections are provided, including:] - Community consultation, - Public disclosure of the research plan and results, - An independent data monitoring committee, - Efforts to contact family members if no authorized representative is available. - **IRB Responsibilities:** - Ensure procedures are in place to inform subjects, or their representatives or family members, about their participation, the details of the investigation, and their right to withdraw without penalty. - Provide information to subjects or their representatives if their condition improves or if the subject dies before a representative can be contacted. - **Documentation and Recordkeeping:** - IRB must retain documentation of determinations and records for at least 3 years after the study's completion, accessible for FDA inspection. - **Separate Protocols for Informed Consent Exceptions:** - Protocols requiring an exception to informed consent must be submitted under a separate IND or IDE, clearly indicating that subjects may be unable to consent. - **IRB Findings and Sponsor Notification:** - If an IRB cannot approve the investigation due to unmet criteria or ethical concerns, it must document and report its findings to the investigator, sponsor, and relevant parties, including FDA and other IRBs. - **[Subpart B -- 50.25: Elements of informed consent]** - **Basic Elements of Informed Consent:** - [Research Explanation:] Inform subjects that the study involves research, including its purpose, expected duration, procedures, and any experimental aspects. - [Risks and Discomforts:] Describe foreseeable risks or discomforts. - [Benefits:] Outline expected benefits to the subject or others. - [Alternative Procedures:] Disclose any alternative procedures or treatments that may benefit the subject. - [Confidentiality:] Explain how confidentiality will be maintained and that records may be inspected by the FDA. - [Compensation and Treatment:] For high-risk research, explain available compensation and medical treatments for research-related injuries. - [Contact Information:] Provide contact details for questions about the research, subjects\' rights, and research-related injuries. - [Voluntary Participation:] State that participation is voluntary, refusal involves no penalty or loss of benefits, and subjects can withdraw at any time without penalty. - **Additional Elements of Informed Consent (if applicable):** - [Unforeseeable Risks:] Note any unforeseeable risks to the subject or embryo/fetus if pregnant. - [Termination by Investigator:] State conditions under which the investigator can terminate participation without the subject\'s consent. - [Additional Costs:] Inform about any extra costs resulting from participation. - [Withdrawal Consequences:] Explain the consequences of withdrawing and procedures for orderly termination. - [New Findings:] State that significant new findings will be shared with the subject. - [Number of Subjects:] Provide the approximate number of subjects involved in the study. - **Clinical Trial Registration:** - For applicable clinical trials, include the statement that information about the trial will be available on ClinicalTrials.gov, which will not identify the subject but may summarize results. - **Legal and Emergency Care:** - The informed consent regulations do not override Federal, State, or local laws requiring additional information for legal consent. - These regulations do not limit a physician\'s authority to provide emergency medical care as permitted by law. - **[Subpart B -- 50.27: Documentation of informed consent ]** - **Standard Requirement: Informed consent must be documented with a written consent form that is:** - Approved by the IRB. - Signed and dated by the subject or their legally authorized representative at the time of consent. - A copy of the signed form must be provided to the signer. - **Types of Consent Forms:** - [Written Consent Document:] - Must include the elements of informed consent as per §50.25. - Can be read to the subject or their representative but must be given adequate time to read before signing. - [Short Form Written Consent Document:] - States that the elements of informed consent have been presented orally. - Requires a witness to the oral presentation. - IRB must approve a written summary of the oral presentation. - Only the short form is signed by the subject or representative. - The witness signs both the short form and the summary; the person obtaining consent also signs the summary. - A copy of the summary is given to the subject or representative along with the short form. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **Part 50, Subpart D -- Additional Safeguards for Children in Clinical Investigations** - **[Subpart D -- 50.50: IRB Duties]** - **Review Requirement:** Each IRB must review clinical investigations involving children. - **Approval Criteria:** Approve only those investigations that meet: - The criteria outlined in §50.51, §50.52, or §50.53. - The conditions of all other applicable sections in subpart D. - **[Subpart D -- 50.51: Clinical Investigations NOT involving greater than minimal risk]** - **Approval Conditions:** - [The IRB must find that:] - The clinical investigation presents no greater than minimal risk to children. - [Adequate provisions are made for:] - Soliciting the assent of the children. - Obtaining the permission of the parents or guardians, as outlined in §50.55. - **[Subpart D -- 50.52: Clinical Investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects]** - **Conditions for Approval:** - [The IRB must determine that:] - The risk is justified by the anticipated benefit to the subjects. - The relation of anticipated benefit to risk is at least as favorable as available alternative approaches. - [Adequate provisions are made for:] - Soliciting the assent of the children. - Obtaining the permission of their parents or guardians, as outlined in §50.55. - **[Subpart D -- 50.53: Clinical Investigations involving greater than minimal risk and NO prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects' disorder or condition]** - **Conditions for Approval:** - [The IRB must determine that:] - The risk represents a minor increase over minimal risk. - The intervention or procedure presents experiences reasonably similar to the subjects\' existing medical, dental, psychological, social, or educational situations. - The intervention or procedure is likely to provide generalizable knowledge crucial for understanding or improving the subjects\' condition. - [Adequate provisions are made for:] - Soliciting the assent of the children. - Obtaining the permission of their parents or guardians, as outlined in §50.55. - **[Subpart D -- 50.54: Clinical Investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children]** - **IRB Findings:** - [The IRB must find that:] - The investigation offers a reasonable opportunity to advance understanding, prevention, or alleviation of a serious problem affecting children\'s health or welfare. - **Commissioner of Food and Drugs Approval:** - [After consulting a panel of experts and public review, the Commissioner must determine:] - **Option 1:** The investigation meets the conditions of §50.51, §50.52, or §50.53, as applicable. - **Option 2:** The following conditions are met: - The investigation provides a reasonable opportunity to address a serious problem affecting children's health or welfare. - The investigation adheres to sound ethical principles. - [Adequate provisions are made for:] - Soliciting the assent of children. - Obtaining the permission of their parents or guardians, as specified in §50.55. - **[Subpart D -- 50.55: Requirements for permission by parents or guardians and for assent by children ]** - **IRB Responsibilities for Children\'s Assent in Clinical Investigations:** - [Assessing Assent Capability:] - The IRB must ensure adequate provisions for soliciting assent from children who are capable of providing it. - The IRB should consider the children's ages, maturity, and psychological state. - This assessment can be done either for all children under a specific protocol or individually, as deemed appropriate by the IRB. - **Conditions for Waiving Assent:** - [Assent is not required if:] - The children's capability to assent is so limited that it is impractical to consult them. - The intervention provides a direct benefit important to the children's health or well-being and is only available through the clinical investigation. - **Conditions for Waiving Assent Requirement:** - [The IRB may waive the assent requirement if:] - The investigation involves no more than minimal risk. - The waiver does not negatively impact the rights and welfare of the subjects. - The investigation cannot be practically conducted without the waiver. - Appropriate additional information will be provided to subjects after participation, if relevant. - **Parental or Guardian Permission:** - The IRB must ensure that each child\'s parent or guardian grants permission in accordance with §50. - **Permission Requirements:** - For investigations under §50.51 or §50.52, the permission of one parent is sufficient. - For investigations under §50.53 or §50.54, permission from both parents is required unless exceptions apply (e.g., one parent is deceased, unknown, or legally responsible for the child). - **Documentation:** - Parental or guardian permission must be documented as per §50.27. - If assent is required, the IRB must also determine and document how assent should be recorded. - **[Subpart D -- 50.56: Wards]** - **Inclusion of Wards in Clinical Investigations:** - [Children who are wards of the State or other entities can participate in clinical investigations only if:] - The investigation is related to their status as wards. - The investigation is conducted in settings where most children are not wards (e.g., schools, camps, hospitals). - **Advocate Requirements for Wards:** - For approved investigations involving wards: - The IRB must require the appointment of an advocate for each ward. - The advocate serves in addition to any other guardian or representative. - One advocate can represent multiple children. - The advocate must have the relevant background and experience to act in the child\'s best interest and must agree to this role for the duration of the study. - The advocate must be independent from the clinical investigation, investigators, or the guardian organization, except in their role as an advocate or IRB member. