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This guidance is intended to assist applicants and other responsible parties in fulfilling the FDA's existing postmarketing safety reporting requirements for human marketed drug and biological products at 21 CFR 310.305, 314.80, 314.98, 600.80, and 600.81 2. Under these regulations, postmarketing safety reports must be submitted to the Agency for the following:
This guidance discusses the following postmarketing reports:
This guidance addresses the following regulations for the following products. 3
If you believe the procedures described in this guidance are inapplicable to a particular product or that other procedures are appropriate, you should discuss the matter with the Agency to ensure that your procedures comply with applicable statutes and regulations.
This guidance does not discuss the following: This guidance does not apply to the following products:
The Agency's good guidance practices (GGPs) regulation 5 does not allow the use of mandatory language in guidances unless it is used to describe regulatory requirements. In most guidances, we provide the related cite whenever mandatory language is used to indicate the basis for the use of such language. This guidance discusses regulatory requirements in great detail. To avoid including the same regulatory cites repeatedly and to make the guidance user friendly, we will indicate at the beginning of those sections that include extensive discussions of regulatory requirements which cites are particularly relevant. The use of mandatory language (e.g., must, have to, required ) will signify a regulatory requirement while the use of words such as should and recommend will indicate Agency policy.
The FDA has undertaken a major effort to clarify and revise its regulations regarding pre- and postmarketing safety reporting requirements for human drug and biological products. To date, the Agency has issued a number of final rules and guidances for industry on this topic; several proposed rules are under development.
In the Federal Register of October 7, 1997 (62 FR 52237), the FDA published a final rule amending its regulations for expedited safety reporting to implement certain definitions, reporting periods, and formats recommended by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). These recommendations are discussed in the ICH guidance E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting; March 1, 1995.
In the Federal Register of June 25, 1997 (62 FR 34166), the FDA published a final rule revoking requirements to submit postmarketing increased frequency reports to the Agency in an expedited manner for human drug and biological products.
With regard to postmarketing safety reporting for human drug and biological products, the FDA has made three final guidances available:
When finalized, this guidance will replace the three guidances listed above and will reflect the new regulatory requirements in the final rules of June 25, 1997, and October 7, 1997.
The Agency currently is in the process of developing proposed rules to further amend its safety reporting requirements for human drug and biological products. Many of the provisions in these proposed rules will be based on recommendations developed by ICH. For instance, the Agency is planning to propose additional amendments to its expedited safety reporting regulations based on the ICH E2A guidance. In addition, the FDA is planning, as indicated in the final rule of October 7, 1997, to repropose amendments to its postmarketing periodic safety reporting requirements that were initially proposed in the Federal Register of October 27, 1994 (59 FR 54046). The new postmarketing periodic safety reporting proposals will be based on recommendations in the ICH guidance E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs (May 19, 1997). The Agency also is planning to issue a proposal requiring the electronic submission of postmarketing safety reports consistent with recommendations developed by ICH 6. As these proposed rules are finalized, this postmarketing safety reporting guidance for human drug and biological products will be revised to provide industry with assistance in fulfilling the new regulatory requirements.
According to the regulations, the following persons have postmarketing safety reporting responsibilities:
For the purposes of this guidance, the term applicant includes all persons with postmarketing safety reporting responsibilities under §§ 310.305, 314.80, 314.98, 600.80, and 600.81. According to the regulations at §§ 310.305(d), 314.80(f), and 600.80(f), if an applicant becomes aware of a reportable adverse experience, the applicant is responsible for preparing a postmarketing safety report and submitting it to the FDA. Applicants should not assume that their responsibilities are fulfilled if they ask the person who pointed out a reportable adverse experience to submit a safety report to the FDA.
The following paragraphs discuss the types of adverse experiences that must be reported to the FDA under §§ 310.305, 314.80, 314.98, and 600.80. This section also describes the minimum data elements that should be included in an individual case safety report. An adverse experience is any undesirable event that is associated with the use of a drug or biological product in humans whether or not considered product-related by the applicant 7. An individual case safety report describes an adverse experience(s) for a patient or subject. Individual case safety reports of domestic adverse experiences for marketed human drug and biological products, except vaccines, must be submitted to the FDA on FDA Form 3500A; a Vaccine Adverse Event Reporting System (VAERS) form must be used for adverse experiences associated with the use of vaccines. Individual case safety reports of foreign adverse experiences can be submitted on FDA Form 3500A (VAERS form for vaccines) or, if preferred, on a Council for International Organizations for Medical Sciences (CIOMS) I form. See section VIII in this guidance for discussion of reporting formats for individual case safety reports.
