§312.32. IND safety reporting. — Inbound Citations

(k) Serious risk or serious adverse effect means an adverse drug experience, or the risk of such an experience, as that term is defined in §§ 310.305, 312.32, 314.80, and 600.80 of this chapter.

(4) A serious adverse event (as defined in § 312.32 of this chapter) is considered “known” if the manufacturer or sponsor is aware of it.

(vii) The name(s) and title(s) of the person(s) responsible under § 312.32 for review and evaluation of information relevant to the safety of the drug.

(5) In all cases of expanded access, sponsors are responsible for submitting IND safety reports and annual reports (when the IND or protocol continues for 1 year or longer) to FDA as required by §§ 312.32 and 312.33, ensuring that licensed physicians are qualified to administer the investigational drug for the expanded access use, providing licensed physicians with the information needed to minimize the risk and maximize the potential benefits of the investigational drug (the investigator's brochure must be provided if one exists for the drug), maintaining an effective IND for the expanded access use, and maintaining adequate drug disposition records and retaining records in a manner consistent with the requirements of § 312.57. Depending on the type of expanded access, other sponsor responsibilities under subpart D may also apply.

(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with § 312.32 or fails to make any other report required under this part.

(b) The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. Important safety information is required to be relayed to investigators in accordance with § 312.32.

(c) The sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA regarding information relevant to the safety of the drug as are required under § 312.32. The sponsor shall make annual reports on the progress of the investigation in accordance with § 312.33.

All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed to ensure the safety of clinical testing and the safety of products following marketing approval apply to drugs covered by this section. This includes the requirements for informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter). These safeguards further include the review of animal studies prior to initial human testing (§ 312.23), and the monitoring of adverse drug experiences through the requirements of IND safety reports (§ 312.32), safety update reports during agency review of a marketing application (§ 314.50 of this chapter), and postmarketing adverse reaction reporting (§ 314.80 of this chapter).

(3) A clinical trial of a combination product with a device primary mode of action under 21 CFR part 3, provided that it meets all other criteria of the definition under this part.

Applicable drug clinical trial means a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug product subject to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or a biological product subject to section 351 of the Public Health Service Act (42 U.S.C. 262), where “clinical investigation” has the meaning given in 21 CFR 312.3 and “phase 1” has the meaning given in 21 CFR 312.21. A clinical trial of a combination product with a drug primary mode of action under 21 CFR part 3 is also an applicable drug clinical trial, provided that it meets all other criteria of the definition under this part.

Approved drug means a drug product that is approved for any use under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or a biological product licensed for any use under section 351 of the Public Health Service Act (42 U.S.C. 262).

Approved or cleared device means a device product that is cleared for any use under section 510(k) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C 360(k)) or approved for any use under sections 515 or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C 360e, 360j(m)).

Arm means a pre-specified group or subgroup of human subject(s) in a clinical trial assigned to receive specific intervention(s) (or no intervention) according to a protocol.

Clinical study means research according to a protocol involving one or more human subjects to evaluate biomedical or health-related outcomes, including interventional studies and observational studies.

Clinical trial means a clinical investigation or a clinical study in which human subject(s) are prospectively assigned, according to a protocol, to one or more interventions (or no intervention) to evaluate the effect(s) of the intervention(s) on biomedical or health-related outcomes.

Clinical trial information means the data elements, including clinical trial registration information and clinical trial results information, that the responsible party is required to submit to ClinicalTrials.gov, as specified in section 402(j) of the Public Health Service Act (42 U.S.C. 282(j)) and this part.

Clinical trial registration information means the data elements that the responsible party is required to submit to ClinicalTrials.gov, as specified in section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or § 11.28, as applicable.

Clinical trial results information means the data elements that the responsible party is required to submit to ClinicalTrials.gov, as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service Act (42 U.S.C. 282(j)(3)(C) and (I)) or § 11.48, as applicable. If a responsible party submits clinical trial results information voluntarily for a clinical trial, clinical trial results information also means § 11.60(b)(2)(i)(B) or § 11.60(c)(2)(i)(B), as applicable.

Comparison group means a grouping of human subjects in a clinical trial that is or may be used in analyzing the results data collected during the clinical trial.

Completion date means, for a clinical trial, including an applicable clinical trial, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol or was terminated. In the case of clinical trials with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all of the primary outcomes. For a pediatric postmarket surveillance of a device product that is not a clinical trial, completion date means the date on which the final report of the pediatric postmarket surveillance of the device product is submitted to FDA. For purposes of this part, completion date is referred to as “primary completion date.”

Control or controlled means, with respect to a clinical trial, that data collected on human subjects in the clinical trial will be compared to concurrently collected data or to non-concurrently collected data (e.g., historical controls, including a human subject's own baseline data), as reflected in the pre-specified primary or secondary outcome measures. For purposes of this part, all clinical trials with one or more arms and pre-specified outcome measure(s) are controlled.

Device means a device as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(h)).

Director means the NIH Director or any official of NIH to whom the NIH Director delegates authorities granted in section 402(j) of the Public Health Service Act (42 U.S.C. 282(j)).

Drug means a drug as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(g)) or a biological product as defined in section 351 of the Public Health Service Act (42 U.S.C. 262).

Enroll or enrolled means a human subject's, or their legally authorized representative's, agreement to participate in a clinical trial following completion of the informed consent process, as required in 21 CFR part 50 and/or 45 CFR part 46, as applicable. For the purposes of this part, potential subjects who are screened for the purpose of determining eligibility for a trial, but do not participate in the trial, are not considered enrolled, unless otherwise specified by the protocol.