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **Part 56 -- Institutional Review Boards** **[Subpart A: General Provisions]** - **Subpart A - Scope (§56.101):** - Outlines general standards for Institutional Review Boards (IRBs) overseeing clinical investigations regulated by the FDA. - Includes clinical investigations for a variety of FDA-regulated products (drugs, medical devices, food, etc.). - Aims to protect the rights and welfare of human subjects involved in these investigations. - References are to Title 21, Chapter I of the Code of Federal Regulations unless noted otherwise. - **Subpart A - Definitions (§56.102):** - [Act:] Refers to the Federal Food, Drug, and Cosmetic Act. - [Application for research or marketing permit:] Includes petitions, applications, and data submissions related to FDA-regulated products and research. - [Clinical investigation:] Experiments involving human subjects for FDA submissions or inspections, excluding nonclinical laboratory studies. - [Emergency use:] Use of a test article in life-threatening situations without prior IRB approval, but reported to IRB within 5 days. - [Human subject:] An individual participating in research. - [Institution:] Public or private entities conducting research. - [IRB:] Board or committee reviewing biomedical research to protect human subjects. - [Investigator:] Individual conducting or leading a clinical investigation. - [Minimal risk:] Risk not greater than everyday life or routine exams. - [Sponsor:] Entity initiating but not conducting an investigation. - [Sponsor-investigator:] Individual who both initiates and conducts a clinical investigation. - [Test article:] Includes drugs, devices, food additives, etc., regulated under FDA or Public Health Service Act. - [IRB approval:] IRB's determination that a clinical investigation meets institutional and federal requirements. - **Subpart A - Circumstances Requiring IRB Review (§56.103):** - Clinical investigations needing FDA submission must be reviewed and approved by an IRB. - FDA may not consider data from investigations lacking IRB approval for research or marketing permits. - Compliance with these regulations does not negate other applicable laws. - **Subpart A - Exemptions from IRB Requirement (§56.104):** - Investigations started before July 27, 1981, under prior IRB review requirements. - Investigations commenced before July 27, 1981, not previously requiring IRB review. - Emergency use of test articles, reported to IRB within 5 days. - Taste and food quality evaluations, if consuming safe or wholesome food without additives. - **Subpart A - Waiver of IRB Requirement (§56.105):** - FDA may waive IRB review requirements for specific research activities or categories upon application by sponsor or sponsor-investigator. **[Subpart B: Organization and Personnel]** - **Subpart B - Registration (§56.106):** - [Who Must Register:] - All IRBs in the U.S. reviewing FDA-regulated clinical investigations or supporting research/marketing permit applications. - Authorized individuals must submit registration information; voluntary registration is allowed for other IRBs. - [Information Required:] - Institution and IRB contact details, including names, addresses, phone numbers, and email addresses. - Number of active protocols involving FDA-regulated products reviewed in the past year. - Description of FDA-regulated products reviewed (e.g., drugs, devices). - [Timing:] - Initial registration before reviewing clinical investigations. - Renew registration every 3 years. - Registration effective after HHS review. - [Registration Methods:] - Electronic registration via http://ohrp.cit.nih.gov/efile. - Written registration if electronic submission is not possible, sent to FDA's Office of Good Clinical Practice. - [Updating Registration:] - Update contact or chairperson changes within 90 days. - Report changes in types of reviewed products or discontinuation of review within 30 days. - Report disbandment within 30 days. - Other changes can be reported at renewal. - **Subpart B - IRB Membership (§56.107):** - [Composition:] - At least five members with diverse backgrounds to ensure comprehensive review. - Members should have experience, expertise, and cultural sensitivity relevant to the research. - Include individuals knowledgeable in vulnerable populations if applicable. - [Diversity and Balance:] - Avoid gender or professional homogeneity; no IRB may consist entirely of one gender or profession. - Include members from both scientific and nonscientific backgrounds. - [Non-affiliation Requirement:] - Include at least one member not affiliated with the institution and not related to anyone affiliated with the institution. - [Conflict of Interest:] - Members with conflicts of interest cannot participate in reviews but may provide requested information. - [Special Expertise:] - IRBs can invite external experts for complex issues, but these individuals cannot vote. **[Subpart C: IRB Functions and Operations]** - **Subpart C -- IRB functions and operations (§56.108):** - [Written Procedures:] - Initial and ongoing review of research. - Determine review frequency and verification requirements. - Ensure prompt reporting of changes in research activity. - Require IRB approval for changes in approved research unless to address immediate hazards. - [Reporting:] - Report unanticipated problems, serious noncompliance, or suspension/termination of IRB approval to IRB, institutional officials, and FDA. - [Review Meetings:] - Most research reviewed at convened meetings with a majority of IRB members present, including at least one nonscientific member. - Majority approval required for research. - **Subpart C - IRB Review of Research (§56.109):** - [Authority:] - Approve, require modifications, or disapprove research activities. - [Informed Consent:] - Ensure compliance with informed consent requirements. - May waive documentation or requirements for minimal risk or emergency research. - Require written notification to investigators and institutions of IRB decisions, including reasons for disapproval. - [Continuing Review:] - Conduct at least annually, observe consent processes, and review research for compliance. - [Children's Research:] - Ensure compliance with specific regulations for research involving children. - **Subpart C - Expedited Review Procedures (§56.110):** - [Categories and Use:] - FDA publishes a list of research categories eligible for expedited review. - Used for minimal risk research or minor changes to approved research. - [Review Process:] - Conducted by IRB chairperson or designated reviewers. - Expedited reviewers cannot disapprove research; only full IRB review can do so. - [Member Notification:] - IRBs must keep members informed of research approved via expedited review. - [FDA Oversight:] - FDA can restrict or terminate expedited review use if necessary. - **Subpart C - Criteria for IRB Approval (§56.111):** - [Risk Minimization:] - Use sound research design and avoid unnecessary risk. - [Risk-Benefit Analysis:] - Risks must be reasonable in relation to anticipated benefits. - [Equitable Selection:] - Ensure fair subject selection, considering special populations. - [Informed Consent:] - Obtain and document consent in accordance with regulations. - [Safety and Privacy:] - Adequate monitoring, privacy protection, and confidentiality. - [Additional Safeguards:] - Include safeguards for vulnerable populations. - [Children's Research Compliance:] - Ensure research complies with specific regulations for children. - **Subpart C - Institutional Review (§56.112):** - [Further Review:] - Institutional officials may review IRB-approved research but cannot approve it if not already approved by IRB. - **Subpart C - Suspension or Termination (§56.113):** - [Authority:] - IRB can suspend or terminate research not conducted per requirements or causing serious harm. - Provide reasons for action and report to investigator, institutional