Spontaneous reports are unsolicited communications from individuals (e.g., health care professional, consumer) to applicants that concern adverse experiences. Spontaneous reports should not include adverse experiences identified from information solicited by applicants such as individual cases or findings derived from a study (e.g., any organized data collection scheme).
Before considering any clinical incident for submission to the FDA in an individual case safety report, applicants should, at a minimum, have knowledge of the following four data elements:
If any one of these basic elements remains unknown after being actively sought by the applicant, a report on the incident should not be submitted to the FDA because reports without such information make interpretation of their significance difficult, at best, and impossible, in most instances. Instead, the applicant should maintain records of its efforts to obtain the basic elements for an individual case in its corporate drug or biological product safety files. If an applicant submits a report to the FDA that lacks any of the four basic elements, it will be returned to the applicant marked insufficient data for a report. An applicant that is actively seeking information on an adverse experience should use direct verbal contact with the initial reporter of the adverse experience (e.g., in person, by telephone or other interactive means such as a videoconference). The applicant should not merely send the initial reporter a letter requesting information concerning the adverse experience. Applicants should use a health care professional (e.g., physician, physician assistant, dentist, pharmacist, nurse) for contacts with initial reporters because such persons should be able to understand the medical consequences of the case and ask appropriate questions to acquire relevant information rapidly to determine the significance of the case. With regard to an identifiable patient , reports of the type "some patients got anaphylaxis" should be excluded until further information about the patients is obtained. A report stating that "an elderly woman had anaphylaxis" or a "young man experienced anaphylaxis" should be included because there is enough information to suspect that specific patients were involved. Patients should not be identified by name or address. Instead, the applicant should assign a unique code (e.g., patient initials) to each report. For spontaneous reports, the applicant should assume that an adverse experience or fatal outcome was suspected to be due to the suspect drug or biological product (implied causality). For clinical studies, an adverse experience or fatal outcome need not be submitted to the FDA unless the applicant concludes that there is a reasonable possibility that the product caused the adverse experience or fatal outcome (see §§ 310.305(c)(1)(ii), 314.80(e)(1) and 600.80(e)(1)). An adverse experience should, at a minimum, consist of signs (including abnormal laboratory findings, if appropriate), symptoms, or disease diagnosis (including any colloquial descriptions obtained) for purposes of reporting. Thus, a report stating that a patient "experienced unspecified injury," or a patient "suffered irreparable damages" should not be included until more specific information about the adverse experience can be determined.
The following paragraphs discuss the types of postmarketing safety reports that must be submitted to the FDA based on the regulations as listed.
The following paragraphs discuss the types of postmarketing safety reports that must be submitted to the FDA based on the regulations as listed. An applicant should not wait for the initial reporter of a serious, unexpected adverse experience to send them written information about the experience before submitting a 15-day report to the FDA. An applicant can and should submit a 15-day report to the FDA based only on verbal information.
The following paragraphs discuss the reporting frequency for submission of periodic reports and the content of these reports. See section XI in this guidance for requests for waivers of the requirement to submit postmarketing periodic safety reports (e.g., waiver to use periodic safety update report (PSUR) format recommended by ICH for periodic report instead of format described in the regulations, waiver to submit individual cases of nonserious, expected adverse experiences in periodic report).
The following paragraphs discuss the content of and reporting considerations for 15-day followup reports that are submitted in an expedited manner and non-15 day followup reports that are submitted as part of a postmarketing periodic report. A followup report provides information about an adverse experience that has been previously reported as an initial report with a unique manufacturer report number. The followup report should be identified with the same unique manufacturer report number as the initial report. A 15-day followup report must be submitted within 15 calendar days of receipt of new information on a 15-day report. Followup information to adverse experiences submitted initially in a periodic report can be submitted in the next periodic report.
