Fda guidance for pharmaceutical post marketing reporting professor pirouzi

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FDA DRAFT GUIDANCE

March 2001

Professor Peivand Pirouzi

Food and Drug Administration 2001 Ref: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074850.htm

I. INTRODUCTION This guidance is intended to assist applicants and other responsible

parties in fulfilling the FDA's existing post marketing safety reporting requirements for human marketed drug and biological products at 21 CFR 310.305, 314.80, 314.98, 600.80, and 600.81.

Under these regulations, post marketing safety reports must be submitted to the Agency for the following:

1. Serious and unexpected AEs from all sources (domestic and foreign) 2. Spontaneously reported AEs that occur domestically and that are: ○ Serious and expected ○ Non serious and unexpected or expected

What Does This Guidance Discuss?

15-Day Reports of Serious, Unexpected AEs Periodic Reports Follow-up Reports Distribution Reports for Biological Products Including

Vaccines

This guidance addresses the following regulations: 21 CFR 310.305 - Prescription drugs marketed for human use without an approved

application 21 CFR 314.80 - Human drugs with approved NDAs 21 CFR 314.98 - Human drugs with approved ANDAs 21 CFR 600.80 - Human biological products with approved BLAs 21 CFR 600.81 - Human biological products with approved BLAs

II. BACKGROUND Final Rules

Expedited Safety Reports for Human Drug and Biological Products Post marketing Expedited Increased Frequency Reports for Human

Drug and Biological Products Guidances

Post marketing Reporting of Adverse Drug Experiences (March 1992) Guideline for AE Reporting for Licensed Biological Products (October 1993) Post marketing AE Reporting for Human Drug and Licensed Biological

Products: Clarification of What to Report (August 27, 1997).

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.

III. WHO MUST REPORT Who What Manufacturers

Submit post marketing expedited safety reports to the FDA

Applicants (individual or corporate entity that holds an NDA or ANDA)

Submit post marketing safety reports to the FDA for human drug products with approved NDAs

Licensed manufacturers (individual or corporate entity that holds a BLA)

Submit post marketing safety reports to the FDA with approved BLAs

Any person whose name appears on the label of a marketed drug or a licensed biological product (manufacturer, packer, or distributor)

Post marketing safety reporting responsibilities

New Drug Application (NDA) is a document submitted to the FDA to request approval to market a new drug. The Biologic License Application (BLA) is a document submitted to the FDA to request approval to market a biologic. Moreover, the BLA is equivalent to an NDA for a biologic (biologic = a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product)

IV. WHAT DO I REPORT? §§ 310.305, 314.80, 314.98, and 600.80 A: Types of AEs 1. AEs that are Serious and Unexpected from All Sources (Domestic and Foreign)

What Comment

Scientific literature Reports include published and unpublished scientific papers that are known to the applicant

Post marketing studies

Include in vitro, animal, clinical, and epidemiological or surveillance investigations

AEs from studies (if ADR) Must only be submitted to the FDA if the applicant believes that there is a reasonable possibility that the drug or biological product caused the AE (ADR)

IV. WHAT DO I REPORT? §§ 310.305, 314.80, 314.98, and 600.80 A: Types of AEs 2. Other Spontaneously Reported AEs (Domestic Only) AEs occurring in the United States from commercial marketing experience

must be submitted to the FDA if they are spontaneously reported to applicants and are:

What Comment

Serious and expected

Non serious and unexpected or expected Applicants can request a waiver Request a waiver of the requirement to

submit individual case safety reports of non serious, expected AEs for drugs and certain biological products

IV. WHAT DO I REPORT? §§ 310.305, 314.80, 314.98, and 600.80 A: Types of AEs 3. Serious AEs The outcome of an AE must be determined before a report

can be identified as serious. A serious report must have one or more of the following outcomes: Death Life-threatening AE Initial inpatient hospitalization or prolongation of hospitalization Significant or persistent disability/incapacity Congenital anomaly/birth defect (including that occurring in a fetus) Important medical event based upon appropriate medical judgment

that may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the other outcomes listed in the definition of serious.

IV. WHAT DO I REPORT? §§ 310.305, 314.80, 314.98, and 600.80 A: Types of AEs

A patient admitted to a hospital for 1 or more days as a result of an AE, even if released on the same day, would qualify for the initial inpatient hospitalization outcome.

