(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.
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 shall promptly review all adverse experience information pertaining to its product obtained or otherwise received by the licensed manufacturer 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. Licensed manufacturers are not required to resubmit to FDA adverse product experience reports forwarded to the licensed manufacturer by FDA; licensed manufacturers, however, must submit all followup information on such reports to FDA. Any person subject to the reporting requirements under paragraph (c) of this section shall also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse experiences to FDA.
(c) Reporting requirements . The licensed manufacturer shall report to FDA adverse experience information, as described in this section. The licensed manufacturer shall submit two copies of each report described in this section for nonvaccine biological products to the Center for Biologics Evaluation and Research (HFM-210), or to the Center for Drug Evaluation and Research (see mailing addresses in 600.2). Submit all vaccine adverse experience reports to: Vaccine Adverse Event Reporting System (VAERS) (see mailing addresses in 600.2). FDA may waive the requirement for the second copy in appropriate instances.
(1)(i) Postmarketing 15-day "Alert reports". The licensed manufacturer shall report each adverse experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the licensed manufacturer.
(ii) Postmarketing 15-day "Alert reports"--followup. The licensed manufacturer shall promptly investigate all adverse experiences that are the subject of these postmarketing 15-day Alert reports and shall 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. Postmarketing 15-day Alert reports and followups to them shall be submitted under separate cover.
(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, shall 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 licensed manufacturer of the final biological product may be met by submission of all reports of serious adverse experiences to the licensed manufacturer of the final product. If a person elects to submit adverse experience reports to the licensed manufacturer of the final product rather than to FDA, the person shall submit each report to the licensed manufacturer of the final product within 5 calendar days of receipt of the report by the person, and the licensed manufacturer of the final product shall then comply with the requirements of this section. Under this circumstance, a person who elects to submit reports to the licensed manufacturer of the final product shall maintain a record of this action which shall include:
(A) A copy of all adverse biological product experience reports submitted to the licensed manufacturer of the final product;
(B) The date the report was received by the person;
(C) The date the report was submitted to the licensed manufacturer of the final product; and--
(D) The name and address of the licensed manufacturer of the final product.
(iv) Report identification. Each report submitted under this paragraph shall bear prominent identification as to its contents, i.e., "15-day Alert report," or "15-day Alert report-followup."
(2) Periodic adverse experience reports. (i) The licensed manufacturer shall 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 licensed manufacturer shall 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 a licensed manufacturer submit quarterly reports, or require that the licensed manufacturer 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 shall contain:
(A) A narrative summary and analysis of the information in the report and an analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the licensed manufacturer's patient identification number, adverse reaction term(s), and date of submission to FDA);
(B) A form designated for Adverse Experience Reporting by FDA for each adverse experience not reported under paragraph (c)(1)(i) of this section (with an index consisting of a line listing of the licensed manufacturer's patient identification number and adverse reaction term(s)); and
(C) A history of actions taken since the last report because of adverse experiences (for example, labeling changes or studies initiated).
(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. (1) A 15-day Alert report based on information from the scientific literature shall 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.
(2) As with all reports submitted under paragraph (c)(1)(i) of this section, reports based on the scientific literature shall be submitted on the reporting form designated by FDA or comparable format as prescribed by paragraph (f) of this section. In cases where the licensed manufacturer believes that preparing the form designated by FDA constitutes an undue hardship, the licensed manufacturer may arrange with the Division of Biostatistics and Epidemiology (HFM-210) for an acceptable alternative reporting format.
(e) Postmarketing studies. (1) Licensed manufacturers 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 licensed manufacturer concludes that there is a reasonable possibility that the product caused the adverse experience.
(2) The licensed manufacturer shall separate and clearly mark reports of adverse experiences that occur during a postmarketing study as being distinct from those experiences that are being reported spontaneously to the licensed manufacturer.
(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of this section, the licensed manufacturer shall complete the reporting form designated by FDA for each report of an adverse experience (FDA Form 3500A, or, for vaccines, a VAERS form; foreign events including those associated with the use of vaccines, may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
(2) Each completed form should refer only to an individual patient or single attached publication.
(3) Instead of using a designated reporting form, a licensed manufacturer may use a computer-generated form or other alternative format (e.g., a computer-generated tape or tabular listing) provided that:
(i) The content of the alternative format is equivalent in all elements of information to those specified in the form designated by FDA; and
(ii) the format is approved in advance by MEDWATCH: The FDA Medical Products Reporting Program; or, for alternatives to the VAERS Form, by the Division of Biostatistics and Epidemiology.
(4) Copies of the reporting form designated by FDA (FDA-3500A) for nonvaccine biological products may be obtained from http://www.fda.gov/medwatch/getforms.htm . Additional supplies of the form may be obtained from the Consolidated Forms and Publications Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of the VAERS form may be obtained from VAERS by calling 1-800-822-7967.
(g) Multiple reports. A licensed manufacturer 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 a licensed manufacturer, the licensed manufacturer should submit the report to the biologics license application for the product listed first in the report.
(h) Patient privacy. For nonvaccine biological products, a licensed manufacturer should not include in reports under this section the names and addresses of individual patients; instead, the licensed manufacturer should assign a unique code number to each report, preferably not more than eight characters in length. The licensed manufacturer should include the name of the reporter from whom the information was received. 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 this of 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.
(i) Recordkeeping. The licensed manufacturer shall maintain for a period of 10 years records of all adverse experiences known to the licensed manufacturer, including raw data and any correspondence relating to the adverse experiences.
(j) Revocation of biologics license. If a licensed manufacturer 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.
(k) 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.
(l) Disclaimer. A report or information submitted by a licensed manufacturer under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the licensed manufacturer or FDA that the report or information constitutes an admission that the biological product caused or contributed to an adverse effect. A licensed manufacturer 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.
Link to an amendment published at 79 FR 33090, June 10, 2014.
[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct. 20, 1999; 70 FR 14982, Mar. 24, 2005]