# Presentation: 392819

## FDA’s Safety Reporting 

**FDA’s Safety Reporting **
**Proposed Rule**

***Audrey A. Thomas, M.S.***
***Office of Regulatory Policy***
***Center for Drug Evaluation and Research***
***Food and Drug Administration***
***April 30, 2003***

## PRESENTATION OVERVIEW

**Premarketing Expedited Safety Reporting**
**Postmarketing Safety Reporting**
**Definitions and General Provisions**
**Expedited Reports**
**Periodic Reports**

## Premarketing Expedited Safety Reporting

## Current Definitions

**Associated with the use of the drug**
**Disability**
**Life-Threatening**
**Serious**
**Unexpected**

## ReplaceAssociated with the Use of the Drug

**There is a reasonable possibility that the experience may have been caused by the drug.**
**With **
_**Suspected Adverse Drug Reaction (SADR)**_
**A noxious and unintended response to any dose of a drug product for which there is a reasonable possibility that the product caused the response.  In this definition, the phrase “a reasonable possibility” means that the relationship cannot be ruled out.**

## Life-Threatening

**Any AE that places the patient or subject, **
**in the view of the investigator ****or sponsor**
**at immediate risk of death from the reaction as it occurred, **
**i.e., it does not include a reaction that, **
**had it occurred in a more severe form, **
**might have caused death.**

## Unexpected 

**Any AE, the specificity or severity of which is not consistent with the current investigator brochure**
**AE not previously observed rather than not anticipated from pharmacological properties of product.**
**SADRs mentioned in investigator brochure as occurring with a class of drugs but not specifically mentioned as occurring with the particular drug are considered unexpected.**

## New Proposed Definition

**Minimum data set**
**Identifiable patient**
**Identifiable reporter**
**Suspect product**
**SADR**

## Current and Proposed Premarketing Expedited Safety Reports

## SADR Reports to Sponsor by Investigators

_**SADR Reports to Sponsor by Investigators**_

## Human Bioavailability & Bioequivalence Studies Not Conducted Under an IND

**Do not currently have any safety reporting requirements**
**Propose to require submission of the same expedited safety reports as described for studies under an IND**

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## Postmarketing Safety ReportingDefinitions and General Provisions 

## Current Definitions

**Adverse Drug Experience**
**Disability**
**Life-Threatening**
**Serious**
**Unexpected**

## ReplaceAdverse Drug Experience

**Any adverse event (AE) associated with the use of a drug in humans, whether or not considered drug related, including AEs occurring:****  ****• during use of a drug in professional practice;****  • from drug overdose whether accidental or intentional; ****  • from drug abuse; ****  • from drug withdrawal; and ****  • Any failure of expected pharmacological action.**
**With **
_**Suspected Adverse Drug Reaction (SADR)**_
**A noxious and unintended response to any dose of a drug product for which there is a reasonable possibility that the product caused the response.  In this definition, the phrase “a reasonable possibility” means that the relationship cannot be ruled out.**

## New Proposed Definitions

_**Minimum data set**_
**Identifiable patient, identifiable reporter, suspect product, & an SADR**
_**Full data set**_
**Completion of all the applicable elements on reporting form including concise medical narrative of the case**
_**Active query**_** **
**Health care professional at company speaks directly to initial reporter of SADR; entails, at a minimum, focused line of questioning designed to capture clinically relevant information**

## New Proposed Definitions (cont.)

_**Nonserious SADR**_** **
**SADR determined not to be serious**
_**SADR with unknown outcome**_
**SADR cannot be classified as serious or nonserious after active query**
_**Contractor**_** **
**Any person that has entered into a contract with the company to manufacture, sell, distribute, or develop the drug or to maintain, create or submit records regarding SADRs or medication errors**

## New Proposed Definitions (cont.)

_**Spontaneous report**_
**Communication from individual to company or regulatory authority that describes SADR or medication error.  **
**Does **_**NOT**_** include:**
** ****Information solicited by company such as individual cases or findings from:**
**A study**
**Company-sponsored patient support program**
**Disease management program **
**Patient registry **
**Any organized data collection scheme. **
**Information compiled in support of class action lawsuits.**