An emergency room visit that results in admission to the hospital would also qualify for the initial inpatient hospitalization outcome. Emergency room visits that do not result in admission to the hospital would not qualify for this outcome and, instead, should be evaluated for one of the other outcomes in the definition of serious (e.g., life-threatening AE, important medical event).

Persons incarcerated because of actions allegedly caused by a drug (e.g., psychotropic drugs and rage reactions) have sustained a substantial disruption in their ability to conduct normal life functions. Thus, these AEs would qualify for the significant or persistent disability/incapacity outcome.


Important medical events would 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.

Applicants should actively seek the outcome for a suspected serious AE reported to them. If unable to initially determine the outcome for an AE, an applicant should continue to actively seek information in an attempt to determine an outcome. For a serious AE that was not initially reported to the applicant by a health care professional (e.g., report from a consumer), the applicant should actively pursue contacting the health care professional associated with the care of the patient to gather further medical perspective on the case.


4. Unexpected and Expected AEs The current FDA-approved labelling for the human drug or

biological product should be used as the reference document to determine whether an AE is unexpected or expected. An AE would be considered unexpected if it is not included in the product's current FDA-approved labelling and expected if it is included in this document.

5. Spontaneous Report Spontaneous reports are unsolicited communications from

individuals (e.g., health care professional, consumer) to applicants that concern AEs. Spontaneous reports should not include AEs identified from information solicited by applicants such as individual cases or findings derived from a study (e.g., any organized data collection scheme).

IV. WHAT DO I REPORT? §§ 310.305, 314.80, 314.98, and 600.80 B: Data Elements to Include In A Post marketing Individual Case Safety Report

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: 1. An identifiable patient 2. An identifiable reporter 3. A suspect drug or biological product 4. An AE or fatal outcome suspected to be due to the suspect drug or biological product

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 AE should use direct verbal contact with the initial reporter of the AE

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.


For spontaneous reports, the applicant should assume that an AE or fatal outcome was suspected to be due to the suspect drug or biological product (implied causality).

For clinical studies, an AE or fatal outcome need not to be submitted to the FDA unless the applicant concludes that there is a reasonable possibility that the product caused the AE or fatal outcome.

An AE should, at a minimum, consist of signs (including abnormal laboratory findings, if appropriate), symptoms, or disease diagnosis. Provide more specific information about AE.

V. TYPES OF REPORTS A. 15-Day Reports Of Serious, Unexpected AEs

1. Determination of reporting period: Serious, unexpected AEs must be submitted to the FDA no later than 15

calendar days of initial receipt of the information by the applicant 2. Supporting documents

FDA encourages to include: 1. relevant hospital discharge summaries and autopsy reports/death certificates 2. list of other relevant documents (e.g., medical records, relevant laboratory data,

electrocardiograms, and other concise critical clinical data) maintained in their corporate drug or biological product safety files.

The FDA can request that copies of one or more of these documents be provided to the Agency. Applicants should submit copies of these documents to the Agency within 5 calendar days after receipt of the request

V. TYPES OF REPORTS A. 15-Day Reports Of Serious, Unexpected AEs

3. Report Identification: Fifteen-day reports must be submitted in duplicate under separate

cover prominently identified as "15-Day Alert Report." For this purpose, the "15-Day Alert Report" identification should be included on the outside envelope.

For prescription drugs marketed for human use without an approved application, a single copy of the 15-day report and a copy of the U.S. labelling must be submitted. These reports should be marked on the outside envelope with "15-Day Alert Report - 310.305."

Multiple 15-day reports and 15-day follow-up reports can be submitted in the same envelope, but they should not be stapled together (see section V.C for discussion of follow-up reports

V. TYPES OF REPORTS B. Periodic Reports

1. Timing of Post marketing Periodic Reports Reports are required to be submitted to the FDA for each approved

NDA, ANDA, and BLA and are due quarterly for the first 3 years after U.S. approval of the application and annually thereafter.

If marketing is delayed, these reports should still be submitted quarterly for the first 3 years of marketing. Upon written notice, the FDA may extend or re-establish the requirement that an applicant submit quarterly reports or require that the applicant submit periodic reports at different time intervals.