This section is based primarily on regulations in § 600.81. These regulations only apply to human biological products with approved BLAs. Unless otherwise notified by the Director, Center for Biologics Evaluation and Research, an applicant must submit at periodic intervals two copies of a report containing information about the quantity of the product distributed domestically (including distributors) under the BLA. Distribution reports are due within the first 6 months after approval of a BLA, and, subsequently, at 6-month intervals. Upon written notice, the FDA can require that the applicant submit reports under this section at alternate times. The report must include the bulk lot, fill lot, and label lot numbers for the total number of dosage units of each strength or potency distributed (e.g., 50,000 per 10-milliliter vials), labeled date of expiration, and date of distribution of fill lot or label lot. The report must also include information about any significant amount of a fill lot or label lot that may have been returned. Disclosure of financial or pricing data is not required. According to the regulations, the FDA can require submission of more detailed product distribution information, if needed. See section VIII.E in this guidance for a suggested reporting format for distribution reports.
Serious, unexpected adverse experiences reported in the scientific literature (or in an unpublished scientific paper) that are known to the applicant must be submitted as 15-day reports on an FDA Form 3500A or comparable format. Applicants can use literature search services (e.g., Weekly Reactions) to identify adverse experiences in the scientific literature. A copy of the article or manuscript must be attached to the completed FDA Form 3500A; it is not sufficient to submit only abstracts of articles. All reports from the scientific literature and unpublished scientific papers should be marked Literature in item G3 of FDA Form 3500A. A separate FDA Form 3500A should be completed for each identifiable patient that experiences a serious, unexpected adverse experience. Thus, if an article describes six patients that experience a given serious, unexpected adverse experience, six FDA Form 3500As should be completed. In such cases, a copy of the article should be attached only to one of the FDA Form 3500As. All other FDA Form 3500As submitted for the article should reference the manufacturer report number of the FDA Form 3500A that has the copy of the article attached. If multiple products are mentioned in the article, an FDA Form 3500A should be submitted only by the applicant whose product is the suspect drug. The suspect product is that identified by the article's author and is usually mentioned in the article's title. If the applicant believes that the suspect product is different from the one identified by the author of the article, the applicant should indicate such information in the narrative section of the FDA Form 3500A. Reports of serious, unexpected adverse experiences described in the scientific literature should be submitted for products that have the same active moiety as a product marketed in the United States. This is true even if the excipient, dosage forms, strengths, routes of administration, and indications vary. When a serious, unexpected adverse experience is based on a foreign language article or manuscript, the applicant should translate the publication into English promptly. The original article or unpublished scientific paper and translation should be attached to the submitted FDA Form 3500A.
For the purposes of this section, a study refers to the systematic collection of data involving solicitation of adverse experience information (e.g., derived from a clinical trial, patient registry). Adverse experiences incidental to other types of studies not involving monitoring adverse experiences of products should be treated as spontaneous reports (see Appendix A in this guidance for definition of spontaneous report ). For purposes of safety reporting, reports of suspected adverse experiences obtained from company sponsored patient support programs and disease management programs should be handled as if they were study reports and not as spontaneous reports. Serious, unexpected adverse experiences that occur during a study must be submitted as 15-day reports. These adverse experiences are only required to be reported if there is a reasonable possibility that the drug or biological product caused the adverse experience. Adverse experiences occurring with marketed drug or biological products during IND trials must also be submitted, as prescribed under § 312.32, to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review office in the Center for Biologics Evaluation and Research that has responsibility for oversight of the IND. For each adverse experience, a suspect product should be identified. Reports from blinded studies should be submitted only after the code is broken. The blind should always be broken for each patient or subject that experiences a serious, unexpected adverse experience unless arrangements have been made otherwise with the responsible FDA review division. Exceptions to breaking the blind usually involve situations in which mortality or certain serious morbidities are indeed the clinical endpoint. This is consistent with the ICH E2A guidance.
