Associated with the use of the drug. There is a reasonable possibility that the experience may have been caused by the drug.

Disability. A substantial disruption of a person's ability to conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience: Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or 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 drug dependency or drug abuse.

Unexpected adverse drug experience: Any adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by

virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. "Unexpected,” as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

(b) Review of safety information. The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the agency by the sponsor.

(c) IND safety reports. (1) Written reports—(i) The sponsor shall notify FDA and all participating investigators in a written IND safety report of:

(A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or

(B) Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification shall be made as soon as possible and in no event later than 15 calendar days after the sponsor's initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological studies shall be submitted in a narrative format) and shall bear prominent identification of its contents, i.e., "IND Safety Report." Each written notification to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility

for review of the IND. If FDA determines that additional data are needed, the agency may require further data to be submitted.

(ii) In each written IND safety report, the sponsor shall identify all safety reports previously filed with the IND concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of the previouos, similar reports.

(2) Telephone and facsimile transmission safety reports. The sponsor shall also notify FDA by telephone or by facsimile transmission of any unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but in no event later than 7 calendar days after the sponsor's initial receipt of the information. Each telephone call or facsimile transmission to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND.

(3) Reporting format or frequency. FDA may request a sponsor to submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the new drug review division in the Center for Drug Evaluation and Research or the director of the products review division in the Center for Biologics Evaluation and Research which is responsible for review of the IND.

(4) A sponsor of a clinical study of a marketed drug is not required to make a safety report for any adverse experience associated with use of the drug that is not from the clinical study itself.

(d) Followup. (1) The sponsor shall promptly investigate all safety information received by it.

(2) Followup information to a safety report shall be submitted as soon as the relevant information is available.

(3) If the results of a sponsor's investigation show that an adverse drug experience not initially determined to be reportable under paragraph (c) of this

section is so reportable, the sponsor shall report such experience in a written safety report as soon as possible, but in no event later than 15 calendar days after the determination is made.

(4) Results of a sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report.

(e) Disclaimer. A safety report or other information submitted by a sponsor under this part (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse experience. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse experience.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990; 62 FR 52250, Oct. 7, 1997]

EFFECTIVE DATE NOTE: At 62 FR 52250, Oct. 7, 1997, § 312.32 was amended by revising paragraphs (a), (b), (c)(1)(i), (c)(2), and (d)(3); by adding in the second sentence of paragraph (c)(3) the words "new drug review" before the phrase "division in the Center for Drug Evaluation and Research" and the words "the director of the product review division in" before the phrase "the Center for Biologics Evaluation and Research"; and by removing in paragraph (e) the word "section" and replacing it with the word "part", effective Apr. 6, 1998. For the convenience of the user, the superseded text is set forth as follows: § 312.32 IND safety reports.

(a) Definitions. The following definitions of terms apply to this section:

Associated with the use of the drug means that there is a reasonable possibility that the experience may have been caused by the drug.

Serious adverse experience means any experience that suggests a significant hazard, contraindication, side effect, or precaution. With respect to human clinical experience, a serious adverse drug experience includes any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. With respect to results obtained from tests in laboratory animals, a

serious adverse drug experience includes any experience suggesting a significant risk for human subjects, including any finding of mutagenicity, teratogenicity, or carcinogenicity.

Unexpected adverse experience means any adverse experience that is not identified in nature, severity, or frequency in the current investigator brochure; or, if an investigator brochure is not required, that is not identified in nature, severity, or freuquency in the risk information described in the general investigational plan or elsewhere in the current application, as amended.

(b) Review of safety information. The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from clinical investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers.

(c) IND safety reports. (1) Written reports. (1) The sponsor shall notify FDA and all participating investigators in a written IND safety report of any adverse experience associated with use of the drug that is both serious and unexpected. Such notification shall be made as soon as possible and in no event later than 10 working days after the sponsor's initial receipt of the information. Each written notification shall bear prominent identification of its contents, i.e., "IND Safety Report." Each written notification to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND.

(11)* * *

8

(2) Telephone report. The sponsor shall also notify FDA by telephone of any unexpected fatal or life-threatening experience associated with use of the drug in the clinical studies conducted under the IND no later than 3 working days after receipt of the information. Each telephone call to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND. For purposes of this section, lifethreatening means that the patient was, in the view of the investigator, at immediate (emphasis added) risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though drug-induced hepatitis can be fatal.

