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Periodic Adverse Drug Experience Reports (PADERS): NDA Periodic Reports and Periodic Safety Update Reports (PSURs)

Most countries now accept and usually require the submission of Periodic Safety Reports for aggregate postmarketing safety reporting. The U.S. Food and Drug Administration (FDA) accepts PSURs, though this must be agreed on with the agency in writing beforehand. The older format, NDA Periodic Reports, also called Periodic Adverse Drug Experience Reports (PADERs), are still required according to the regulations (unless there is the PSUR waiver), though FDA will likely require PSURs in the near future.

In addition to the 15-day alert reports, the FDA requires the submission of New Drug Application (NDA), Abbreviated NDA, and Biologic License Application (BLA) periodic reports. The regulations covering this are found in 21CFR314.80(c)(2)(I, II).

As with Investigational New Drug application (IND) regulations, there are updates scattered in various other FDA documents. Some are arguably specific to premarketing settings (e.g., drug-induced liver injury) but should be kept in mind with postmarketing aggregate reporting too:

• Postmarketing Reporting of Adverse Drug Experiences (March 1992)
  
• Guideline for Adverse Experience Reporting for Licensed Biological Products (October 1993)
  
• Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report (August 27, 1997)
  
• Post-marketing Safety Reporting for Human Drugs and Biological Products Including Vaccines (March 2001)
  
• Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review (February 2005)
  
• Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009)
  
• Drug Safety Information—FDA’s Communication to the Public (March 2007)
  
• Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (March 2009)
  
• Postmarketing Studies and Clinical Trials—Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act (July 2009)
  
• Enforcement of the Postmarketing Adverse Drug Reporting Regulation. Staff Manual Guide: Chapter 53; Postmarketing Surveillance and Epidemiology: Human Drugs. Adverse Drug Effects

See FDA’s guidance pages (Web Resource 17-1).

The basic regulations state the following (21CFR314.80(c)(2)(I, II)):

All “adverse drug experiences” not submitted as 15-day alert reports must be submitted in the periodic report. A periodic report for each NDA must be submitted quarterly (every 3 months) for the first 3 years after the approval of the NDA. After the 3-year period is over, the reporting frequency is then yearly unless the FDA requests otherwise.

Each report must be submitted 30 days after the close of the quarter for quarterly reports and 60 days after the close of the anniversary date for yearly reports. Thus, the company has 30 or 60 days to prepare the report. The FDA may alter this schedule if they wish to continue quarterly reporting after the 3-year period is over.

Each periodic report is required to contain the following:

• 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 must appropriately reference the applicant’s patient identification number, adverse reaction term(s), and date of submission to the FDA).
  
• A MedWatch form (3500A) for each adverse drug experience not reported as a 15-day expedited report (with an index consisting of a line listing of the applicant’s patient identification number and adverse reaction term(s)).
  
• A history of actions taken since the last report because of adverse drug experiences (e.g., labeling changes or studies initiated).
  
• Periodic reporting, except for information regarding 15-day alert reports, does not apply to adverse drug experience information obtained from postmarketing studies (whether or not they were conducted under an investigational New Drug Application), from reports in the scientific literature, or from foreign marketing experience.
  
• Follow-up information to adverse drug experiences submitted in a periodic report may be submitted in the next periodic report.

In August 1997, the FDA published a guidance encouraging NDA holders to submit requests to waive the requirements to submit MedWatch forms for nonserious labeled AEs (Web Resource 17-2).

The March 2001 Guidance at Web Resource 17-3 explains the requirements for a periodic report and is officially in effect even though it remains a draft a decade after being published. It is summarized below.

The March 2001 Guidance describes the mechanism to obtain a waiver to submit PSURs using the ICH E2C requirements (see Chapter 37) instead of NDA Periodic Reports:

• If all dosage forms and formulations for the active substance, as well as indications, are combined in one PSUR, this information should be separated into specific sections of the report when such separation is appropriate to portray accurately the safety profile of the specific dosage forms. For example, one should not combine information from ophthalmic drop dosage forms and solid oral dosage forms.
  
• Copies of the FDA Form 3500A or VAERS form that are required by the regulations must be included. These forms should be included with the PSUR as an appendix. You can request a waiver for submitting certain nonserious, expected adverse experiences on an FDA Form 3500A.
  
• 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 adverse experience terms and counts of occurrences and should be segregated by type (i.e., serious/unexpected; serious/expected; nonserious/unexpected; and nonserious/expected).
  
• A narrative should be included as an appendix that references the changes, if any, to the approved U.S. labeling for the dosage forms covered by the PSUR based on new information in the PSUR. A copy of the most recently approved U.S. labeling for the product(s) covered by the PSUR should be included.
  
• 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 by regulation.

The information contained within a classic NDA Periodic Report should be divided into four sections in the order described below and should be clearly separated by an identifying tab. If information for one of these sections is not included, the applicant should explain why the information is not provided.

Section 1: Narrative Summary and Analysis

A narrative summary and analysis of the information in the postmarketing periodic report and an analysis of the 15-day reports (i.e., serious, unexpected, adverse experiences) submitted during the reporting period must be provided and should include the following:

• The number of non-15-day initial adverse experience reports and the number of non-15-day followup reports contained in this periodic report and the time period covered by the periodic report.
  
• A line listing of the 15-day reports submitted during the reporting period. This line listing should include the manufacturer report number, adverse experience term(s), and the date the 15-day report was sent to the FDA.
  
• A summary tabulation by body system (e.g., cardiovascular, central nervous system, endocrine, renal) of all adverse experience terms and counts of occurrences submitted during the reporting period. The information should 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 nonserious, expected, adverse experiences not submitted to the FDA but maintained on file by the applicant

For the adverse experience term “product interaction,” the interacting products should be identified in the tabulation.

• A summary listing of the adverse experience reports in which the drug or biologic product was listed as one of the suspect products but the report was filed to another NDA, Abbreviated NDA, or BLA held by the applicant.
  
• A narrative discussion of the clinical significance of the 15-day reports submitted during the reporting period and of any increased reporting frequency of serious, expected, adverse experiences when, in the judgment of the applicant, it is believed the data reflect a clinically meaningful change in adverse experience occurrence.
  

  This narrative should assess clinical significance by type of adverse experience, body system, and overall product safety, relating the new information received during this reporting period to what was already known about the product.

  
  

  The narrative should also state what further actions, if any, the applicant plans to undertake based on the information gained during the reporting period and include the time period for completing the actions (i.e., when the applicant plans to start and finish the action and submit the information to the agency).

  
  
• The narrative discussion should indicate, based on the information learned during the reporting period, whether the applicant believes either that (1) no change in the product’s current approved labeling is warranted or (2) there are safety-related issues that need to be addressed in the approved product labeling. If the FDA is considering changes in the approved product labeling, the applicant should state in the narrative the date and number of the supplemental application submitted to address the labeling changes.

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