Periodic reports due quarterly must be submitted within 30 calendar days of the last day of the reporting quarter.

Reports due annually must be submitted each year within 60 calendar days of the anniversary date of U.S. approval of the application for the drug or biological product (i.e., NDA, ANDA, BLA).

V. TYPES OF REPORTS B. Periodic Reports

Periodic submissions should be clearly marked "Periodic AE Submission" on the front cover of each volume.

Each page of the periodic report should be numbered and include the name and NDA or ANDA number if the periodic report is for a drug product; the name and submission tracking number (STN) should be used if the periodic report is for a biological product

A STN for a biological product can be found on the Internet at www.fda.gov/cber/stn/stn.htm

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report The regulations require a post marketing periodic report to

contain:

The information contained within a post marketing periodic report should be divided into four sections in the order described in next slide and should be clearly separated by an identifying tab. If information for one of these sections is not included, the applicant should simply explain why the information is not provided. (The actual E2C format “PSUR” is also accepted)

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 A Form 3500A for each spontaneously reported AE occurring in the United States that was not reported in a 15-day Alert report

A history of actions taken since the last report because of AEs

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report Section 1: Narrative summary and analysis

The number of non 15-day reports The number of non-15-day initial AE reports and the number of non-15-day follow-up reports contained in this periodic report

A line listing of the 15-day reports Should include the manufacturer report number, AE term(s), and the date the 15-day report was sent to the FDA

A summary tabulation by body system To be taken from: •15-day reports submitted to the FDA •non-15-day reports submitted in the periodic report •reports forwarded to the applicant by the FDA •any non serious, expected AEs not submitted to the FDA but maintained on file by the applicant.

A summary listing of the AE reports In which the drug or biological product was listed as one of the suspect products, but the report was filed to another NDA, ANDA, or BLA held by the applicant.

A narrative discussion of the clinical significance of the 15-day reports

Any increased frequency of serious, expected AEs if it is believed by applicant that it reflects a clinically meaningful change in AE occurrence. Assessment of clinical significance by type of AE, body system, and overall product safety relating the new information

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report Section 1: Narrative summary and analysis

The narrative discussion Includes whether the applicant believes either that: (1) No change in the product’s current

approved labelling is warranted or (2) There are safety-related issues that

need to be addressed in the approved product labelling.

• If changes in the approved product labelling are under consideration by the FDA, the applicant should state in the narrative the date and number of the supplemental application submitted to address the labelling changes.

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report Section 2: Narrative discussion of actions taken

A narrative discussion of actions taken must be provided, including any labelling changes and studies initiated since the last periodic report.

1. Copy of current U.S. product labelling 2. A list of any labelling changes made

during the reporting period 3. A list of studies initiated 4. A summary of important foreign

regulatory actions (e.g., new warnings, limitations in the indications and use of the product)

5. Any communication of new safety information (e.g., a Dear Doctor letter)

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report Section 3: Index line listing

An index line listing of Form 3500As or VAERS forms included in section 4 of the periodic report must be provided.

1. Manufacturer report number 2. AE term(s) 3. Page number of Form 3500A or

VAERS form as located in the periodic report

4. Identification of interacting products for any product interaction listed as an AE

V. TYPES OF REPORTS B. Periodic Reports 2. Content of a Post marketing Periodic Report Section 4: Form 3500As or VAERS forms

Form 3500As or VAERS forms must be provided for the spontaneously reported AEs that occurred in the United States during the reporting period.

1. Serious and expected 2. Non serious and unexpected 3. Non serious and expected


Applicants may request a waiver of the requirement to submit individual case safety reports of non serious, expected AEs; however, they should report them in the periodic safety reports

AEs due to a failure to produce the expected pharmacologic action (i.e., lack of effect) should be included in this section

For individual case safety reports of serious, expected AEs, the FDA encourages applicants to include relevant hospital discharge summaries and autopsy reports/death certificates, as well as lists of other relevant documents as described for 15-day reports of serious, unexpected AEs

An Form 3500A or VAERS form for a serious, unexpected AE should not be included in a periodic report because this AE should have been previously submitted to the FDA as a 15-day report.


