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

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

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

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

Development of Pediatric Information 1979- FDA Regulation on Pediatric Use Subsection of Product Package Insert Precautions Section (21 CFR 201.57 (f)(9)) 1983-Federal Regulations for protection of Federally funded research 1994- Pediatric Rule revised 21 CFR 201.57(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

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.

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

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

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

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,

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.

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

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.

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.

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

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

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.''

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.  

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.  

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

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

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

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.

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.

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.

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).

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

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.