Human subjects protection review board means an institutional review board (IRB) as defined in 21 CFR 50.3 or 45 CFR 46.102, as applicable, that is responsible for assuring the protection of the rights, safety, and well-being of human subjects involved in a clinical trial and is adequately constituted to provide assurance of that protection. An IRB may also be known as an “independent ethics committee.”

Interventional means, with respect to a clinical study or a clinical investigation, that participants are assigned prospectively to an intervention or interventions according to a protocol to evaluate the effect of the intervention(s) on biomedical or other health-related outcomes.

Investigational Device Exemption (IDE) has the meaning given in 21 CFR part 812.

Investigational New Drug Application (IND) has the meaning given in 21 CFR 312.3.

NCT number means the unique identification code assigned to each record in ClinicalTrials.gov, including a record for an applicable clinical trial, a clinical trial, or an expanded access program.

Ongoing means, with respect to a clinical trial of a drug product (including a biological product) or a device product and to a date, that one or more human subjects is enrolled in the clinical trial, and the date is before the primary completion date of the clinical trial. With respect to a pediatric postmarket surveillance of a device product, ongoing means a date between the date on which FDA approves the plan for conducting the surveillance and the date on which the final report is submitted to FDA.

Outcome measure means a pre-specified measurement that will be used to determine the effect of an experimental variable on the human subject(s) in a clinical trial. See also the definitions of “primary outcome measure” and “secondary outcome measure.”

Pediatric postmarket surveillance of a device product means the active, systematic, scientifically valid collection, analysis, and interpretation of data or other information conducted under section 522 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360l) about a marketed device product that is expected to have significant use in patients who are 21 years of age or younger at the time of diagnosis or treatment. A pediatric postmarket surveillance of a device product may be, but is not always, a clinical trial.

Primary completion date means, for purposes of this part, “completion date.” See the definition of “completion date.”

Primary outcome measure means the outcome measure(s) of greatest importance specified in the protocol, usually the one(s) used in the power calculation. Most clinical trials have one primary outcome measure, but a clinical trial may have more than one. For purposes of this part, “primary outcome” has the same meaning as primary outcome measure.

Principal investigator means the individual who is responsible for the overall scientific and technical direction of the study.

Protocol means the written description of the clinical trial, including objective(s), design, and methods. It may also include relevant scientific background and statistical considerations.

Responsible party means, with respect to a clinical trial, the sponsor of the clinical trial, as defined in 21 CFR 50.3; or the principal investigator of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the principal investigator is responsible for conducting the trial, has access to and control over the data from the clinical trial, has the right to publish the results of the trial, and has the ability to meet all of the requirements under this part for the submission of clinical trial information. For a pediatric postmarket surveillance of a device product that is not a clinical trial, the responsible party is the entity who FDA orders to conduct the pediatric postmarket surveillance of the device product.

Secondary outcome measure means an outcome measure that is of lesser importance than a primary outcome measure, but is part of a pre-specified analysis plan for evaluating the effects of the intervention or interventions under investigation in a clinical trial and is not specified as an exploratory or other measure. A clinical trial may have more than one secondary outcome measure. For purposes of this part, “secondary outcome” has the same meaning as secondary outcome measure.

Secretary means the Secretary of Health and Human Services or any other official(s) to whom the Secretary delegates the authority contained in section 402(j) of the Public Health Service Act (42 U.S.C. 282(j)).

Serious adverse event means an adverse event that results in any of the following outcomes: Death, a life-threatening adverse event as defined in 21 CFR 312.32, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the human subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of a substance use disorder.

Sponsor means either a “sponsor” or “sponsor-investigator,” as each is defined in 21 CFR 50.3.

Study completion date means, for a clinical trial, the date the final subject was examined or received an intervention for purposes of final collection of data for the primary and secondary outcome measures and adverse events (e.g., last subject's last visit), whether the clinical trial concluded according to the pre-specified protocol or was terminated.

U.S. FDA-regulated device product means, for purposes of this part, a device product subject to section 510(k), 515, 520(m), or 522 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m), 21 U.S.C. 360l).

U.S. FDA-regulated drug product means, for purposes of this part, a drug product subject to section 505 of the Federal Food, Drug, and Cosmetic Act or a biological product subject to section 351 of the Public Health Service Act (21 U.S.C. 355, 42 U.S.C. 262) .

(3) The person conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event, as defined in § 312.32(a), observed during the conduct of the study as soon as possible but in no case later than 15 calendar days after becoming aware of its occurrence. Each report must be submitted on FDA Form 3500A or in an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). Each report must bear prominent identification of its contents, i.e., “bioavailability/bioequivalence safety report.” The person conducting the study, including any contract research organization, must also notify FDA of any fatal or life-threatening adverse event from the study as soon as possible but in no case later than 7 calendar days after becoming aware of its occurrence. Each notification under this paragraph must be submitted to the Director, Office of Generic Drugs in the Center for Drug Evaluation and Research at FDA. Relevant followup information to a bioavailability/bioequivalence safety report must be submitted as soon as the information is available and must be identified as such, i.e., “Followup bioavailability/bioequivalence safety report.” Upon request from FDA, the person conducting the study, including any contract research organization, must submit to FDA any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request.

(5) Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as described in the protocol and ordinarily would not be reported under paragraph (c) of this section. However, if a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis), the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause mortality).