Foreign reports of serious, unexpected adverse experiences must be submitted as 15-day reports. Other foreign reports, including serious and expected, nonserious and unexpected, and nonserious and expected adverse experiences are not required to be submitted. Reports of foreign serious, unexpected adverse experiences should be submitted for products that have the same active moiety as a product marketed in the United States. This is true even if the excipient, dosage forms, strengths, routes of administration, and indications vary. When a foreign report is submitted on a product that is not identical to a product marketed in the United States, item C1 of FDA Form 3500A should contain the foreign trade name, the generic name, and the NDA number for the product with the same active moiety that is marketed in the United States.
Death is always a serious outcome (see definition of serious in Appendix A of this guidance and at §§ 310.305(b), 314.80(a) and 600.80(a)). Thus, if death is associated with an unexpected adverse experience, or if death is associated with an expected adverse experience but the labeling does not specifically state that the adverse experience may be associated with a fatal outcome, a 15-day report should be submitted.
Reports of overdose should be submitted only when the overdose is associated with an adverse experience. If the adverse experience associated with the overdose is serious and unexpected, a l5-day report should be completed. If the adverse experience is serious and expected, nonserious and unexpected, or nonserious and expected, a non-15 day report should be submitted in the periodic report for spontaneously reported domestic cases.
The definition of adverse experience includes any failure of expected pharmacological action that is synonymous with lack of effect (see definition of adverse experience in Appendix A of this guidance and at §§ 310.305(b), 314.80(a) and 600.80(a)). All spontaneously reported cases of a lack of effect that occur in the United States should be reported on FDA Form 3500A and submitted in the periodic report with other adverse experiences. The lot number of the suspect product should be included in item C6 of FDA Form 3500A. If the report of lack of effect is for an unapproved indication, the event should not be reported to the FDA as an individual case safety report. Instead, this information should be included in the narrative summary section of the periodic report.
Adverse experience information that is submitted to an applicant via the Internet (e.g., e-mail) should be reported to the FDA if the applicant has knowledge of the four basic elements for an individual case safety report (see section IV.B in this guidance). Applicants should review any Internet sites sponsored by them for adverse experience information, but are not responsible for reviewing any Internet sites that are not sponsored by them. However, if an applicant becomes aware of an adverse experience on an Internet site that it does not sponsor, the applicant should review the adverse experience and determine if it should be reported to the FDA.
For children under 3 years of age, the child's date of birth and age in days or months (e.g., 15 months ) should be included under item A2 of FDA Form 3500A. The word days or months should be clearly written. For all pediatric patients, body weight (item A4 of FDA Form 3500A) and dose (item C2 of FDA Form 3500A) should be included. For reports of a congenital anomaly, the age and sex of the infant should be included. Followup reports for the infant should be considered followup to the initial report; followup for the mother should be submitted as a new initial individual case safety report on a separate FDA Form 3500A. The date that the congenital anomaly is detected should be used as the event onset date (e.g., birth date of the infant, date pregnancy is terminated, date congenital anomaly is detected by ultrasound or other diagnostic technique). This date should be used in item B3 of FDA Form 3500A.
For prescription drugs marketed for human use without an approved NDA or ANDA, all serious, unexpected adverse experiences must be reported to the FDA on an FDA Form 3500A within 15 calendar days. These reports must be submitted in SINGLE copy under separate cover. The report should be marked on the outside envelope "15-Day Alert Report - 310.305." A copy of the U.S. product labeling must accompany each report. Postmarketing periodic reports should not be submitted for these drugs.
Reports of adverse experiences in which the initial reporter identifies the suspect product as one marketed by another applicant should be promptly forwarded to that applicant. An applicant who receives a report of an adverse experience regarding one of its products from another applicant must submit the report to the FDA within the same time constraints applicable to any report received from a third party (see section VI.K in this guidance). An applicant should only submit a report of an adverse experience to the FDA for a suspect product marketed by another applicant if the applicant of the suspect product is unknown or the report is for a serious, unexpected adverse experience occurring during the conduct of a study.
