21 C.F.R. § 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this section:
Adverse experience. Any adverse event associated with the use of a biological product in humans, whether or not considered product related, including the following: An adverse event occurring in the course of the use of a biological product in professional practice; an adverse event occurring from overdose of the product whether accidental or intentional; an adverse event occurring from abuse of the product; an adverse event occurring from withdrawal of the product; and any failure of expected pharmacological action.
Blood Component. As defined in § 606.3(c) of this chapter.
Disability. A substantial disruption of a person's ability to conduct normal life functions.
Individual case safety report (ICSR). A description of an adverse experience related to an individual patient or subject.
ICSR attachments. Documents related to the adverse experience described in an ICSR, such as medical records, hospital discharge summaries, or other documentation.
Life-threatening adverse experience. Any adverse experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse experience as it occurred, i.e., it does not include an adverse experience that, had it occurred in a more severe form, might have caused death.
Serious adverse experience. Any adverse experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse 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 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 experience: Any adverse experience that is not listed in the current labeling for the biological product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.
(b) Review of adverse experiences. Any person having a biologics license under § 601.20 of this chapter must promptly review all adverse experience information pertaining to its product obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers. Applicants are not required to resubmit to FDA adverse product experience reports forwarded to the applicant by FDA; applicants, however, must submit all followup information on such reports to FDA. Any person subject to the reporting requirements under paragraph (c) of this section must also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse experiences to FDA.
(c) Reporting requirements. The applicant must submit to FDA postmarketing 15-day Alert reports and periodic safety reports pertaining to its biological product as described in this section. These reports must be submitted to the Agency in electronic format as described in paragraph (h)(1) of this section, except as provided in paragraph (h)(2) of this section.
(1)(i) Postmarketing 15-day “Alert reports”. The applicant must report each adverse experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant.
(ii) Postmarketing 15-day “Alert reports”—followup. The applicant must promptly investigate all adverse experiences that are the subject of these postmarketing 15-day Alert reports and must submit followup reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.
(iii) Submission of reports. The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, also apply to any person whose name appears on the label of a licensed biological product as a manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any other participant involved in divided manufacturing. To avoid unnecessary duplication in the submission to FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of persons other than the applicant of the final biological product may be met by submission of all reports of serious adverse experiences to the applicant of the final product. If a person elects to submit adverse experience reports to the applicant rather than to FDA, the person must submit, by any appropriate means, each report to the applicant within 5 calendar days of initial receipt of the information by the person, and the applicant must then comply with the requirements of this section. Under this circumstance, a person who elects to submit reports to the applicant of the final product shall maintain a record of this action which must include:
(A) A copy of all adverse biological product experience reports submitted to the applicant of the final product;
(B) The date the report was received by the person;
(C) The date the report was submitted to the applicant of the final product; and—
(D) The name and address of the applicant of the final product.
(2) Periodic adverse experience reports. (i) The applicant must report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years from the date of issuance of the biologics license, and then at annual intervals. The applicant must submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of issuance of the biologics license) and each annual report within 60 days of the anniversary date of the issuance of the biologics license. Upon written notice, FDA may extend or reestablish the requirement that an applicant submit quarterly reports, or require that the applicant submit reports under this section at different times than those stated. Followup information to adverse experiences submitted in a periodic report may be submitted in the next periodic report.
(ii) Each periodic report is required to contain:
(A) Descriptive information. (1) A narrative summary and analysis of the information in the report;
(2) An analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the applicant's patient identification code for nonvaccine biological product reports or by the unique case identification number for vaccine reports, adverse reaction term(s), and date of submission to FDA);
(3) A history of actions taken since the last report because of adverse experiences (for example, labeling changes or studies initiated);
(4) An index consisting of a line listing of the applicant's patient identification code for nonvaccine biological product reports or by the unique case identification number for vaccine reports and adverse reaction term(s) for ICSRs submitted under paragraph (c)(2)(ii)(B) of this section; and
(B) ICSRs for serious, expected and, nonserious adverse experiences. An ICSR for each adverse experience not reported under paragraph (c)(1)(i) of this section (all serious, expected and nonserious adverse experiences). All such ICSRs must be submitted to FDA (either individually or in one or more batches) within the timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must only be submitted to FDA once.
(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.
(d) Scientific literature. A 15-day Alert report based on information in the scientific literature must be accompanied by a copy of the published article. The 15-day Alert reporting requirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse experiences) apply only to reports found in scientific and medical journals either as case reports or as the result of a formal clinical trial.
(e) Postmarketing studies. Applicants are not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse experience obtained from a postmarketing clinical study (whether or not conducted under a biological investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the product caused the adverse experience.
(f) Information reported on ICSRs for nonvaccine biological products. ICSRs for nonvaccine biological products include the following information:
(1) Patient information.
(i) Patient identification code;
(ii) Patient age at the time of adverse experience, or date of birth;
(iii) Patient gender; and
(iv) Patient weight.
(2) Adverse experience.
(i) Outcome attributed to adverse experience;
(ii) Date of adverse experience;
(iii) Date of report;
(iv) Description of adverse experience (including a concise medical narrative);
(v) Adverse experience term(s);
(vi) Description of relevant tests, including dates and laboratory data; and
(vii) Other relevant patient history, including preexisting medical conditions.
(3) Suspect medical product(s).
