# Presentation: 541022

## Growth and Development of Pediatric Drug Development at the FDA

- Lisa Mathis, MD
- Associate Director
- Pediatric and Maternal Health Team
- Office of New Drugs
- Center for Drug Evaluation and Research

- June 2006

## FDA and Pediatric Health

- Series of adverse events resulting from the treatment of children with drugs and biologics in the early 20th century influenced the Food and Drug Administration’s ability to regulate medicine

## Biologics Control Act of 1902

- Diphtheria antitoxin was made by inoculating horses with increasingly concentrated doses of diphtheria bacteria, then bleeding the animals to obtain their blood serum, which was bottled as antitoxin
- Possibilities for contamination were vast in the  production process
- In 1901, thirteen children in St. Louis died after receiving diphtheria antitoxin contaminated with tetanus spores
- This tragedy spurred Congress into passing the Biologics Control Act

## 1906 Pure Food and Drugs Act

- Medicines from the 19th century contained dangerous substances
- Mrs. Winslow's Soothing Syrup:
- "For children teething. Greatly facilitates the process of Teething, by softening the gums, reducing all inflammation; will allay ALL PAIN and spasmodic action, and is SURE TO REGULATE THE BOWELS. Depend on it, Mothers, it will give rest to yourselves and RELIEF AND HEALTH TO YOUR INFANTS. Sold by all chemists, at 1s 1/2d per bottle."
- Contained alcohol and morphine sulfate Causing coma, addiction & death in infants
- Pure Food and Drugs Act prohibited interstate commerce in adulterated or misbranded drugs

## 1938 Food, Drug and Cosmetic Act 

- Elixir of Sulfanilamide introduced in September 1937
- Compounded with an untested solvent, diethylene glycol (chemically related to antifreeze)
- Caused 107 deaths including many children
- President Roosevelt signed the Food, Drug and Cosmetic Act on June 25, 1938
- Firms had to prove to FDA that any new drug was safe before it could be marketed

## 1962 Kefauver-Harris Amendment

- 1960 a New Drug Application was filed with the FDA for Kevadon (Thalidomide), which had been marketed in Europe since 1956
- FDA felt that the data were incomplete to support the safety
- 1961 the drug was pulled off the market in Germany because of congenital anomalies
- Over 20,000 Americans received thalidomide under the guise of investigational use
- 1962 Kefauver-Harris Amendment that manufacturers had to prove efficacy as well as safety

## FDA and Pediatric Health

- These crisis involved children, but resulting laws actually benefited adults
- Information on use of therapeutics in children remained inadequate
- Finally, in the 21st century, laws were passed to specifically address drug use in children

## Benchmarks Pediatric Drug Development

- 1979  Labeling Requirement
- 1994  Pediatric Labeling Rule
- 1997  Food and Drug Administration 			    Modernization Act (FDAMA)
- 1998  Pediatric Rule
- 2002  Best Pharmaceuticals for Children Act
- 2002  Pediatric Rule Enjoined
- 2003  Pediatric Research Equity Act

## General Principles*

- Pediatric patients should be given medicines that have been properly evaluated for their use in the intended population

- Product development programs should include pediatric studies when pediatric use is anticipated
- Pediatric development should not delay adult studies nor adult availability

- Shared responsibility among companies, regulatory authorities, health professionals, and society as a whole
******* ****from ICH E-11**

## Best Pharmaceuticals for Children Act (BPCA) 

- Signed into law January 4, 2002
- Renewed pediatric exclusivity incentive
- Provides additional process for “off-patent” drug  development
- Public posting of results
- Reporting of all AE’s for 1 year after 	  pediatric exclusivity granted

## BPCA

- Clinical Investigators may be involved in BPCA through the
- On-patent process, or
- Off-patent process