officials, and FDA. - **Subpart C - Cooperative Research (§56.114):** - [Joint Review:] - Institutions in multi-institutional studies may use joint reviews or rely on another qualified IRB to avoid duplication of effort. **[Subpart D: Records and Reports]** - **Subpart D - IRB Records (§56.115):** - [Documentation Required:] - Research proposals, scientific evaluations, approved consent documents, progress reports, and injury reports. - Minutes of IRB meetings detailing attendance, actions taken, votes, reasons for requiring changes or disapproving research, and summaries of discussions. - Records of continuing review activities. - Correspondence between the IRB and investigators. - List of IRB members with details on name, degrees, representative capacity, experience, and any employment or other relationships with the institution. - Written IRB procedures. - Statements of significant new findings provided to subjects. - [Record Retention:] - Maintain records for at least 3 years after research completion. - Records must be accessible for inspection and copying by FDA representatives. - [FDA Inspection:] - FDA may refuse to consider clinical investigations for research or marketing permits if the institution or IRB denies inspection. **[Subpart E: Administrative Actions and Noncompliance]** - **Subpart E - Lesser Administrative Actions (§56.120):** - [Initial Response:] - FDA inspector presents noncompliance observations to IRB; FDA then sends a letter to the IRB and parent institution detailing the noncompliance. - IRB or institution must respond with corrective action plans within a specified timeframe. - [Follow-up Actions:] - FDA may schedule a reinspection to verify corrective actions. - Until compliance is achieved, FDA may: - Withhold approval of new studies. - Direct that no new subjects be added to ongoing studies. - Terminate ongoing studies if it does not endanger subjects. - [Significant Threats:] - FDA may notify relevant State and Federal agencies and other interested parties if noncompliance significantly threatens human subjects. - [Responsibility:] - The parent institution is typically held responsible, but actions may be directed specifically at the IRB or responsible components. - **Subpart E - Disqualification (§56.121):** - [Proceedings:] - If noncompliance persists, the FDA Commissioner may initiate regulatory hearing proceedings to consider disqualification. - [Grounds for Disqualification:] - Persistent noncompliance affecting human subjects\' rights or welfare. - [Order and Notification:] - Commissioner issues a disqualification order, with explanations and prescribed actions for ongoing research. - Disqualification notices are sent to the IRB, parent institution, sponsors, clinical investigators, and may be published in the FEDERAL REGISTER. - [Impact:] - FDA will not approve research permits or consider data from studies reviewed by disqualified IRBs or institutions, unless reinstated. - **Subpart E - Public Disclosure (§56.122):** - Information about disqualification and related administrative records are publicly disclosable. - **Subpart E - Reinstatement (§56.123):** - An IRB or institution can be reinstated if it provides adequate assurance of compliance through a written corrective action plan. - Reinstatement notifications are sent to all previously notified parties. - **Subpart E - Alternative Actions (§56.124):** - Disqualification is separate from other legal actions. - FDA may pursue judicial proceedings (civil or criminal) or other regulatory actions in addition to or instead of disqualification, and refer matters to other agencies as appropriate. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ **Part 312 -- Investigational New Drug Application** **[Subpart A: General Provisions]** - **Subpart A - Scope (§312.1):** - Governs procedures and requirements for investigational new drugs (INDs), including submission and review by the FDA. - INDs are exempt from premarketing approval and can be shipped for clinical investigations. - **Subpart A - Applicability (§312.2):** - [General Applicability:] Applies to clinical investigations of drugs under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. - [Exemptions:] - Clinical investigations of marketed drugs are exempt if they meet specific conditions, including no new indication or significant risk increase. - In vitro diagnostic biological products and drugs for laboratory research are also exempt under certain conditions. - Investigations involving placebos are exempt if no IND is required. - Investigations with informed consent exceptions under §50.24 are not exempt. - **Bioavailability Studies:** Subject to §320.31 provisions. - **Unlabeled Indications:** Not covered if used in medical practice for unlabeled indications. - **Guidance:** FDA may issue guidance or advice on applicability for specific investigational uses. - **Subpart A - Definitions (§312.3):** - [Act:] Refers to the Federal Food, Drug, and Cosmetic Act. - [Clinical Investigation:] Experiment involving drug use in humans. - [Contract Research Organization:] Independent contractor handling sponsor obligations. - [FDA:] Food and Drug Administration. - [IND:] Investigational New Drug application. - [Independent Ethics Committee (IEC):] Panel ensuring subject protection; includes IRBs. - [Investigational New Drug:] Drug used in clinical investigation or for in vitro diagnostic purposes. - [Investigator:] Individual conducting a clinical investigation. - [Marketing Application:] Application for new drug or biologics license. - [Sponsor:] Person initiating and taking responsibility for a clinical investigation. - [Sponsor-Investigator:] Individual who both initiates and conducts an investigation. - [Subject:] Human participant in an investigation. - **Subpart A - Labeling (§312.6):** - Must include "Caution: New Drug---Limited by Federal (or United States) law to investigational use." - Labels must not be false or misleading or claim safety/effectiveness. - **Subpart A - Promotion (§312.7):** - [Promotion Restrictions:] No claims of safety or effectiveness for investigational drugs; scientific information exchange allowed. - [Commercial Distribution:] Prohibited. - [Investigation Duration:] Sponsors cannot unduly prolong an investigation. - **Subpart A - Charging for Investigational Drugs (§312.8):** - [General Criteria:] Sponsors must meet requirements for charging; need FDA authorization. - [Clinical Trial Charging:] - Requires justification for potential benefit, essential data, and extraordinary cost. - [Expanded Access Charging:] - Assurance that charging won\'t interfere with drug development; limited to patient number and duration. - [Cost Recovery:] - Only direct costs can be recovered; documentation required. - **Subpart A - Waivers (§312.10):** - Sponsors can request waivers for requirements. - Must explain why compliance is unnecessary or provide alternatives. - FDA may grant waivers if they do not pose significant risk and if conditions are met. **[Subpart B: Investigational New Drug Application (IND)]** - **Subpart B - IND Requirement (§312.20):** - Sponsors must submit an IND to the FDA if conducting a clinical investigation with an investigational new drug (IND) under §312.2(a). - Clinical investigations cannot begin until the IND is effective according to §312.40. - Separate IND submission is required for investigations involving an exception from informed consent under §50.24. FDA must provide written determination within 30 days. - **Subpart B - Phases of Investigation (§312.21):** - [Phase 1:] - Initial introduction of the drug into humans. - Studies assess drug metabolism, pharmacologic actions, side effects, and early effectiveness. - Includes 20 to 80 subjects; may also involve studies on drug metabolism and mechanisms. - [Phase 2:] - Controlled clinical studies to evaluate effectiveness for specific indications and short-term side effects. - Involves several hundred patients. - [Phase 3:] - Expanded trials to confirm effectiveness and safety, providing data for physician labeling. - Includes several hundred to several thousand subjects. - **Subpart B - General Principles of IND Submission (§312.22):** - [FDA Review Objectives:] - Ensure subject safety and rights in all phases. - In Phases 2 and 3, also evaluate scientific quality and effectiveness. - [Submission Information:] - Depends on drug novelty, prior study, risks, and development phase. - [Submission Focus:] - Initial IND should cover general investigational plans and specific study protocols. - Amendments should be supported by new or revised information, including animal studies. - Annual reports should update study status and investigational plans. - [IND Format:] - Follow §312.23 format, with discretion based on drug type and information available. - Sponsor-investigators may reference manufacturer's IND for drugs already under one, or submit all technical information if not covered by existing INDs. - **Subpart B - Summary of IND Content and Format (§312.23)** - [Cover Sheet (Form FDA-1571)] - Sponsor details (name, address, phone number). - Date and name of investigational new drug. - Phase(s) of investigation. - Commitment not to start until IND