# Presentation: 332745

## Safety Assessment in Pediatrics

- Rosemary Roberts, MD
- Medical  Officer, Pediatrics Team
- Center for Drug Evaluation and Research
- Food and Drug Administration

## SafetyHistorical perspective

- Tragedies in children lead to regulations
- 1902 - Biologics Control Act
- diphtheria antitoxin contaminated with live tetanus bacilli
- 1938 - Food, Drug and Cosmetic Act
- sulfanilamide
- 1962 - Amendments
- thalidomide

## Assumption:

- “What is licensed is good,
- what is ‘off-label’ is bad.”
- Dr. Elliot Brown

## “Off-label is bad”

- Pediatric patient in “experiment” with every use
- not accruing data to learn how to administer the drug in a safe and efficacious manner

## Consequences

- Treatment concerns
- undertreatment: failure of therapy /continuation of disease
- overtreatment:  toxicity
- appropriate dose and use may lead to effect on growth and development

## Concerns

- Drug safety for pediatric patients cannot be adequately assessed from adult studies
- increased toxicity vs. decreased toxicity

## Toxicity

- Examples of increased toxicity
- chloramphenicol in the newborn
- tetracyclines in infants and children
- benzyl alcohol-containing IV fluids in premies/neonates

## Toxicity

- Examples of decreased toxicity
- aminoglycosides in the newborn
- acetaminophen acute overdose in young children

- Years of “experimentation”  have resulted in enough experience to allow  for the safe and effective use for drugs such as the penicillins and aminoglycosides
- Is this the way to continue to proceed?

## Why not?

- Increased percentage of vulnerable population with less tolerance for errors
- increased polypharmacy decreases ability to assign causality
- exposes a larger number of children to toxicity before defined

## Is licensed  “good”?

- Drug withdrawals/marketing restrictions after approval indicate that rare but serious adverse events may be identified after licensing
- examples:
- bromfenac
- terfenadine
- alatrofloxacin/trovafloxacin

## Safety assessment during drug development - premarketing

- Preclinical information
- Clinical trial information
- Types of studies requested

## Preclinical considerationsre: juvenile animal studies

- No standard package for preclinical assessment before initiating trials in the pediatric population
- Note:  careful consideration of study design for Segment 3 studies
- Determination on a case by case basis
- Consistent with ICH

## Juvenile animal studies

- When to consider:
- chronic use
- specific issues for the product (e.g., neurotoxic)
- drug class problems, e.g., genotoxicity (+), bone/joint toxicity in the adult (animal or human) studies
- combination

## Clinical trial information

- pK, efficacy and safety evaluated in the pediatric population(s)
- efficacy extrapolated from the adult studies with supporting pK and safety in the pediatric population(s)
- efficacy evaluated in adult and pediatric populations,  plus pK and safety

## Types of studies requested

- Efficacy/safety		63
- pK/safety			58
- pK/pD			10
- Safety			26
- Other			14
- Total		         171
- As of 5/31/99 for 76 WRs

## Safety studies

- 26 safety only studies
- in 20 products for which  Written Requests have been issued
- patient numbers:  30 (270) to 3000
- As of 5/31/99

## Safety studies

- Safety collected during study drug administration
- long-term observational study
- growth and development (steroids)
- CNS development  (drugs affecting neurotransmitters, drugs given chronically during CNS/brain development, drugs with CNS toxicity)
- musculoskeletal system (quinolones)

## Pediatric specific reporting

- Pediatric Rule of 1998 reporting requirements
- Reporting by sponsors to the NDA under 314.81(b)(2) - Other postmarketing reports -Annual report
- Pediatric study and labeling information submitted under the Summary, Clinical Data and Status reports subsections

## Postmarketing safety information

## FDA Adverse Event Reporting System (AERS) Database 

- Database Origin 1969
- SRS until 11/1/97 ; change to AERS
- Over 1.7 million reports in database
- All SRS data migrated into AERS
- Contains Drug and "Therapeutic" Biologic Reports
- exception = vaccines                                                                         VAERS 1-800-822-7967

## Report Processing in AERS

- Goal: adverse event reports received electronically (electronic pilot program ongoing)
- Current: Paper reports (3500 and 3500A forms):
- scanned upon arrival
- data entered (full text entry)
- adverse events coded in MEDDRA
- OPDRA Safety Evaluator review of reports:
- on-screen “inbox” - hands-on review of  15-day (unlabeled, serious) Manufacturer and Direct reports
- adverse event screening / surveillance / searching tools

## Slide 23

## Features of a Spontaneous Reporting System: Source of Reports	

- Reporting of adverse events by health professionals in U.S. is voluntary
- Direct to FDA (10-15%)
- Via the manufacturer (85-90%)
- Manufacturers: required by regulation (21 CFR 314.80) to forward adverse event reports to the FDA

## Direct Reports:  10-15% of Reporting  MedWatch Program  (1993) 

- The program has four goals:
- To increase awareness of drug and device-induced disease
- To clarify what should (and should not) be reported to the agency.
- To make it easier to report by operating a single system for health professionals to report adverse events and product problems to the agency.
- To provide regular feedback to the health care community about safety issues involving medical products
- The MEDWATCH program is supported by over 120 organizations, representing health professionals and industry, that have signed on as MedWatch Partners to help achieve these goals.

## Features of a Spontaneous Reporting System: Signal Generation	

- Early detection of rare events
- One or more reports can trigger further evaluation of a possible safety signal
- literature reports or other sources may also stimulate further evaluation of a safety issue
- Case series evaluation: identification of trends, possible risk factors, clinical significance
- cases from: Adverse Event Reporting System (AERS) , WHO , literature

## Signal Evaluation: Epidemiologic  Analysis of Selected Issues

- Reporting Rates vs. Occurrence Rates
- drug utilization data
- Query Large Databases
- FDA funded cooperative agreements, others
- Coordinate Further Study

## Percentage of AERs cases by age1997-1998

- 0-30 days			0.5%
- 0-16 years			 5%
- 17 years and up	        70%
- age unknown		        25%

## FDA

- Pediatric Safety