## Process for the Study of On-Patent Drugs

**FDA issues **
**Written Request**

**Industry agrees **
**to conduct studies**

**Industry declines**
**to conduct studies**

**Referral to Foundation**
** ****for NIH**

**Industry has 180 days to respond**

**Industry submits**
**a Proposed Pediatric Study Request**

**FDA determines**
**public health benefit **
**to support pediatric studies**

** ****yes**

** ****yes**

** ****no**

## Process for the Study of Off-Patent Drugs

**Priority List of**
**Off-Patent Drugs**

**FDA issues **
**Written Request**

**Industry agrees **
**to conduct studies**

**Industry declines**
**to conduct studies**

**Referral to NIH**

**Industry has 30 days to respond**

**yes**

**no**

## Considerations for Issuing a Written request

**Public Health Benefit? **
**Is this a serious, life-threatening condition?**
**How frequently does disease/condition occur?   **
**Are there therapeutic options approved for this indication, and are they labeled for use in pediatrics?**
**How often is this drug or others like it used in children (off-label use)? **

## Considerations for Issuing a Written request

**What do we know about the drug?**
**Are there any safety signals?**
**Animals?**
**Adult trials?**
**Spontaneous reports?**
**Is there enough safety information to start clinical trials in children?**
**Is there an appropriate risk/benefit?**

## Considerations for Issuing a Written request

**What information do we need?**
**In what age groups do we need the information?**
**What studies are needed to obtain this information?**
**Extrapolation may prevent children from unneeded**** exposure to studies, and**
**May result in expedited access for children**

## Ethics

**Ethical considerations are always important in pediatric trials**
**Subpart D (21CFR50)**
**Code of Federal Regulations gives additional protection for children**
**Institutional Review Board may refer a research protocol to a federally mandated ethics panel**
**If involves FDA regulated drug, comes to FDA panel**

## Pediatric Exclusivity Stats(April 2006)

- Proposed Pediatric Study Requests		          465
- Written Requests issued				317
- Exclusivity granted					118
- Label changes						115
- Number of patients in requested studies         44,763+
- Summaries of Medical/Clinical Pharmacology
- Summaries on fda.gov/cder/pediatrics	 	             65
- www.fda.gov/cder/pediatric/summaryreview.htm

## PREA

- Signed December 3, 2003
- Drugs and Biologics affected
- Restored some important aspects from the Pediatric Rule, enjoined in 2002
- Pediatric Assessment required for certain applications unless waived or deferred
- Established the Pediatric Advisory Committee

## PREA

- Assessment required for applications:
- New ingredient
- New indication
- New dosage form
- New dosing regimen
- New route of administration
- Guidance Published

## Pediatric Assessment

- Assessment must contain:
- Data adequate to assess the safety and effectiveness of the drug or biological product, and
- Data to support dosing and administration for each subpopulation

## PREA - Waiver

- Waiver granted when:
- Necessary studies impossible or highly impracticable;
- Strong evidence suggests the drug or biologic would be ineffective or unsafe; or
- Product does not represent a meaningful therapeutic benefit over existing therapies and is not likely to be used in a substantial number of pediatric patients

## PREA - Partial Waiver

- Partial Waiver granted (applies to an age subset of the pediatric population) when:
- Same criteria as waivers but with additional requirement
- Reasonable attempts to produce a pediatric formulation necessary for that age group have failed

## PREA - Deferral

**PREA - Deferral**

- Deferral granted when:
- Drug or biologic is ready for approval in adults;
- Additional safety and effectiveness data determined to be necessary; or
- There is another appropriate reason for deferral

## BPCA vs. PREA

**PREA**
**Studies are **_**required**_
**Orphan drugs designated exempt**
**Biologics and Drugs**
**Studies limited to drug/indication under development **
**10-1-07 Sunset****	**

**BPCA**
**Studies are **_**voluntary**_
**Includes orphan drugs and orphan drug indications**
**Drugs only**
**Studies on whole moiety**
**10-1-07 Sunset**

## Slide 26