If no AEs were identified for the human drug or biological product for the time period involved and no regulatory actions concerning safety were taken anywhere in the world where the product is marketed, the periodic report should simply state this and be submitted to the FDA along with a copy of the current U.S. labelling.

V. TYPES OF REPORTS C. Follow-up Reports 1. Content of a Follow-up reports

A follow-up report should provide a complete picture of the current understanding of the AE. All new information including correction of previously submitted inaccurate information that is included in a follow-up report should be highlighted (e.g., with an asterisk, underlined).

The narrative section of the follow-up report should be concise because the FDA’s AERS is limited for this section of the form.

For SAEs, applicants should exercise due diligence in obtaining follow-up information for completing all the applicable elements for a case safety report. For non serious AEs, additional follow-up is not necessary.

Any attachments submitted with an initial report (e.g. scientific journal articles, hospital discharge summaries) should not be resubmitted with a follow-up report.

V. TYPES OF REPORTS C. Follow-up Reports 2. Reporting considerations A copy of the initial report or a previous follow-up report should not be sent with

the latest follow-up report.

If the initial report was submitted as a 15-day report, the follow-up report should be submitted as a 15-day follow-up report even if AE was expected or not serious. Subsequent follow-up reports for AEs that are expected or not serious should be submitted in periodic reports. A 15-day follow-up report should be submitted if the AE is found to be serious and unexpected, even if the original report was not submitted as a 15-day report.

If a new AE occurs that is associated with the initial AE, a follow-up report should be submitted. The applicant should consider the clinical relevance of the AEs to each other when determining whether an initial report or follow-up report should be submitted.

Follow-up reports should not be submitted if additional relevant information is not obtained for the AE. However, as described in the regulations, applicants should maintain records of their efforts to obtain additional information, particularly for serious AEs. FDA may request this documentation.

V. TYPES OF REPORTS C. Follow-up Reports 3. Reporting forms

For follow up reports, particular attention should be paid to completing the following items on Form 3500A:

Item G3 - Mark health professional if at any time a health professional provided information for the report. Item G4 - Use the date the follow-up information was received by the applicant. Item G7- Mark follow-up, and indicate whether this is the 1st, 2nd, 3rd, ... Follow-up report. Item G9 - Use the same unique manufacturer report number assigned to the initial report to prevent duplicate counting of reports

For follow-up reports, particular attention should be paid to completing the following items on the VAERS form for vaccines:

Top right - Indicate the name of the person who provided information for the report. Box 24 - Use the same manufacturer report number assigned to the initial report. This is essential to prevent duplicate counting of reports and to ensure that the follow-up information is coupled with the correct initial report. Box 25 - Use the date the follow-up information was received by the applicant. Box 27 - Mark follow-up, and indicate whether this is the 1st, 2nd, 3rd,.. Follow-up report.

V. TYPES OF REPORTS C. Follow-up Reports 4. Reporting identification

Fifteen-day follow-up reports must be submitted in duplicate under separate cover prominently identified as "15-Day Alert Report-Follow-up." For this purpose, the “15-Day Alert Report-Follow-up” identification should be included on the outsideenvelope.

V. TYPES OF REPORTS D. Distribution Reports for Biological Products Including Vaccines This section is based primarily on regulations in § 600.81.

These regulations only apply to human biological products with approved BLAs. Unless otherwise notified, 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, labelled 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

VI. Special Report Situations A. Scientific Literature Reports

What Comments

Serious, unexpected AEs reported in the scientific literature

Submitted as 15-day reports on an Form 3500A or comparable format for each identifiable patient

If multiple products are mentioned in the article, a Form 3500A should be submitted only by the applicant whose product is the suspect drug.

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 Form 3500A.

Reports of serious, unexpected AEs 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 excipients, dosage forms, strengths, routes of administration, and indications vary. When a serious, unexpected AE 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 Form 3500A

VI. Special Report Situations B. Post marketing, Clinical Trial, or Surveillance Studies

AE spontaneous reports are not from clinical trials (systematic collection of data including AEs)

AEs 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 AEs that occur during a study must be submitted as 15-day reports if related to drug.

AEs occurring with marketed drug or biological products during IND trials must be submitted.

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 AE unless arrangements made with FDA.

VI. Special Report Situations C. Foreign Reports

Foreign reports of serious, unexpected AEs experiences must be submitted as 15-day reports.