(i) Name;
(ii) Dose, frequency, and route of administration used;
(iii) Therapy dates;
(iv) Diagnosis for use (indication);
(v) Whether the product is a combination product as defined in § 3.2(e) of this chapter;
(vi) Whether the product is a prescription or nonprescription product;
(vii) Whether adverse experience abated after product use stopped or dose reduced;
(viii) Whether adverse experience reappeared after reintroduction of the product;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number, or other unique identifier; and
(xii) Concomitant medical products and therapy dates.
(4) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
(iii) Occupation, if a health care professional.
(5) Applicant information.
(i) Applicant name and contact office address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date the report was received by applicant;
(v) Application number and type;
(vi) Whether the ICSR is a 15-day “Alert report”;
(vii) Whether the ICSR is an initial report or followup report; and
(viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).
(g) Information reported on ICSRs for vaccine products. ICSRs for vaccine products include the following information:
(1) Patient information.
(i) Patient name, address, telephone number;
(ii) Patient age at the time of vaccination, or date of birth;
(iii) Patient gender; and
(iv) Patient birth weight for children under age 5.
(2) Adverse experience.
(i) Outcome attributed to adverse experience;
(ii) Date and time of adverse experience;
(iii) Date of report;
(iv) Description of adverse experience (including a concise medical narrative);
(v) Adverse experience term(s);
(vi) Illness at the time of vaccination;
(vii) Description of relevant tests, including dates and laboratory data; and
(viii) Other relevant patient history, including preexisting medical conditions.
(3) Suspect medical product(s), including vaccines administered on the same date.
(i) Name;
(ii) Dose, frequency, and route or site of administration used;
(iii) Number of previous vaccine doses;
(iv) Vaccination date(s) and time(s);
(v) Diagnosis for use (indication);
(vi) Whether the product is a combination product (as defined in § 3.2(e) of this chapter);
(vii) Whether the adverse experience abated after product use stopped or dose reduced;
(viii) Whether the adverse experience reappeared after reintroduction of the product;
(ix) Lot number;
(x) Expiration date;
(xi) National Drug Code (NDC) number, or other unique identifier; and
(xii) Concomitant medical products and therapy dates.
(4) Vaccine(s) administered in the 4 weeks prior to the vaccination date.
(i) Name of vaccine;
(ii) Manufacturer;
(iii) Lot number;
(iv) Route or site of administration;
(v) Date given; and
(vi) Number of previous doses.
(5) Initial reporter information.
(i) Name, address, and telephone number;
(ii) Whether the initial reporter is a health care professional; and
(iii) Occupation, if a health care professional.
(6) Facility and personnel where vaccine was administered.
(i) Name of person who administered vaccine;
(ii) Name of responsible physician at facility where vaccine was administered; and
(iii) Name, address (including city, county, and state), and telephone number of facility where vaccine was administered.
(7) Applicant information.
(i) Applicant name and contact office address;
(ii) Telephone number;
(iii) Report source, such as spontaneous, literature, or study;
(iv) Date received by applicant;
(v) Application number and type;
(vi) Whether the ICSR is a 15-day “Alert report”;
(vii) Whether the ICSR is an initial report or followup report; and
(viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).
(h) Electronic format for submissions. (1) Safety report submissions, including ICSRs, ICSR attachments, and the descriptive information in periodic reports, must be in an electronic format that FDA can process, review, and archive. FDA will issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).
(2) Persons subject to the requirements of paragraph (c) of this section may request, in writing, a temporary waiver of the requirements in paragraph (h)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (h)(1) of this section. Requests for waivers must be submitted in accordance with § 600.90.
(i) Multiple reports. An applicant should not include in reports under this section any adverse experience that occurred in clinical trials if they were previously submitted as part of the biologics license application. If a report refers to more than one biological product marketed by an applicant, the applicant should submit the report to the biologics license application for the product listed first in the report.
(j) Patient privacy. For nonvaccine biological products, an applicant should not include in reports under this section the names and addresses of individual patients; instead, the applicant should assign a unique code for identification of the patient. The applicant should include the name of the reporter from whom the information was received as part of the initial reporter information, even when the reporter is the patient. The names of patients, health care professionals, hospitals, and geographical identifiers in adverse experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter. For vaccine adverse experience reports, these data will become part of the CDC Privacy Act System 09-20-0136, “Epidemiologic Studies and Surveillance of Disease Problems.” Information identifying the person who received the vaccine or that person's legal representative will not be made available to the public, but may be available to the vaccinee or legal representative.
(k) Recordkeeping. The applicant must maintain for a period of 10 years records of all adverse experiences known to the applicant, including raw data and any correspondence relating to the adverse experiences.
(l) Revocation of biologics license. If an applicant fails to establish and maintain records and make reports required under this section with respect to a licensed biological product, FDA may revoke the biologics license for such a product in accordance with the procedures of § 601.5 of this chapter.
(m) Exemptions. Manufacturers of the following listed products are not required to submit adverse experience reports under this section:
(1) Whole blood or components of whole blood.
(2) In vitro diagnostic products, including assay systems for the detection of antibodies or antigens to retroviruses. These products are subject to the reporting requirements for devices.
(n) Disclaimer. A report or information submitted by an applicant under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the biological product caused or contributed to an adverse effect. An applicant need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the biological product caused or contributed to an adverse effect. For purposes of this provision, this paragraph also includes any person reporting under paragraph (c)(1)(iii) of this section.