If a reportable adverse experience involves two or more suspect products from the same applicant, only one FDA Form 3500A should be completed. The FDA Form 3500A should reference only one manufacturer report number. The report should be submitted to the NDA, ANDA, or BLA considered most suspect by the initial reporter. If each product is equally suspect, the report should be submitted to the product first in alphabetical order. The adverse experience should also be reported in the narrative summary section of the periodic report for the other product(s). However, if one suspect product is a licensed non-vaccine biologic and the other is a licensed vaccine, separate reporting forms should be submitted. An FDA Form 3500A should be used for the licensed non-vaccine biologic and a VAERS form should be used for the licensed vaccine. If a reportable adverse experience involves two or more suspect products and two or more applicants, an applicant may choose to submit an FDA Form 3500A to the FDA on the adverse experience that describes detailed information including the product(s) from the other applicant. In such a case, the other applicant should receive a copy of the FDA Form 3500A including its manufacturer report number so that the other applicant can reference this report when providing any relevant followup information to the FDA. The other applicant should not submit to the FDA information originally submitted to the Agency by the first applicant.
A drug substance can be the subject of more than one approved NDA or ANDA. If an applicant receives a report for a drug and the specific application is identifiable, the report should be submitted to that application. However, if a drug substance has more than one application and it cannot be determined which of the approved applications is involved, the report should be submitted to the application for the drug product that was approved first and that has the same general route of administration as the suspect drug substance. This would usually be the application with the lowest number.
If two or more companies that co-market a specific drug product have an approved NDA for the product, one of the companies should be identified as having primary responsibility for reporting adverse experiences for the drug product to the FDA to avoid duplicative reporting of adverse experiences. This would also be true for two or more companies that co-market a specific biological product and have an approved BLA for the product.
An adverse experience associated with the use of a product for an unapproved indication should be reported to the FDA as is required for any other spontaneously reported adverse experience occurring in the United States (e.g., 15-day report for a serious, unexpected adverse experience or periodic report for a nonserious, unexpected adverse experience). However, a lack of effect report for an unapproved indication should not be reported on an FDA Form 3500A. Instead, such information should be included in the narrative summary section of a periodic report.
If an applicant receives a report identified as a product interaction, each of the products should be identified as a suspect product in item C1 of FDA Form 3500A.
Sometimes FDA forwards individual case safety reports (i.e., FDA Form 3500As) to applicants. For example, applicants can participate in the FDA's MedWatch-to-Manufacturer Program. This program is designed to expedite transmission from the FDA to applicants participating in the program cases of serious adverse experiences reported directly to the FDA voluntarily by initial reporters (e.g., health care professionals, consumers). Details of the program can be found on the Internet at www.fda.gov/medwatch/report/mmp.htm. Applicants that receive individual case safety reports from FDA are not required to resubmit them to the Agency. However, followup information to these initial reports must be submitted to the FDA (see section V.C in this guidance).
If a product defect results in an adverse experience, the adverse experience should be reported as any other spontaneously reported adverse experience occurring in the United States (e.g., 15-day report for a serious, unexpected adverse experience or periodic report for a nonserious, unexpected adverse experience).
In some cases, it may be difficult to interpret specific criteria used for reporting. Examples include determining whether an adverse experience is expected or unexpected or whether a patient is identifiable or not. For these and any other ambiguities, the applicant should use a conservative approach and err on the side of reporting the adverse experience to the FDA. Thus, if there is doubt, consider an adverse experience to be unexpected, consider a patient to be identifiable, and so on.
Companies currently use a variety of medical terminologies to code adverse experiences in individual case safety reports (e.g., COSTART, WHOART, MedDRA). At this time, the FDA will accept adverse experiences coded with any of these terminologies. However, as recommended by ICH, the Agency encourages companies to use MedDRA for this purpose and as indicated in the FDA's advanced notice of proposed rulemaking on this topic (63 FR 59746; November 5, 1998), the Agency plans to propose to require use of MedDRA as the terminology for coding adverse experiences in individual case safety reports submitted to the FDA. Companies can license MedDRA from an international maintenance and support services organization (MSSO) (toll free number 877-258-8280 (703-345-7799 in Washington D.C. area), fax 703-345-7755, e-mail subscrib@meddramsso.com, Internet at www.meddramsso.com).
