1. History of Pediatric Labeling
Steven Hirschfeld, MD PhD
CDR USPHS
Division of Oncology Drug Products & Division of Pediatric Drug Development, CDER, FDA

2. Food and Drug Administration (FDA) Principles
Labeling -1906
Safety-1938
Efficacy-1962

3. Development of Pediatric Information
1974- Congress passes National Research Act and establishes National Commission for the Protection Of Human Subjects Of Medical And Behavioral Research
1974-American Academy of Pediatrics (AAP) report commissioned by FDA on “General Guidelines for the Evaluation of Drugs to be Approved for Use during Pregnancy and for Treatment of Infants and Children”
1977- National Commission Report on “Research Involving Children”
1977-FDA Pediatric Guidance “General Considerations for the Clinical Evaluation of Drugs in Infants and Children”
1977-AAP Statement on Ethical Conduct

4. AAP Report-FDA Guidance 1977 Highlights
Emphasis on unexpected toxicities
Reasonable evidence for efficacy should exist prior to study in infants and children
Sick children should be enrolled
Active or historical controls preferred over placebo
Decreasing age order for study enrollment

5. Development of Pediatric Information
1979- FDA Regulation on Pediatric Use Subsection of Product Package Insert Precautions Section (21 CFR (f)(9))
1983-Federal Regulations for protection of Federally funded research
1994- Pediatric Rule revised 21 CFR (f)(9) with added subsection (iv) on using extrapolation as a basis for Pediatric Use
1996- FDA Guidance on “Content and Format of Pediatric Use Section”
1996-AAP Update on Statement

6. 1996 Guidance on Pediatric Use
To consider extrapolation:
Disease course in adult and pediatric patients should be similar
Effects of the drugs, both beneficial and adverse, in adult and pediatric patients should be described. Critical references should be included.

7. Development of Pediatric Information
1997- Food & Drug Administration Modernization Act- initial pediatric incentive program
1998- Pediatric Rule- mandated pediatric studies under particular circumstances
2001-Adaptation of HHS Subpart D (pediatric) regulations to FDA regulated research
2002-Best Pharmaceuticals for Children Act
renewal of pediatric incentive program
study of off patent drugs
public dissemination of pediatric information

8. General Label Sections
Description. Clinical Pharmacology. Indications and Usage. Contraindications. Warnings. Precautions. Adverse Reactions. Drug Abuse and Dependence. Overdosage. Dosage and Administration. How Supplied.

9. Additional Label Sections
Animal Pharmacology and/or Animal Toxicology
Clinical Studies References

10. Label Principles
(a) The labeling shall contain a summary of the essential scientific information needed for the safe and effective use of the drug. (b) The labeling shall be informative and accurate and neither promotional in tone nor false or misleading in any particular. (c) The labeling shall be based whenever possible on data derived from human experience. Conclusions based on animal data but necessary for safe and effective use of the drug in humans shall be identified as such and included with human data in the appropriate section of the labeling,

11. Part 201 Subpart B Section 201.57-(c)"Indications & Usage”
(iv) If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective, the Food and Drug Administration may require that the labeling state that there is a lack of evidence that the drug is effective for that use or condition.

12. 201.57(f)(9) “Pediatric Use”
Under f (Precautions), subsection 9 pertains to pediatrics. There are 8 subsections under subsection 9
(i) Pediatrics is defined as birth to 16
Note that in other settings for clinical studies and consent “child” is defined as of minority age in jurisdiction
(ii) If there is a pediatric indication different from adult indication, it should be listed under Indications & Usage and Dosage & Administration. Pediatric Use section should cite any limitations as well as appropriate information in Contraindications, Warnings and elsewhere in Precautions

13. 201.57(f)(9) “Pediatric Use”
(iii) For pediatric use based on adequate and well controlled trials for an approved adult indication, they should be summarized in Pediatric Use with additional information in Dosage & Administration, Clinical Pharmacology, and Clinical Studies. Pediatric Use will also cite limitations as well as appropriate information in Contraindications, Warnings and elsewhere in Precautions.