Other foreign reports, including serious and expected, non-serious and unexpected, and non-serious and expected AEs are not required to be submitted.

Reports of foreign serious, unexpected AEs 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 excipients, 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 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.

VI. Special Report Situations D. Death Reports

Death is always a serious outcome

If death is associated with an unexpected AE, or if death is associated with an expected AE but the labelling does not specifically state that the AE may be associated with a fatal outcome, a 15-day report should be submitted.

VI. Special Report Situations E. Overdose Reports

Reports of overdose should be submitted only when the overdose is associated with an AE.

If the AE associated with the overdose is serious and unexpected, a 15-day report should be submitted.

If the AE is serious and expected, non-serious and unexpected, or non-serious and expected, a non-15 day report should be submitted in the periodic report for spontaneously reported domestic cases.

VI. Special Report Situations F. Lack of Effect Reports

The definition of AE includes “any failure of expected pharmacological action that is synonymous with lack of effect”

All spontaneously reported cases of a “lack of effect” that occur in the United States should be reported on Form 3500A and submitted in the periodic report with other AEs. The lot number of the suspect product should be included in item C6 of 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.

VI. Special Report Situations G. Information on the Internet

AE 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.

Applicants should review any Internet sites sponsored by them for AE information, but are not responsible for reviewing any Internet sites that are not sponsored by them. However, if an applicant becomes aware of an AE on an Internet site that it does not sponsor, the applicant should review the AE and determine if it should be reported to the FDA.

VI. Special Report Situations H. Pediatric Patients

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 in Form 3500A.

The word days or months should be clearly written. For all paediatric patients, body weight and dose should be included.

For reports of a congenital anomaly, the age and sex of the infant should be included. Follow-up reports for the infant should be considered follow-up to the initial report; follow-up for the mother should be submitted as a new initial individual case safety report on a separate 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).

VI. Special Report Situations I. Prescription Drugs Marketed for Human Use Without an Approved Application

For prescription drugs marketed for human use without an approved NDA or ANDA, all serious, unexpected AEs must be reported to the FDA on an 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 labelling must accompany each report.

Post marketing periodic reports should not be submitted for these drugs.

VI. Special Report Situations J. Another Applicant’s Product

Reports of AE 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 AE 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.

An applicant should only submit a report of an AE 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 AE occurring during the conduct of a study.

VI. Special Report Situations K. Multiple Suspect Products

If a reportable AE involves 2 or more suspect products from the same applicant, only one Form 3500A should be completed.

The Form 3500A should reference only one manufacturer report number. If each product is equally suspect, the report should be submitted to the product first in alphabetical order.

The AE should also be reported in the narrative summary section of the periodic report for the other product(s).

If a reportable AE involves 2 or more suspect products and 2 or more applicants, an applicant may choose to submit a Form 3500A on the AE 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 Form 3500A including its manufacturer report number so that the other applicant can reference this report when providing any relevant follow-up information to the FDA.

The other applicant should not submit to the FDA information originally submitted to the Agency by the first applicant.

VI. Special Report Situations L. Suspect Drugs with Multiple NDAs or ANDAs by the Same 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.

VI. Special Report Situations M. Two or More Marketers of a Product

If 2 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 AEs for the drug product to the FDA to avoid duplicative reporting of AEs.

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.

VI. Special Report Situations N. Unapproved Indications

An AE 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 AE occurring in the United States (e.g., 15-day report for a serious, unexpected AE or periodic report for a non-serious, unexpected AE).

However, a lack of effect report for an UNAPPROVED indication should not be reported on a Form 3500A. Instead, such information should be included in the narrative summary section of a periodic report.

VI. Special Report Situations O. Product Interactions

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 Form 3500A.

VI. Special Report Situations P. Reports from the FDA

Sometimes FDA forwards individual case safety reports (i.e., Form 3500A) 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 AEs 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, follow-up information to these initial reports must be submitted to the FDA

http://www.fda.gov/medwatch/report/mmp.htm

VI. Special Report Situations Q. Product Defects

If a product defect results in an AE, AE should be reported as any other spontaneously reported AE occurring in the United States (e.g., 15-day report for a serious, unexpected AE or periodic report for a non serious, unexpected AE).