## New Proposed Definitions (cont.)

_**Medication error**_
**Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional or consumer.**
_**Actual medication error**_
**Involves an identifiable patient, whether or not the product was administered or if administer, whether or not error results in serious SADR, nonserious SADR or no SADR**
_**Potential Medication error**_
**Does not involve a patient but rather describes information or complaint about product name, labeling or packaging similarities**

## Some General Postmarketing Safety Reporting Provisions

**Minimum data set required for all SADRs**
**Full data set required for serious SADRs**
**Supporting documentation required for reports of deaths and hospitalizations**
**For nonserious SADRs, no information required to be collected other than minimum data set**
**Active query required if additional information needed**

## Additional Postmarketing Safety Reporting Provisions

**Licensed physician required to be responsible for content of safety reports**
**Contractors must submit all safety reports of SADRs and medication errors to applicant within 5 calendar days**
**Individual case safety reports must be coded using MedDRA**

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## Postmarketing Expedited Safety Reporting

## Current and Proposed Postmarketing Expedited Safety Reports — Initial

## Always Expedited Reports Include

**Congenital Anomalies**
**Acute Respiratory Failure**
**Ventricular Fibrillation**
**Torsades de Pointe**
**Malignant Hypertension**
**Seizure**
**Agranulocytosis**
**Aplastic Anemia**
**Toxic Epidermal Necrolysis**
**Liver Necrosis**

**Acute Liver Failure**
**Anaphylaxis**
**Acute Renal Failure**
**Sclerosing Syndromes**
**Pulmonary Hypertension**
**Pulmonary Fibrosis**
**Confirmed or Suspected Transmission of Infectious Agent by Marketed Product**
**Confirmed or Suspected Endotoxin Shock**

## Current and Proposed Postmarketing Expedited Safety Reports — Initial

## Current and Proposed Postmarketing Expedited Safety Reports — Followup

## Postmarketing Safety Reporting for Blood and Blood Components

## ?????????????????

## Postmarketing Periodic Safety Reporting

## New Proposed Definitions 

**Company core data sheet (CCDS)**
**Prepared by company**
**Company core safety information (CCSI)**
**Safety information in CCDS**
**Listed/Unlisted SADRs**
**Based on information in CCSI**
**International Birthdate **
**1st approval in the world**
**Data Lock Point**
**Cut-off date for data to be included in report**

## Current Postmarketing Periodic Safety Reporting

**Descriptive Information**
**Narrative summary and analysis**
**Information in the report**
**Alert reports submitted during reporting interval**
**History of actions taken because of AEs**
**Individual Case Safety Reports **
**Serious & Expected AEs**
**All Nonserious AEs**

## Proposed Postmarketing Periodic Safety Reports

**Two separate reports:**
**Descriptive Information**
**Traditional periodic safety report (TPSR)**
**Periodic safety update report (PSUR)**
**Interim periodic safety report (IPSR)**
**Individual Case Safety Reports**
**No longer submit for nonserious expected SADRs except for vaccines**
**Now submit foreign serious, expected SADRs**

## Differences Between Current Postmarketing Periodic Report & TPSR

## PSUR - Core Document

**Title page, table contents, introduction**
**Worldwide marketing status**
**Actions taken for safety reasons**
**Changes to CCSI**
**Worldwide patient exposure**
**Individual cases and summary tabulations**
**Safety studies**
**Other information**
**Overall safety evaluation**
**Conclusion**

## PSUR- Appendices 

**Company Core Data Sheet**
**U.S. labeling**
**Consumer reports**
**SADRs with unknown outcome**
**Class action lawsuits**
**Lack of efficacy reports**
**Resistance to antimicrobial drug products**
**Medication errors**
**U.S. patient exposure**
**Location safety records**
**Contact person**

## Frequency for Submitting Postmarketing Periodic Safety Reports

_**Current**_** **
**Quarterly for 3 years after U.S. approval**
**Annually thereafter**
_**Proposed**_** **
**Descriptive Information**
**Semiannually for 2 years after U.S. approval**
**Annually for the next 3 years**
**Every 2.5 years for the next 10 years**
**Every 5 years thereafter**
**Individual Case Safety Reports**
**Semiannually after U.S. approval**

## Postmarketing Annual Report

**Proposing removal of:**
**Section on nonclinical laboratory studies**
**Safety-related and patient exposure information in the summary **
**Safety-related information in the clinical data section**

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