is in effect. - IRB review and approval commitment. - Compliance with all regulatory requirements. - Monitoring and safety review personnel. - If applicable, details on contract research organization. - Signature of sponsor or authorized representative (U.S. address required if non-U.S. sponsor). - [Table of Contents] - [Introductory Statement and General Investigational Plan] - Drug name, active ingredients, pharmacological class, structural formula, dosage form, route, objectives, and duration. - Summary of previous human experience and relevant investigational or marketing experience. - Information on drug withdrawals due to safety or effectiveness. - Overview of the investigation plan for the upcoming year, including rationale, indications, trial types, patient estimates, and anticipated risks. - [Investigator\'s Brochure (if required)] - Drug description, pharmacology, toxicology, pharmacokinetics, and previous human safety and effectiveness data. - Risks, side effects, and monitoring precautions. - [Protocols] - Detailed protocols for each study, including study objectives, investigator qualifications, patient criteria, study design, dosing, observations, and monitoring. - [Chemistry, Manufacturing, and Control Information] - Description of drug substance and product, including manufacturing processes, quality controls, stability data, and placebo description. - Labeling and environmental analysis requirements. - [Pharmacology and Toxicology Information] - Pharmacological effects, drug disposition, and toxicology data from animal and in vitro studies. - Compliance with good laboratory practice regulations if applicable. - [Previous Human Experience] - Summary of past investigations or marketing, including effectiveness and safety data. - Information on drug components if a combination product. - [Additional Information] - Details on drug dependence, radioactive drugs, pediatric studies, or other relevant information. - [Relevant Information] - Any additional information requested by FDA. - [Information Previously Submitted] - Reference previously submitted information with proper identification and authorization. - [Material in Foreign Language] - Accurate English translations of non-English parts and original literature publications. - [Number of Copies] - Submit an original and two copies of all submissions. - [Numbering of Submissions] - Sequential numbering for each IND submission. - [Identification of Exception from Informed Consent] - Prominently identify investigations involving exceptions to informed consent. - **Subpart B - Summary of Protocol Amendments (§312.30):** - [New Protocols] - Submit a protocol amendment for any new study not covered by existing protocols. - Study may begin once: - The protocol is submitted to FDA for review. - The protocol is approved by the Institutional Review Board (IRB). - These conditions can be met in either order. - [Changes in Protocols] - Submit an amendment for changes that significantly impact safety, scope, or scientific quality, such as: - Increase in drug dosage or duration, or a significant increase in subjects. - Significant changes in study design (e.g., control group modifications). - Addition or removal of tests/procedures related to safety monitoring. - Changes must be submitted to FDA and approved by the IRB, though immediate changes to address hazards can be made with subsequent FDA and IRB notifications. - [New Investigator] - Submit a protocol amendment when adding a new investigator to an existing protocol. - No amendment needed for licensed practitioners added under specific treatment protocols. - Notify FDA within 30 days of adding the new investigator. - [Content and Format of Protocol Amendments] - Clearly identify the type of amendment (e.g., "New Protocol," "Change in Protocol," "New Investigator"). - [Include:] - For new protocols: the new protocol and a summary of key differences. - For protocol changes: a description of the change and references to previous submissions. - For new investigators: their name, qualifications, reference to the original protocol, and additional study information. - Reference specific technical information if relevant, and request FDA comments if needed. - [Submission Timing] - Submit amendments for new or changed protocols before implementation. - Amendments to add new investigators can be grouped and submitted at 30-day intervals. - For multiple submissions within a short period, consider combining them into a single submission. - **Subpart B - Summary of Information Amendments (§312.31):** - [Requirement for Information Amendment] - Report essential information not covered by protocol amendments, IND safety reports, or annual reports. - [Examples include:] - New toxicology, chemistry, or technical information. - Reports on the discontinuance of a clinical investigation. - [Content and Format] - Clearly identify the amendment type (e.g., "Chemistry," "Pharmacology-Toxicology"). - [Include:] - A statement of the amendment\'s nature and purpose. - Organized data in a scientific review format. - Request for FDA comments if desired. - [Submission Timing] - Submit amendments as necessary, but ideally not more frequently than every 30 days. - **Subpart B -- IND Safety Reporting (§312.32):** - [Definitions:] - [Adverse event:] Any undesirable medical occurrence associated with drug use, regardless of drug relation. - [Life-threatening adverse event:] An event placing the patient at immediate risk of death, as assessed by investigator or sponsor. - [Serious adverse event:] Results in death, life-threatening condition, hospitalization, significant incapacity, or congenital anomaly. May include important medical events requiring intervention to prevent serious outcomes. - [Suspected adverse reaction:] An adverse event with a reasonable possibility of drug causation. - [Unexpected adverse event:] An event not listed in the investigator brochure or differing in severity/specification from expected. - [Review of Safety Information:] - Sponsors must promptly review all safety-related information from various sources including clinical trials, literature, and regulatory reports. - [IND Safety Reports:] - Sponsors must notify FDA and investigators of serious and unexpected adverse reactions within 15 calendar days. - Reports should include previous similar reports and analyze the new information. - [Specific reporting requirements for:] - Serious and unexpected suspected reactions. - Findings from epidemiological, clinical, and animal studies suggesting significant risks. - Increased rate of serious suspected adverse reactions. - Reports can be submitted in narrative format, FDA Form 3500A, or electronically, and must be prominently identified. - [Unexpected Fatal or Life-Threatening Reactions:] - Sponsors must report these within 7 calendar days of receipt. - [Reporting Format or Frequency:] - FDA may adjust reporting formats or frequencies, and sponsors may propose changes with FDA agreement. - [Investigations of Marketed Drugs:] - Sponsors must report suspected adverse reactions from clinical studies of marketed drugs under IND, in addition to postmarketing requirements. - [Reporting Study Endpoints:] - Serious and unexpected adverse events must be reported, even if they are part of study endpoints, if there is evidence of causation. - [Follow-up:] - Sponsors must investigate and submit follow-up information promptly, identifying it as such. If an initially non-reportable event becomes reportable, it must be reported within 15 calendar days. - [Disclaimer:] - Submission of safety reports does not imply an admission of causation by the sponsor or FDA. - **Subpart B -- Annual Reports (§312.33):** - Sponsors must submit an annual progress report within 60 days of the IND anniversary date. - [Individual Study Information:] - [Study Summary:] Title, purpose, patient population, and completion status. - [Enrollment Details:] Total planned subjects, number entered, demographics (age, gender, race), completion rate, and dropout numbers. - Results: Brief description of study results if completed or interim results are available. - [Summary Information:] - [Adverse Experiences:] Narrative or tabular summary of most frequent and serious adverse experiences by body system. - [IND Safety Reports:] Summary of all safety reports submitted in the past year. - [Deaths:] List of subjects who died during the investigation with cause of death. - [Dropouts:] List of subjects who dropped out due to adverse experiences, regardless of drug relation. - [Drug Actions:] Description of findings related to drug actions, including dose response, controlled trials, and bioavailability. - [Preclinical Studies:] List and summary of major findings from preclinical (animal) studies. - [Manufacturing Changes:] Summary of significant changes in manufacturing or microbiological processes. - [General Investigational Plan:] - Description of the plan for the coming year, replacing the previous year's plan, including required information. - [Investigator Brochure:] - Description and copy of any revisions made to the investigator brochure. - [Phase 1 Protocol Modifications:] - Description of any significant modifications to Phase 