VI. Special Report Situations R. Reporting Ambiguities

In some cases, it may be difficult to interpret specific criteria used for reporting.

Examples include determining whether an AE 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 AE to the FDA.

Thus, if there is doubt, consider an AE to be unexpected, consider a patient to be identifiable, and so on.

VII. CODING OF AES IN INDIVIDUAL CASE SAFETY REPORTS

FDA accepts AE codes with COSTART, WHOART, MedDRA

However, as per ICH, the Agency encourages companies to use MedDRA for this purpose

The Agency plans to propose to require use of MedDRA as the terminology for coding AEs in individual case

VIII. REPORTING FORMATS A. FDA forms

1- Form 3500A can be requested from FDA offices From Internet By Fax By Mail

2- Copies can be created by: Photocopying Computer Generation (requires approval from FDA) Details are provided in this guideline (margins, fonts, etc…)

Form 3500A

VIII. REPORTING FORMATS B. VAERS Form for Vaccines

Appendix D Request by phone Request by mail

VIII. REPORTING FORMATS C. CIOMS I Form for Foreign AEs

CIOMS, working with several member nations and industry, has developed a format for international AE reporting (CIOMS I form)

Applicants can use an Form 3500A or, if preferred, a CIOMS I form for submission of 15-day reports of foreign AEs to the FDA.

Applicants cannot use a CIOMS I form for submissions of AEs that occur within the United States. For these AEs, an Form 3500A must be used.

CIOMS form

VIII. Reporting Formats D. Distribution Reports for Biological Products Including Vaccines

This section on distribution reports only applies to human biological products with approved BLAs.

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), labelled 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.

VIII. Reporting Formats E. Electronic submissions The FDA is in the process

of developing a system for electronic submission of post marketing safety reports. Details of this pilot program are available on the Internet at www.fda.gov/cder/aerssub.

The Agency also plans to have a system for electronic submission of distribution reports for biological products including vaccines in the near future.

IX. HOW AND WHERE TO SUBMIT POSTMARKETING SAFETY REPORTS A. Human Drug Products B. Human Biological Products and Vaccines

Addresses are provided in this section

X. WRITTEN PROCEDURES FOR POSTMARKETING SAFETY REPORTING

SOPs: Each applicant must develop written standard operating procedures for the surveillance, receipt, evaluation, and reporting of AEs to the FDA

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 AE reports.

Records of due diligence should be maintained. This applies to surveillance and processing for both domestic and foreign reports of AEs.

XI. REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING REQUIREMENTS

Applicants may ask the FDA to waive any post marketing safety reporting requirement that applies to the applicant

The following slides discuss certain post marketing periodic safety reporting requirements for which the FDA is currently granting waivers.

XI. REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING REQUIREMENTS B. Submission of PSUR format for the Periodic Report

Applicants can request a waiver of the requirement to submit post marketing 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: Information on dosage forms and formulations for the active substance, as well as indications should be

in specific sections to accurately portray the safety profile of the specific dosage forms.

Copies of the Form 3500A or VAERS form that are required by the regulations must be included in the PSUR as an appendix.

A summary tabulation should be included as an appendix listing all spontaneously reported U.S. individual case safety reports from consumers if such cases are not already included in the PSUR. Summary tabulations should be presented by body system of all AE terms and counts of occurrences and be segregated by type (i.e., serious/unexpected; serious/expected; non serious/unexpected; and non serious/expected),

A narrative should be included as an appendix that references the changes, if any, to the approved U.S. labelling for the dosage forms covered by the PSUR based on new information in the PSUR. A copy of the most recently approved U.S. labelling for the product(s) covered by the PSUR should be included.

XI. REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING REQUIREMENTS C. Submission Date and Frequency for PSUR Reports

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.

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)

Applicants can also request a waiver to submit PSURs to the FDA at a frequency other than those required.

XI. REQUESTS FOR WAIVERS TO POSTMARKETING SAFETY REPORTING REQUIREMENTS D. How and Where to Submit Waiver Requests

Addresses are provided in the guidelines.

XII. VALIDATION OF AE COMPUTER SYSTEMS

If an electronic record of an AE 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.

Fda guidance for pharmaceutical post marketing reporting professor pirouzi

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