Individual case safety reports of adverse experiences that occur domestically for marketed human drugs and biological products, except vaccines, must be submitted to the FDA on FDA Form 3500A; a VAERS form must be used for vaccines. Foreign adverse experiences can be submitted either on FDA Form 3500A or, if preferred, on a CIOMS I form. Foreign adverse experiences associated with the use of vaccines can be submitted on either a VAERS form or, if preferred, a CIOMS I form. A separate FDA Form 3500A, VAERS form, or CIOMS I form must be completed for each individual person experiencing an adverse experience. The following paragraphs describe how to acquire or generate the various reporting forms for individual case safety reports and how to obtain information on FDA's pilot program for electronic submission of these reports. This section also describes a suggested reporting format for distribution reports for human biological products with approved BLAs. The following abbreviations should be used when specific information is not available for an individual case safety report or distribution report:
See Appendix C of this guidance for a copy of the form.23
See Appendix D of this guidance for a copy of the form. 24
CIOMS, working with several member nations and industry, has developed a format for international adverse experience reporting (CIOMS I form) (see Appendix E of this guidance). Applicants can use an FDA Form 3500A or, if preferred, a CIOMS I form for submission of 15-day reports of foreign adverse experiences to the FDA. Applicants cannot use a CIOMS I form for submissions of adverse experiences that occur within the United States. For these adverse experiences, an FDA Form 3500A must be used.
This section on distribution reports only applies to human biological products with approved BLAs. Under § 600.81, distribution reports must include the bulk lot, fill lot, and label lot numbers for the total number of dosage units of each strength or potency distributed (e.g., 50,000 per 10-milliliter vials), labeled date of expiration, and date of distribution of fill lot or label lot. The report must also include information about any significant amount of a fill lot or label lot that may have been returned. The regulations do not specify a reporting form or format for distribution reports. One suggested report format is shown here:
If there is more than one distribution date for a lot, the report should include each distribution date and the number of doses distributed. When reporting returned doses, the number of doses distributed should not be repeated. For vaccines, if available, distribution of doses can be reported by public, private, or military sectors.
The FDA is in the process of developing a system for electronic submission of postmarketing safety reports. At this time, applicants can submit, under a pilot program, certain individual case safety reports electronically. Details of this pilot program are available on the Internet at www.fda.gov/aerssub. The Agency also plans to have a system for electronic submission of distribution reports for biological products including vaccines in the near future.
All submissions should be legible and typewritten with a minimum acceptable font size of 10 point. Legible photostatic copies can be submitted. However, visual contrast should be adequate to ensure clear readable archival images. The applicant must submit one or two copies of each safety report as specified in this section unless a waiver is granted permitting a different number of copies (see section XI in this guidance).
Each applicant must develop written standard operating procedures for the surveillance, receipt, evaluation, and reporting of adverse experiences to the FDA (§§ 310.305(a), 314.80(b) and 600.80(b)). The FDA will consider an applicant responsible for information known to its employees, affiliates, and contractors. For this purpose, applicants should develop procedures that allow for expedited handling of adverse experience reports. Records of due diligence should be maintained. This applies to surveillance and processing for both domestic and foreign reports of adverse experiences.
Under §§ 314.90(a) and 600.90(a), applicants may ask the FDA to waive any postmarketing safety reporting requirement that applies to the applicant under §§ 314.80 and 600.80. The following paragraphs discuss certain postmarketing periodic safety reporting requirements for which the FDA is currently granting waivers.
Applicants are encouraged to request a waiver for submission of FDA Form 3500As for individual case safety reports of nonserious, expected adverse experiences that, at a minimum, contain the four basic elements (see section IV.B in this guidance). In such cases, applicants should maintain records of these nonserious, expected adverse experiences in their corporate drug or biological product safety files. The FDA may request that an applicant submit to the Agency FDA Form 3500As of one or more of these adverse experiences. The agency would expect these forms to be submitted within 5 calendar days after receipt of the request. Applicants who obtain a waiver for the requirement to submit individual case safety reports of nonserious, expected adverse experiences would still be expected to submit information on these adverse experiences to the FDA in the summary tabulations section of postmarketing periodic reports (see section V.B.2.a in this guidance). At this time, the FDA does not intend to grant waiver requests for new biological molecular entities within one year of licensure or for blood products, plasma derivatives, or vaccines. The Agency believes that it is important to continue periodic review of all individual case safety reports of adverse experiences for these products to identify safety problems due to lot-to-lot variations and also to monitor the safety of newly approved biological products.