1 protocols made in the past year and not reported in a protocol amendment. - [Foreign Marketing Developments:] - Summary of significant international marketing updates, including approvals, withdrawals, or suspensions. - [Outstanding Business Log:] - Optional log of any outstanding business related to the IND, including requests or expected replies or meetings. - **Subpart B -- Withdrawal of an IND (§312.38):** - [Sponsor\'s Right:] A sponsor can withdraw an effective IND at any time without prejudice. - [Notification Requirements:] Upon withdrawal, the sponsor must: - Notify the FDA. - End all clinical investigations under the IND. - Inform all current investigators. - Return or dispose of all drug stocks as per §312.59. - [Safety Withdrawals:] If the withdrawal is due to safety concerns, the sponsor must promptly notify: - The FDA. - All participating investigators. - All reviewing Institutional Review Boards (IRBs). - Provide reasons for the withdrawal. **[Subpart C -- Administrative Actions]** - **Subpart C -- General requirements for use of an investigational new drug in a clinical investigation (§312.40):** - [Conditions for Using an Investigational New Drug (IND):] - IND Submission: Sponsor must submit an IND to the FDA and ensure it is in effect, complying with requirements in parts 50 and 56. - Investigator Compliance: Each participating investigator must follow applicable requirements in parts 50 and 56. - [Effectiveness of IND:] - Automatic Effectiveness: An IND goes into effect 30 days after FDA receipt, unless a clinical hold is issued. - Early Authorization: IND can go into effect earlier if FDA provides written notification. - [Shipping the Drug:] - Timing: Sponsor can ship the investigational drug to investigators 30 days after FDA receipt of the IND or earlier with FDA authorization. - [Administration to Subjects:] - Restriction: Investigators cannot administer the drug to human subjects until the IND goes into effect. - **Subpart C -- Comment and advice on an IND (§312.41):** - [FDA Communication on IND:] - [Deficiencies and Data Needs:] FDA may communicate about deficiencies or the need for more data at any time during the investigation, either orally or in writing. - [Sponsor Requests:] Sponsors can request FDA advice on specific matters, such as: - Adequacy of technical data. - Clinical trial design. - Likelihood of investigations producing necessary data for a marketing application. - [Advisory Nature:] Unless accompanied by a clinical hold order, FDA communications are advisory and do not require changes to planned or ongoing investigations or responses from the sponsor. - **Subpart C -- Clinical holds and requests for modification (§312.42):** - [Clinical Holds:] - Definition: A clinical hold is an FDA order to delay or suspend a proposed or ongoing clinical investigation. It can apply to one or more investigations under an IND. - [Restrictions During Hold:] - [Proposed studies:] Subjects cannot receive the investigational drug. - [Ongoing studies:] New subjects cannot be recruited, and existing subjects should be removed from therapy unless permitted by FDA for safety reasons. - [Grounds for Clinical Hold:] - [Phase 1 Studies:] - Unreasonable risk to subjects. - Investigators lack qualification. - Misleading or incomplete investigator brochure. - Insufficient information in the IND. - Exclusion of individuals with reproductive potential from studies on life-threatening conditions. - [Phase 2 or 3 Studies:] - Applies if conditions from Phase 1 hold are met or if the study design is inadequate. - [Expanded Access IND or Protocol:] - [Final Use:] Holds if criteria for expanded access are not met. - [Ongoing Use:] Holds if criteria are no longer satisfied. - [Non-Well-Controlled Studies]: - Applies if interfering with well-controlled studies or if other reasons are met (e.g., lack of effectiveness, better alternatives). - [Informed Consent Exceptions:] - Applies if conditions or criteria for informed consent exceptions are not met. - [Process and Communication:] - [Discussion of Deficiencies:] FDA will discuss deficiencies with the sponsor, unless there is immediate risk. - [Issuance of Clinical Hold:] Can be communicated by phone or in writing, specifying the studies and reasons. A written explanation will follow within 30 days. - [Resumption:] Investigations can only resume after FDA notifies the sponsor that deficiencies have been corrected. Sponsors cannot proceed until notified. - [Appeal:] Sponsors can request reconsideration if they disagree with the clinical hold reasons. - [Inactive Status:] If all investigations under an IND are on clinical hold for over a year, the IND may be converted to inactive status. - **Subpart C -- Termination (§312.44):** - [General Termination Procedures:] - FDA may terminate an IND if deficiencies are found. - Sponsor must end all clinical investigations and dispose of unused drug supplies. - Termination generally follows a proposal and an opportunity for sponsor response, except in urgent situations. - [Grounds for Termination:] - [Phase 1:] - Unreasonable risk to subjects. - Insufficient safety information in the IND. - Inadequate drug manufacturing standards. - Significant deviations from submitted protocols. - Unjustified commercial promotion. - Misleading or incomplete IND information. - Failure to report serious adverse experiences or annual reports. - Non-compliance with applicable regulations. - IND inactive for 5+ years. - Failure to address a clinical hold. - [Phase 2 or 3:] - Any Phase 1 conditions apply. - Unreasonable investigational plan or protocol. - Evidence of drug ineffectiveness. - [Treatment IND:] - Any Phase 1 conditions apply. - Conditions related to expanded access protocols. - [Opportunity for Sponsor Response:] - FDA will notify the sponsor in writing with a 30-day response period. - Sponsor can provide a written explanation, correction, or request a conference. - Failure to respond leads to termination. - If response is unsatisfactory, FDA may offer a regulatory hearing. - [Immediate Termination:] - FDA can immediately terminate an IND if there is an immediate and substantial danger to health. - The IND can be reinstated if the sponsor addresses the safety concerns. - A regulatory hearing on reinstatement will be provided if the IND is terminated under this condition. - **Subpart C -- Inactive Status (§312.45):** - [An IND may be placed on inactive status if:] - No subjects are entered into clinical studies for 2 years or more. - All investigations are on clinical hold for 1 year or more. - FDA can initiate inactive status action or act on sponsor\'s request. - FDA must notify the sponsor in writing before taking action, giving the sponsor 30 days to respond. - [Actions Upon Inactive Status:] - All investigators are notified. - Stocks of the drug must be returned or disposed of per §312.59. - Annual reports are not required for an inactive IND. - The inactive IND remains in effect for public disclosure purposes under §312.130. - [Resuming Clinical Investigations:] - [To resume clinical studies, the sponsor must:] - Submit a protocol amendment under §312.30 with the proposed investigational plan and appropriate protocols. - Reference previously submitted information if applicable. - Submit additional information in an information amendment if needed. - [Investigations may resume:] - 30 days after FDA receives the protocol amendment unless subject to a clinical hold. - On earlier notification from FDA that the investigations may begin. - **Subpart C -- Meetings (§312.47):** - FDA encourages meetings between sponsors and the agency to resolve questions and issues in clinical investigations. - These meetings should involve free, full, and open communication on scientific and medical questions. - Meetings are conducted and documented per part 10. - [Types of Meetings:] - [End-of-Phase 2 Meetings:] - [Purpose:] Assess safety for proceeding to Phase 3, evaluate Phase 3 plans, and identify additional information needed for a marketing application. - [Eligibility:] Primarily for new molecular entities or major new uses, but any IND sponsor can request it. - [Timing:] Should be held before significant Phase 3 commitments, but not to delay the transition from Phase 2 to 3. - [Advance Information:] Sponsors must submit relevant background information at least 1 month before the meeting. - Conduct: Arrangements made with the relevant FDA division; both parties may bring consultants. Agreements are recorded in minutes. - [Pre-NDA and Pre-BLA Meetings:] - [Purpose:] Address major unresolved issues, review studies, and discuss data presentation and formatting for the marketing application. - [Preparation:] Sponsors should submit a summary of clinical studies, proposed submission format, status of pediatric studies, and other relevant information at least 1 month before the meeting. - [Objective:] Reduce delays in the initial review of the marketing application by addressing potential issues early. - **Subpart C -- Dispute Resolution (§312.48):** - [General Commitment:] - FDA aims to resolve differences with sponsors quickly and amicably through cooperative communication. - [Administrative and Procedural