# Presentation: 863367

## Safety Reporting Requirements:Proposed Rule

- Victor F. C. Raczkowski, M.D., M.S.
- Director, Office of Drug Safety
- Center for Drug Evaluation and Research
- Food and Drug Administration
- June 19, 2003

## Background

- Title: Safety Reporting Requirements for Human Drug and Biological Products
- 68 FR 12405-12497, March 14, 2003
- FR Doc. 03-05204
- Docket No. 00N-1484
- Comment period extended until October 14, 2003

- Victor F. C. Raczkowski, M.D.

## Rationale

- Further worldwide consistency
- Collection of safety information
- Submission of safety reports
- Increase quality of safety reports
- Expedite FDA review of critical safety information
- Protect and promote the public health

- Victor F. C. Raczkowski, M.D.

## Consistency in Safety Reporting

- Greater worldwide consistency in content, format, reporting frequency, and standardization of terminology
- Harmonize with safety reporting standards developed by CIOMS and ICH
- ICH E2A:  Expedited Reporting
- ICH E2C:  Periodic Safety Update Reports
- ICH M1: Postmarketing coding with MedDRA

- Victor F. C. Raczkowski, M.D.

## Changes based on ICH E2A 

*Adverse drug experience*
*+*
*Associated with the use of the drug*
**changed to**
*Suspected adverse drug reaction (SADR)*
- and
*Suspected adverse reaction (SAR)*

- Victor F. C. Raczkowski, M.D.

## 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.**

## Changes based on ICH E2A

- For individual case safety reports (ICSRs):
- Minimum data set required for all ICSRs of SADRs
- Causality of ICSRs in clinical trials (either in IND or while marketing) based on opinion of either sponsor/applicant or investigator
- Determination of life-threatening SADR in an IND study based on opinion of either sponsor or investigator

- Victor F. C. Raczkowski, M.D.

## Changes based on ICH E2A

- Expedited report (for marketed products) for information sufficient to consider product administration changes
- Unanticipated safety finding from in vitro, animal epidemiological, or clinical study that suggest a significant human risk
- Mutagenicity, teratogenicity, or carcinogenicity
- Lack of efficacy in life-threatening or serious disease

- Victor F. C. Raczkowski, M.D.

## Changes based onICH E2A and ICH E2C

- Lack of efficacy reports
- Submission of individual reports not required
- Submit expedited report if data are sufficient to consider a product administration change

- Victor F. C. Raczkowski, M.D.

## Changes based on ICH E2A and ICH E2C

- Reporting requirements for spontaneous reports codified
- definition of *spontaneous* consistent with ICH E2C
- SADR info from class action law suits neither *spontaneous* nor *study* information

- Victor F. C. Raczkowski, M.D.

## Changes based on ICH E2C

- Standardize submission date (month, day) for PSURs
- Company Core Safety Information (CCSI) used to determine whether an SADR is “listed” or “unlisted”
- “Listed SADR” is an SADR whose nature, specificity, severity, and outcome are consistent with the information in the CCSI

- Victor F. C. Raczkowski, M.D.

## Frequency for Submission of 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

- Victor F. C. Raczkowski, M.D.

## Changes based on ICH M1

- ICSRs arising in marketing use of a product would be required to be coded using MedDRA

- Victor F. C. Raczkowski, M.D.

## Quality

- Risk-based approach: greater emphasis, effort, and information for serious SADRs than on nonserious SADRs
- For postmarketing reports:
- Direct (active) contact with initial reporter by a health care professional at the company
- Licensed physician at company is responsible for the content of postmarketing safety reports

- Victor F. C. Raczkowski, M.D.

## Proposal for PostmarketingExpedited and Periodic Safety Reporting

- Active query required if additional information needed
- For nonserious SADRs, no information required to be collected other than minimum data set
- Contractors must submit all safety reports of SADRs and medication errors to applicant within 5 calendar days

- Victor F. C. Raczkowski, M.D.

## New Postmarketing Expedited Safety Reports

- Already capture *serious and unexpected* adverse drug experiences in an expedited way
- Formally capture Medication Errors as expedited reports
- Submit unexpected SADRs with unknown outcome as expedited reports
- Define a new category of *Always Expedited *reports

- Victor F. C. Raczkowski, M.D.

## Always Expedited Reports

- 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

- Victor F. C. Raczkowski, M.D.

## New Postmarketing Expedited Safety Reports (continued)

- Blood and blood component safety reports: Submit all serious SADRs, not just fatalities, within 45 days
- Bioavailability and Bioequivalence Studies not Subject to an IND: Submit all serious and unexpected SADRs as expedited reports

- Victor F. C. Raczkowski, M.D.

## Conclusions

- Goal of proposed rule is to improve consistency, quality, timely reporting, and analysis of important safety information
- Comment period for the proposed rule has been extended to October 14, 2003

- Victor F. C. Raczkowski, M.D.

## AppendixCurrent and Proposed Definitions

- Victor F. C. Raczkowski, M.D.

## Current Safety Reporting Definitions

- Associated with the use of the drug
- Adverse drug experience (AE)
- Disability
- Life-Threatening
- Serious
- Unexpected

- Victor F. C. Raczkowski, M.D.

## Associated with the Use of the Drug

- There is a reasonable possibility that the experience may have been caused by the drug

- Victor F. C. Raczkowski, M.D.

## Adverse Drug Experience

- Any adverse event (AE) associated with the use of a drug in humans, whether or not considered drug related, including the following:
- An AE occurring in the course of the use of a drug product in professional practice;
- An AE occurring from drug overdose whether accidental or intentional;
- An AE occurring from drug abuse;
- An AE occurring from drug withdrawal; and
- Any failure of expected pharmacological action

- Victor F. C. Raczkowski, M.D.

## New Definition of “Suspected Adverse Drug Reaction (SADR)”

- Replaces Definitions of “Associated with the Use of the Drug” and “Adverse Drug Experience”
- 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.

- Victor F. C. Raczkowski, M.D.

## Life-Threatening

- Premarketing
- Based on opinion of investigator or sponsor, not just the investigator
- Postmarketing
- No change

- Victor F. C. Raczkowski, M.D.

## Unexpected: Pre- and Postmarketing

- Not in investigator brochure (pre-marketing) or in labeling (postmarketing)
- Added: SADRs that are mentioned in the investigator brochure or U.S. labeling as occurring with a class of drugs but not specifically mentioned as occurring with the particular drug are considered unexpected

- Victor F. C. Raczkowski, M.D.

## New Proposed Definitions

- Nonserious SADR
- SADR determined not to be serious
- SADR with unknown outcome
- SADR cannot be classified as serious or nonserious
- Minimum data set
- Identifiable patient, identifiable reporter, suspect product, and 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

- Victor F. C. Raczkowski, M.D.

## New Proposed Definitions (cont.)

- 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
- 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 or any organized data collection scheme.
- Information compiled in support of class action lawsuits

- Victor F. C. Raczkowski, M.D.

## 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 administered, 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

- Victor F. C. Raczkowski, M.D.

## New Proposed Definitions (cont.)

- Postmarketing Periodic Safety Reporting
- 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 world
- Data Lock Point
- Cut-off date for data to be included in report

- Victor F. C. Raczkowski, M.D.

## 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

- Victor F. C. Raczkowski, M.D.