Applicants can request a waiver of the requirement to submit postmarketing periodic safety reports in the format described in the regulations. Instead, applicants can prepare these reports using the PSUR (Periodic Safety Update Report) format described in the ICH E2C guidance. In addition, the Agency recommends the following:
Applicants can request a waiver to submit PSURs to the FDA based on the month and day of the international birth date of the product instead of the month and day of the anniversary date of U.S. approval of the product. 26 The waiver request should specify that these PSURs would be submitted to the FDA within 60 calendar days of the data lock point (i.e., month and day of the international birth date of the product or any other day agreed on by the applicant and the FDA).27 Applicants can also request a waiver to submit PSURs to the FDA at a frequency other than those required under §§ 314.80(c)(2)(i) and 600.80(c)(2)(i).
If an electronic record of an adverse experience is created, modified, maintained, archived, retrieved, or transmitted, the applicant is required, among other things, to employ procedures to ensure that records are trustworthy, reliable, and consistent with FDA's ability to promote and protect public health (21 CFR part 11). Those procedures must include validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.
Adverse Experience - Any adverse event associated with the use of a drug or 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 drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action. Reporting an adverse experience does not necessarily reflect a conclusion by the applicant or the FDA that the product caused or contributed to the adverse experience. Adverse experience is synonymous with adverse drug experience, adverse biological experience, adverse product experience, and adverse event. Affiliate - Any individual or entity related by employment or organizational structure to the applicant, including all subsidiaries, whether domestic or foreign. Applicant - An individual or entity who holds the new drug application (NDA), abbreviated new drug application (ANDA), or the biologics license application (BLA). For purposes of this guidance, this term includes any person whose name appears on the label of a marketed drug or licensed biological product as its manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any participant involved in divided manufacturing. Causality Assessment - Determination of whether there is a reasonable possibility that the product is etiologically related to the adverse experience. Causality assessment includes, for example, assessment of temporal relationships, dechallenge/rechallenge information, association with (or lack of association with) underlying disease, presence (or absence) of a more likely cause, and physiologic plausibility. Challenge - Administration of a suspect product by any route. Dechallenge - Withdrawal of a suspect product from a patient's therapeutic regimen. Negative Dechallenge - Continued presence of an adverse experience after withdrawal of the suspect product. Positive Dechallenge - Partial or complete disappearance of an adverse experience after withdrawal of the suspect product. Rechallenge - Reintroduction of a suspect product suspected of having caused an adverse experience following a positive dechallenge. Negative Rechallenge - Failure of the product, when reintroduced, to produce signs or symptoms similar to those observed when the suspect product was previously introduced. Positive Rechallenge - Reoccurrence of similar signs and symptoms upon reintroduction of the suspect product. Disability - A substantial disruption in one's ability to conduct normal life functions. Expected Adverse Experience - Adverse experience listed in the current FDA-approved labeling for the drug or licensed biological product. This would include any section of the labeling that refers to adverse experience information. Initial Reporter - The original source of information concerning an adverse experience (e.g., consumer, healthcare professional). Life-threatening Adverse Experience - An adverse experience that, in the view of the initial reporter, places the patient at immediate risk of death from the adverse experience as it occurred. It does not include an adverse experience that, had it occurred in a more severe form, might have caused death. Serious Adverse Experience - An adverse experience occurring at any dose that results in any of the following outcomes:
Spontaneous Report - A communication from an individual (e.g. health care professional, consumer) to a company or regulatory authority that describes a suspected adverse experience. It does not include cases identified from information solicited by the applicant such as individual cases or findings derived from a study. Study - Any organized data collection system (e.g., adverse experience information derived from a clinical trial, patient registry including pregnancy registries). Reports from company sponsored patient support programs and disease management programs should be handled as if they were study reports and not as spontaneous reports. Suspect Product - Drug or biological product associated with an adverse experience as determined by the initial reporter, regardless of the opinion of the applicant. Unexpected Adverse Experience - Adverse experience not included in any section of the current FDA-approved labeling for the drug or licensed biological product. This includes an adverse experience that may differ from a labeled adverse experience because of greater severity or specificity (e.g., abnormal liver function versus hepatic necrosis). Adverse experiences listed as occurring with a class of drugs or biological products but not specifically mentioned with a particular drug or biological product are considered unexpected (e.g., rash with antibiotic X would be unexpected if the labeling said "rash may be associated with antibiotics"). This is because the labeling does not specifically state "rash is associated with antibiotic X." Reports of death from an adverse experience are considered unexpected unless the possibility of a fatal outcome from that adverse experience is stated in the labeling.