Disputes:] - [Initial Resolution:] Sponsors should first address issues with the FDA division responsible for their IND, starting with the assigned consumer safety officer. - [Ombudsman:] If unresolved, sponsors can involve the FDA ombudsman to investigate and facilitate a resolution. - [Details:] More information is available in FDA Staff Manual Guide 4820.7. - [Scientific and Medical Disputes:] - [Direct Discussion:] Sponsors should discuss scientific or medical disputes directly with reviewing officials. - [Request for Meetings:] If needed, sponsors can request meetings with reviewing officials and management, directed to the division director. - [End-of-Phase 2 and Pre-NDA Meetings:] These meetings provide opportunities to discuss and resolve scientific and medical issues. - [External Experts:] Sponsors may suggest involving outside experts; FDA may invite advisory committee members or consultants if deemed appropriate. - [Advisory Committees:] Major unresolved issues may be referred to FDA's standing advisory committees for recommendations. **[Subpart D -- Responsibilities of Sponsors and Investigators ]** - **Subpart D -- General responsibilities of sponsors (§312.50):** - Select qualified investigators for clinical investigations. - Provide necessary information to investigators for proper conduct. - Ensure proper monitoring of the investigations. - Conduct investigations in line with the general investigational plan and IND protocols. - Maintain an effective IND throughout the investigations. - Promptly inform FDA and participating investigators of any significant new adverse effects or risks related to the drug. - Additional specific responsibilities are detailed in other sections of the regulations. - **Subpart D -- Transfer of obligations to a contract research organization (§312.52):** - Sponsors may transfer responsibilities to a contract research organization (CRO). - The transfer must be documented in writing. - If not all obligations are transferred, the document must specify which obligations are assumed by the CRO. - A general statement is acceptable if all obligations are transferred. - Any obligation not mentioned in the written description is considered not transferred. - [Compliance and Accountability:] - CROs must comply with the specific regulations applicable to the obligations they assume. - CROs are subject to the same regulatory actions as sponsors for non-compliance with assumed obligations. - **Subpart D -- Selecting investigators and monitors (§312.53):** - [Selecting Investigators:] - Sponsors must choose investigators who are qualified by training and experience. - [Control of Drug:] - Investigational new drugs may only be shipped to participating investigators. - [Obtaining Information from Investigators:] - [Before allowing participation, sponsors must obtain:] - [Signed Investigator Statement (Form FDA-1572) including:] - Investigator\'s name and address. - Protocol name/code from the IND. - Locations of clinical investigations and laboratories. - IRB details responsible for review and approval. - Commitments to conduct the study per protocol, comply with regulations, supervise the investigation, inform subjects of investigational use, report adverse experiences, understand the investigator\'s brochure, and inform associates of their obligations. - Assurance that an IRB will oversee the investigation\'s review and changes. - List of subinvestigators assisting in the study. - Curriculum Vitae of the investigator, showing qualifications. - [Clinical Protocol detailing:] - **[For Phase 1:]** General outline, study duration, and maximum subjects. - **[For Phase 2 or 3:]** Detailed outline including subject demographics, clinical observations, estimated study duration, and case report forms. - Financial Disclosure Information to ensure accurate certification and commitment to update information as necessary. - [Selecting Monitors:] - Sponsors must select a qualified monitor to oversee the investigation\'s progress. - **Subpart D -- Emergency research under §50.24 of this chapter (§312.54):** - [Monitoring Investigations:] - Sponsors must monitor investigations involving exceptions from informed consent under §50.24. - [Public Disclosures:] - [Upon receiving IRB information about public disclosures required by §50.24(a)(7)(ii) and (a)(7)(iii):] - Sponsors must promptly submit copies of the disclosed information to the IND file and Docket Number 95S-0158 at the FDA. - [IRB Approval Monitoring:] - [Sponsors must monitor to identify when an IRB cannot approve research due to:] - Non-compliance with §50.24(a) criteria. - Other relevant ethical concerns. - [Reporting to FDA and Others:] - [Sponsors must provide written notification to:] - FDA. - Investigators involved in the investigation. - Other IRBs reviewing the same or substantially equivalent investigations. - **Subpart D -- Informing Investigators (§312.55):** - [Investigator Brochure:] - Sponsors (other than sponsor-investigators) must provide each participating clinical investigator with an investigator brochure before the investigation begins, containing information specified in §312.23(a) (5). - [Ongoing Communication:] - Sponsors must keep participating investigators informed of new observations related to the drug throughout the investigation, especially regarding adverse effects and safe use. - [Methods of Information Distribution:] - [Information can be shared through:] - Periodically revised investigator brochures. - Reprints or published studies. - Reports or letters to clinical investigators. - Other appropriate means. - [Safety Information Requirement:] - Important safety information must be communicated to investigators as required by §312.32. - **Subpart D -- Review of ongoing investigations (§312.56):** - [Monitoring Responsibilities:] - Sponsors must monitor the progress of all clinical investigations conducted under their IND. - [Compliance Issues:] - [If an investigator is found non-compliant with the signed agreement (Form FDA-1572), investigational plan, or regulatory requirements:] - The sponsor must secure compliance or discontinue shipments of the investigational drug. - The sponsor must end the investigator\'s participation and ensure proper disposal or return of the drug per §312.59, notifying FDA accordingly. - [Safety and Effectiveness Evaluation:] - Sponsors must review and evaluate evidence related to the drug\'s safety and effectiveness as obtained from investigators. - Required reports on drug safety must be submitted to FDA under §312.32, along with annual progress reports as per §312.33. - [Risk Management:] - [If an investigational drug is determined to present unreasonable and significant risk:] - The sponsor must discontinue the investigation and notify FDA, all institutional review boards, and participating investigators. - The sponsor must manage the disposition of all drug stocks as required by §312.59 and report actions to FDA. - Investigations must be discontinued as soon as possible, but no later than 5 working days after the risk determination. - Sponsors may consult with FDA regarding the need for discontinuation. - **Subpart D -- Recordkeeping and record retention (§312.57):** - [Record Maintenance:] - Sponsors must keep adequate records of the receipt, shipment, and disposition of investigational drugs. - Records should include the investigator\'s name, shipment date, quantity, and batch or code mark. - [Financial Interest Documentation:] - Sponsors must maintain accurate records of any financial interests paid to clinical investigators, as outlined in §54.4(a)(3). - Records should also cover all other financial interests of investigators subject to part 54. - [Retention Period:] - Records and reports must be kept for 2 years after a marketing application is approved. - If the application is not approved, records should be retained for 2 years after investigational use is discontinued, with FDA notified. - [Sample Retention:] - Sponsors must retain reserve samples of test articles and reference standards used in bioequivalence or bioavailability studies. - These samples must be released to FDA upon request and retained for the period specified in §320.38. - **Subpart D -- Inspection of sponsors records and reports (§312.58):** - [FDA Inspection:] - Sponsors must allow FDA officers access to records and reports related to clinical investigations upon request. - Records must be made available for copying and verification at reasonable times. - If requested in writing by FDA, sponsors must submit records or reports to the agency. - Sponsors must stop shipments of the drug to any investigator who fails to maintain or provide required records. - [Controlled Substances:] - For investigational drugs classified under the Controlled Substances Act, relevant records must be accessible for inspection by authorized Drug Enforcement Administration (DEA) employees. - Sponsors must ensure proper security measures for investigational drugs, including storage in securely locked cabinets or enclosures to prevent theft or diversion. - **Subpart D -- Disposition of unused supply of investigational drug (§312.59):** - Sponsors must ensure the return of all unused investigational