14. 201.57(f)(9) “Pediatric Use”
(iv) Pediatric Use may also be approved on the basis of adequate and well controlled adult studies with other information supporting pediatric use. In such cases, the agency will have concluded that the course of the disease and the effects of the drug,both beneficial and adverse, are sufficiently similar in the pediatric and adult populations to permit extrapolation from the adult efficacy data to pediatric patients.

15. 201.57(f)(9) “Pediatric Use”
Additional information supporting  pediatric use must ordinarily include
data on the pharmacokinetics of the drug in the pediatric population for determination of appropriate  dosage.
Other information (that may be used), such as data from
pharmacodynamic studies of the drug in the pediatric population
studies supporting the safety or effectiveness of the drug in pediatric patients,
pertinent premarketing or postmarketing studies or experience, may be necessary to show that the drug can be used safely and effectively in pediatric patients

16. 201.57(f)(9) “Pediatric Use”
(v) If the requirements for a finding of substantial evidence to support a pediatric indication or a pediatric use statement have not been met for a particular pediatric population, the Pediatric Use section shall state “Safety and effectiveness in pediatric patients below the age of (--  ) have not been established.” Pediatric Use will also cite limitations as well as appropriate information in Contraindications, Warnings and elsewhere in Precautions

17. 201.57(f)(9) “Pediatric Use”
(vi) Absence of substantial evidence for any pediatric population, label shall state “``Safety and effectiveness in  pediatric patients have not been established.''

18. 201.57(f)(9) “Pediatric Use”
If use of the drug in premature or neonatal infants, or other pediatric subgroups, is associated with a specific hazard, the hazard shall be described in this subsection of the labeling, or, if appropriate, the hazard shall be stated in the ``Contraindications'' or ``Warnings'' section of the labeling and this subsection shall refer to it.  

19. 201.57(f)(9) “Pediatric Use”
(vii) If sponsor believes none of above apply, alternate wording may be proposed
(viii) If the drug product contains one or more inactive ingredients that present an increased risk of toxic effects to neonates or other  pediatric subgroups, a special note of this risk shall be made, generally in the  ``Contraindications,'' ``Warnings,'' or ``Precautions'' section.  

20. Label Changes from FDA Pediatric Initiatives
At least 12 from Rule alone
About 48 from Exclusivity

21. Label Options for Pediatric Data
Precautions- Pediatric Use Section
Dosing
Indication
Clinical Pharmacology
Clinical Studies
Contraindications
Warnings

22. Options to submit pediatric data to the FDA
New indication
Label change with clinical data

23. Rationale for Questions to Committee
Federal government initiatives are aimed at developing therapeutics for pediatric patients and including product information in the approved package insert or product label.
Although the majority of children with cancer in the United States are treated on protocols from National Cancer Institute supported study groups, the majority of products used in children with cancer are used without dosing and safety information in the package insert.
The U.S. Congress has indicated in the Best Pharmaceuticals for Children Act of 2002 that pediatric use information should be included in product labels as one of the mechanisms to publicly disseminate information.

24. Same Adult and Pediatric Indications
Previously the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee, at a meeting in November 2001, recommended that to extend efficacy from an adult indication to a pediatric population, pediatric dosing studies and a demonstration of clinical proof of concept should be performed.

25. Same Adult and Pediatric Indications
If a product is approved for an adult disease or condition that also exists in children, consider what information from pediatric studies you would consider necessary and appropriate to be in the product label.

26. Different Adult and Pediatric Conditions
If pediatric dosing information and proof of concept data exist for a pediatric disease or condition that does not exist in adults, consider what information, if any, should be included in the product label
An example may be that a product is approved for second line colorectal cancer in adults and pediatric data are available for dosing and pharmacokinetics plus a single arm phase II study showing a modest response rate in 20 pediatric patients with refractory neuroblastoma (There is no existing product with this profile).

27. Lack of Activity
If dosing, safety, and lack of activity information are available from studies that enrolled children with cancer, consider what information, if any, be included in the product label.
Absence of activity in diseases other than the approved indication(s) have not been included in the label for oncology products for adults

28. No pediatric data
When no efficacy or safety data are available in pediatric patients consider if a statement that safety and efficacy have not been tested in children be included in the product label.