Before mailing your postmarketing safety reports to the FDA, you should make sure that the following questions have been addressed:
APPENDIX F: ONE-PAGE FDA FORM 3500A
1 This guidance has been prepared by FDA's Safety Reporting Regulations Working Group, which includes representatives from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). 2 The FDA is planning to propose revisions to these regulations (see section II.C in this guidance). As these proposals are finalized the Agency will revise this guidance to provide industry with assistance in fulfilling the new regulatory requirements. 3 NDA means new drug application, ANDA means abbreviated new drug application, and BLA means biologics license application 4 IND means investigational new drug application 5 The Agency's regulation on good guidance practices published on September 19, 2000 (21 CFR 10.115; 65 FR 56468). 6 See advance notice of proposed rulemaking on electronic reporting of postmarketing adverse drug reactions; request for comments, 63 FR 59746, November 5, 1998.
7 See Appendix A for definition of adverse experience. (See also §§ 310.305(b), 314.80(a) and 600.80(a).) 8 The requirements for reports of serious, unexpected adverse experiences can be found in §§ 310.305(c), 314.80(c)(1) and 600.80(c)(1). 9 The requirements for reports describing these adverse experiences can be found in §§ 314.80(c)(2) and 600.80(c)(2). 10 See Appendix A for definition of serious adverse experience. (See also §§ 310.305(b), 314.80(a) and 600.80(a).) 11 See Appendix A for definitions of unexpected and expected adverse experiences. (See also §§ 310.305(b), 314.80(a) and 600.80(a).) 12 See Appendix A for definition of spontaneous report. 13 The requirements for 15-Day Reports can be found in §§ 310.305(a), (c)(1)(i) and (d)(1), 314.80(c)(1)(i) and (f)(1), and 600.80(c)(1)(i) and (f)(1). 14 The requirements for periodic reports can be found in §§ 314.80(c)(2) and 600.80(c)(2). 15 These include serious and expected adverse experiences, nonserious and unexpected adverse experiences, and nonserious and expected adverse experiences. 16 The requirements for followup reports can be found in §§ 310.305(c)(2), 314.80(c) and 600.80(c). 17 The requirements for scientific literature reports can be found in §§ 314.80(c)(1)(i), 314.80(d), 600.80(c)(1)(i), and 600.80(d). 18 The requirements for reporting adverse experiences from studies can be found in §§ 310.305(c)(1), 314.80(c)(2)(iii), 314.80(e)(1), 600.80(c)(2)(iii), and 600.80(e)(1). 19 The requirements for reporting of foreign adverse experiences can be found in §§ 310.305(c)(1)(i), 314.80(c)(2)(iii) and 600.80(c)(2)(iii). 20 The requirements for prescription drugs marketed for human use without an approved application can be found in § 310.305. 21 The requirements for submitting reports received from the FDA can be found in §§ 310.305(c)(5), 314.80(b), and 600.80(b). 22 The requirements for reporting formats can be found in §§ 310.305(d), 314.80(f) and 600.80(f). 23 Instructions for completing FDA Form 3500A are available on the Internet at www.fda.gov/medwatch/report/instruc.htm. 24 A guidance for industry entitled How to Complete the Vaccine Adverse Event Reporting System Form (VAERS-1) (October 1999) is available on the Internet at www.fda.gov/cber/guidelines.htm or from the Office of Communication, Training and Manufacturers Assistance (HFM-40), CBER, 1401 Rockville Pike, Rockville, MD 20852-1448, (Fax) 1-888-CBERFAX or 301-827-3844, (Voice Information) 1-800-835-4709 or 301-827-1800. 25 See §§314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B). 26 The international birth date for a product is the date the first regulatory authority in the world approved the first marketing application for a human drug product containing the drug substance or a human biological product. 27 The data lock point is the date designated as the cut-off date for data to be included in a PSUR.
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