drug supplies from investigators whose participation is discontinued or terminated. - Alternative disposition of unused supplies may be authorized by the sponsor, as long as it does not pose risks to humans. - Sponsors must maintain written records of any disposition of the drug in accordance with §312.57. - **Subpart D -- General responsibilities of investigators (§312.60):** - Investigators must conduct investigations according to the signed investigator statement, investigational plan, and applicable regulations. - They are responsible for protecting the rights, safety, and welfare of subjects under their care. - Investigators must control the drugs being investigated. - Informed consent must be obtained from each human subject, except as specified in §§50.23 or 50.24. - Additional specific responsibilities for clinical investigators are outlined in parts 50 and 56. - **Subpart D -- Control of the investigational drug (§312.61):** - Investigators must administer the drug only to subjects they personally supervise or to subjects under a responsible sub investigator. - Investigators are prohibited from supplying the investigational drug to anyone not authorized to receive it. - **Subpart D -- Investigator recordkeeping and record retention (§312.62):** - [Disposition of Drug:] Investigators must keep records of the drug\'s disposition, including dates, quantity, and subject use. Upon termination or completion of the investigation, unused supplies must be returned to the sponsor or disposed of as per §312.59. - [Case Histories:] Investigators must prepare and maintain accurate case histories for each subject, documenting all relevant observations and data. This includes case report forms, consent forms, medical records, and documentation of informed consent prior to study participation. - [Record Retention:] Investigators must retain required records for 2 years after a marketing application is approved, or for 2 years after the investigation is discontinued and the FDA is notified if no application is filed. - **Subpart D -- Investigator reports (§312.64):** - [Progress Reports:] Investigators must provide all reports to the sponsor, who is responsible for collecting and evaluating results. Sponsors must submit annual progress reports to the FDA as required under §312.33. - [Safety Reports:] Investigators must immediately report any serious adverse events to the sponsor, including an assessment of whether the drug could have caused the event. Serious adverse events must be reported as outlined in the protocol unless evidence suggests a causal relationship, in which case immediate reporting is required. Nonserious adverse events should be recorded and reported according to the protocol\'s timetable. - [Final Report:] Investigators must submit an adequate report to the sponsor shortly after completing their participation in the investigation. - [Financial Disclosure Reports:] Clinical investigators must provide accurate financial information to the sponsor for certification or disclosure statements as required by part 54. They must promptly update this information if changes occur during the investigation and for one year after the study\'s completion. - **Subpart D -- Assurance of IRB review (§312.66):** - [IRB Responsibility:] Investigators must ensure that an Institutional Review Board (IRB) compliant with part 56 handles the initial and ongoing review and approval of the clinical study. - [Reporting Changes:] Investigators are required to promptly report any changes in research activity and any unanticipated problems involving risks to human subjects to the IRB. - [Approval for Changes:] Investigators cannot make changes to the research without IRB approval, except when necessary to address immediate hazards to human subjects. - **Subpart D -- Inspection of Investigators records and reports (§312.68):** - [FDA Access:] Investigators must allow authorized FDA officers or employees to access, copy, and verify records or reports related to the investigation as per §312.62. - [Subject Anonymity:] Investigators are not required to disclose subject names unless a detailed study of individual cases is necessary or if there are concerns about the accuracy of the records. - [Conditions for Disclosure:] Disclosure of subject identities is warranted only if there\'s reason to doubt the validity of the reported results. - **Subpart D -- Handling of controlled substances (§312.69):** - [Controlled Substances Compliance:] If the investigational drug falls under the Controlled Substances Act, specific precautions must be taken. - [Secure Storage:] The drug must be stored in a securely locked and substantially constructed cabinet or enclosure. - [Limited Access:] Access to the storage area must be restricted to prevent theft or diversion of the substance into illegal distribution channels. - **Subpart D -- Disqualification of a clinical investigator (§312.70):** - [Notification of Non-Compliance:] If the FDA finds that an investigator has repeatedly failed to comply with regulations or submitted false information, they will notify the investigator and offer a chance to explain, either in writing or in an informal conference. - [Explanation and Hearing:] If the investigator\'s explanation is accepted, disqualification proceedings will cease. If not accepted, a regulatory hearing will be offered regarding the investigator\'s eligibility to conduct clinical investigations. - [Determination of Ineligibility:] If the Commissioner finds that the investigator has repeatedly failed to comply or provided false information, the investigator will be declared ineligible to receive test articles, and this will be communicated to the investigator, the sponsor, and relevant IRBs. - [Implications of Ineligibility:] An investigator deemed ineligible cannot conduct clinical investigations supporting applications for FDA-regulated products, including drugs and biologics. - [Examination of Submissions:] Any application containing data from an ineligible investigator will be scrutinized for unreliable data essential to investigations or marketing approvals. - [Regulatory Hearing Opportunity:] If remaining data after excluding unreliable information is inadequate for safety conclusions, the sponsor will have the opportunity for a regulatory hearing. If there\'s a public health risk, the IND will be terminated immediately. - [Withdrawal of Product Approval:] If the continued approval of a product cannot be justified based on the remaining data, the FDA will proceed to withdraw its approval. - [Reinstatement of Eligibility:] An investigator may be reinstated as eligible if they provide adequate assurances of compliance with regulations for future investigations. **[Subpart E -- Drugs Intended to Treat Life-Threatening and Severely-debilitating Illnesses]** - **Subpart E -- Purpose (§312.80):** - [Purpose:] Establish procedures to expedite the development, evaluation, and marketing of therapies for life-threatening and severely debilitating illnesses, particularly when no satisfactory alternatives exist. - [Flexibility in Standards:] - Safety and effectiveness standards apply to all drugs, but flexibility is necessary due to the variety of drugs and their uses. - FDA aims to exercise broad flexibility while ensuring safety and effectiveness guarantees. - [Risk Acceptance:] - Physicians and patients are generally willing to accept greater risks or side effects for treatments of serious conditions compared to less serious ones. - [Benefit Evaluation:] - Drug benefits should be assessed relative to the severity of the disease being treated. - Interpretation: Procedures should be understood in light of the above purposes and principles**.\ ** - **Subpart E -- Scope (§312.81):** - [Scope:] This section pertains to new drug and biological products studied for safety and effectiveness in treating: - [Life-threatening diseases:] - Conditions where death is likely unless the disease is interrupted. - Conditions with potentially fatal outcomes, where survival is the primary endpoint in clinical trials. - [Severely debilitating diseases:] - Conditions causing major irreversible morbidity. - [Consultation:] Sponsors are encouraged to consult with the FDA regarding the applicability of these procedures to specific products. - **Subpart E -- Early consultation (§312.82):** - [Purpose:] Sponsors may request early meetings with FDA reviewing officials for products targeting life-threatening or severely debilitating illnesses to discuss and agree on study designs. - [Meeting Invitations:] FDA may invite outside expert scientific consultants or advisory committee members to these meetings if appropriate. - [Pre-IND Meetings:] - Sponsors can request a meeting before submitting the initial IND. - [Focus:] - Review and agree on the design of necessary animal studies for human testing. - Discuss scope and design of phase 1 testing. - Plans for studying the drug in pediatric populations. - Presentation and formatting of data in the IND. - [End-of-Phase 1 Meetings:] - After phase 1 data is available, sponsors can request a meeting with FDA. - [Focus:] - Review and agree on the design of phase 2 controlled clinical trials to ensure sufficient