(d)* * *

*

(3) If the results of a sponsor's investigation show that an adverse experience not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor shall report such experience in a safety report as soon as possible after the determination is made, but in no event longer than 10-working days.

§ 312.33 Annual reports.

A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes:

(a) Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study:

(1) The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed.

(2) The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the number who dropped out of the study for any rea

son.

(3) If the study has been completed, or if interim results are known, a brief description of any available study results.

(b) Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including:

(1) A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.

(2) A summary of all IND safety reports submitted during the past year.

(3) A list of subjects who died during participation in the investigation, with the cause of death for each subject.

(4) A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related.

(5) A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose response, information from controlled trails, and information

about bioavailability.

(6) A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings.

(7) A summary of any significant manufacturing or microbiological changes made during the past year.

(c) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier. The general investigational plan shall contain the information required under §312.23(a)(3)(iv).

(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.

(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment.

(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country.

(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment, or meeting.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

§ 312.34 Treatment use of an investigational new drug.

(a) General. A drug that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients not in the clinical trials, in accordance with a treatment protocol or treatment IND. The purpose of this section is to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before general marketing begins, and to obtain additional data on the drug's safety and effectiveness. In the case of a serious disease, a drug ordinarily may be made available for treatment use under this section during Phase 3 investigations or after all clinical trials have been completed; however, in appropriate circumstances, a drug may be made available for treatment use during Phase 2. In the case of an immediately life-threatening disease, a drug may be made available for treatment use under this section earlier than Phase 3, but ordinarily not earlier than Phase 2. For purposes of this section, the "treatment use" of a drug includes the use of a drug for diagnostic purposes. If a protocol for an investigational drug meets the criteria of this section, the protocol is to be submitted as a treatment protocol under the provisions of this section.

(b) Criteria. (1) FDA shall permit an investigational drug to be used for a treatment use under a treatment protocol or treatment IND if:

(i) The drug is intended to treat a serious or immediately life-threatening disease;

(ii) There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the

disease in the intended patient population;

(iii) The drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed; and

(iv) The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence.

(2) Serious disease. For a drug intended to treat a serious disease, the Commissioner may deny a request for treatment use under a treatment protocol or treatment IND if there is insufficient evidence of safety and effectiveness to support such use.

(3) Immediately life-threatening disease. (i) For a drug intended to treat an immediately life-threatening disease, the Commissioner may deny a request for treatment use of an investigational drug under a treatment protocol or treatment IND if the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug:

(A) May be effective for its intended use in its intended patient population;

or

(B) Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury.

(ii) For the purpose of this section, an "immediately life-threatening" disease rneans a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

(c) Safeguards. Treatment use of an investigational drug is conditioned on the sponsor and investigators complying with the safeguards of the IND process, including the regulations governing informed consent (21 CFR part 50) and institutional review boards (21 CFR part 56) and the applicable provisions of part 312, including distribution of the drug through qualified experts, maintenance of adequate manufacturing facilities, and submission of IND safety reports.

(d) Clinical hold. FDA may place on clinical hold a proposed or ongoing

(a) Treatment protocol submitted by IND sponsor. Any sponsor of a clinical investigation of a drug who intends to sponsor a treatment use for the drug shall submit to FDA a treatment protocol under §312.34 if the sponsor believes the criteria of §312.34 are satisfied. If a protocol is not submitted under §312.34, but FDA believes that the protocol should have been submitted under this section, FDA may deem the protocol to be submitted under §312.34. A treatment use under a treatment protocol may begin 30 days after FDA receives the protocol or on earlier notification by FDA that the treatment use described in the protocol may begin.

(1) A treatment protocol is required to contain the following:

(i) The intended use of the drug.

(ii) An explanation of the rationale for use of the drug, including, as appropriate, either a list of what available regimens ordinarily should be tried before using the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available marketed treatments.

(iii) A brief description of the criteria for patient selection.

(iv) The method of administration of the drug and the dosages.

(v) A description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk.

(2) A treatment protocol is to be supported by the following:

(i) Informational brochure for supplying to each treating physician.

(ii) The technical information that is relevant to safety and effectiveness of the drug for the intended treatment purpose. Information contained in the sponsor's IND may be incorporated by reference.

(iii) A commitment by the sponsor to assure compliance of all participating investigators with the informed consent requirements of 21 CFR part 50.