data for marketing approval. - Discuss pediatric studies, including design and timing. - FDA will provide guidance on the necessity of pediatric studies and potential deferral of submission until after approval. - [Documentation:] Procedures from §312.47(b)(1) regarding end-of-phase 2 conferences will also apply to end-of-phase 1 meetings, including documentation of agreements reached. - **Subpart E -- Treatment protocols (§312.83):** - [Promising Phase 2 Results:] If preliminary analysis of phase 2 test results is positive, FDA may request a treatment protocol from the sponsor. - [Review Process:] The treatment protocol will be reviewed under the procedures and criteria specified in §§312.305 and 312.320. - [Duration of Protocol:] - If granted, the treatment protocol typically remains in effect while the sponsor assembles complete data for a marketing application and FDA reviews it. - The protocol may be subject to clinical hold if specific grounds exist, as outlined in §312.42(b)(3)(ii). - **Subpart E -- Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses (§312.84):** - [Risk-Benefit Evaluation:] - FDA will make medical risk-benefit judgments when deciding on marketing approval. - The evaluation will assess whether the benefits of the drug outweigh known and potential risks, considering disease severity and lack of satisfactory alternatives. - [Consultation with Experts:] - For products discussed in end-of-phase 1 meetings, FDA will typically consult outside expert scientific advisors or committees. - Upon filing a marketing application, FDA will notify relevant advisory committee members about the application's availability for review. - [Complete Response Letter:] - If data are insufficient for approval, FDA will issue a complete response letter outlining application deficiencies. - The letter will explain why the agreed research design did not provide enough evidence for approval and include any advisory committee recommendations. - [Compliance with Regulations:] - Marketing applications will follow requirements and procedures in part 314 or part 600, in addition to those in this subpart. - **Subpart E -- Phase 4 studies (§312.85):** - [Postmarketing Agreement:] FDA may request sponsors to conduct postmarketing studies concurrent with marketing approval. - [Purpose:] These studies aim to gather additional information about the drug\'s risks, benefits, and optimal use. - [Potential Study Focus Areas:] - Different doses or administration schedules than those used in phase 2. - Use of the drug in various patient populations or disease stages. - Long-term use of the drug over extended periods. - **Subpart E -- Focused FDA regulatory research (§312.86):** - [Discretionary Research:] FDA may conduct focused regulatory research on key aspects of drug development, including preclinical, chemical/manufacturing, and clinical phases. - [Purpose:] The research aims to address public health needs and facilitate the development of therapies for life-threatening or severely debilitating illnesses. - [Goal:] To enhance understanding and improve processes related to drug development and evaluation. - **Subpart E -- Active monitoring of conduct and evaluation of clinical trials (§312.87):** - For drugs covered under this section, the Commissioner and other agency officials will monitor the progress of the conduct and evaluation of clinical trials and be involved in facilitating their appropriate progress. - **Subpart E -- Safeguards for patient safety (§312.88):** - [Comprehensive Safeguards:] All safeguards from parts 50, 56, 312, 314, and 600 apply to drugs under this section. - [Informed Consent:] Requirements for informed consent are outlined in part 50. - [Institutional Review Boards:] Oversight by institutional review boards (IRBs) is mandated in part 56. - [Animal Study Review:] Animal studies must be reviewed prior to initial human testing as per §312.23. - [Adverse Drug Experience Monitoring:] - **IND Safety Reports:** Monitoring through IND safety reports as outlined in §312.32. - **Safety Update Reports:** Required during agency review of marketing applications per §314.50. - **Postmarketing Reporting:** Ongoing reporting of adverse reactions is mandated in §314.80. **[Subpart F -- Miscellaneous]** - **Subpart F -- Import and export requirements (§312.110):** - [Imports:] - [An investigational new drug (IND) may be imported if:] - It is subject to an active IND under §312.40. - The consignee is the IND sponsor, a qualified investigator, or a domestic agent of a foreign sponsor responsible for the drug\'s control and distribution. - [Exports:] - [An investigational new drug can be exported under certain conditions:] - There is an active IND, compliance with the importing country\'s laws, and recipients are investigators in an allowed study. - The drug has valid marketing authorization in specified countries and meets relevant laws. - The drug complies with applicable laws when exported without an IND. - [A written certification is sent to the FDA's Office of International Programs detailing:] - Drug specifications. - Purpose and compliance with laws. - Assurance of safety and labeling as per foreign laws. - [National Emergencies:] - [In national emergencies, different rules apply for exporting drugs:] - Stockpiling: Requires a written statement explaining non-compliance with specific certifications and agreement from the importing country's official. - Immediate emergencies: Allows export without prior FDA authorization if justified with sufficient information from the importing country\'s government. - [Limitations:] - [Exportation cannot occur if:] - The IND is no longer active. - Requirements of relevant acts are unmet. - Conditions of certifications are no longer satisfied. - The drug does not comply with importing country laws. - [Insulin and Antibiotics:] - New insulin and antibiotic products may be exported for investigational use without compliance with these requirements. - **Subpart F -- Foreign clinical studies not conducted under an IND (§312.120):** - [Conditions for Acceptance:] - [FDA will accept foreign clinical studies as support for an IND or marketing application if:] - The study follows Good Clinical Practice (GCP), ensuring data credibility and subject safety. - **[GCP includes:]** - Independent ethics committee (IEC) review and approval. - Continuing IEC oversight. - Obtaining informed consent (with exceptions for life-threatening situations). - FDA can validate study data through onsite inspection if necessary. - [Non-Acceptance of Studies:] - Studies that do not meet these conditions will not support an IND or marketing application but will be reviewed for data. - [Supporting Information:] - [Sponsors must submit additional information to demonstrate GCP compliance, including:] - Investigator qualifications. - Research facility descriptions. - Study protocol and results. - Drug substance and product details. - Effectiveness evidence (if applicable). - IEC details and decisions. - Informed consent process. - Incentives for subjects. - Study monitoring and compliance with the protocol. - Investigator training on GCP and commitments. - [Waivers:] - [Sponsors can request waivers for GCP requirements:] - Must include justification or alternative approaches. - FDA may grant waivers in the interest of public health. - [Record Retention:] - [Records from foreign clinical studies must be retained for:] - 2 years after an FDA decision for marketing approval applications. - 2 years after IND submission for IND-only studies. - **Subpart F -- Availability for public disclosure of data and information in an IND (§312.130):** - [Confidentiality of IND Applications:] - FDA will not disclose the existence of an investigational new drug (IND) application unless it has been publicly acknowledged. - [Public Disclosure of Data:] - Data in IND applications for new drugs will be disclosed following the rules in §314.430 regarding confidentiality. - For biological products, disclosure is governed by §601.50 and §601.51. - [Safety Reports Disclosure:] - FDA must provide IND safety reports to individuals who have received the investigational drug upon request. - [Information on Informed Consent Exceptions:] - Requests for publicly disclosable information in INDs related to exceptions from informed consent (under §50.24) must be filed in Docket Number 95S-0158 at the FDA\'s Division of Dockets Management. - **Subpart F -- Address for correspondence (§312.140):** - [Initial IND Submission:] - [Must be sent to the appropriate FDA center based on product type:] - [For drug products regulated by CDER:] - Address: Central Document Room, CDER, FDA, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. - [For biological products regulated by CDER:] - Same as above. - [For biological products regulated by CBER:] - Address: CBER, Document Control Center, FDA, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. - [Post-Submission Communication:] - The responsible Center will notify the sponsor of the relevant division handling the IND. - Amendments, reports, and correspondence must be sent to the appropriate center and marked for the

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