FDA and EMEA Interactions: Pediatric Oncology Products

Dr. Jean Temeck Lead Medical Officer Office of Pediatric Therapeutics Office of the Commissioner Food and Drug Administration April 16, 2008

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Scientific Discussions

Similarities: common goals Differences in regulatory approaches to the study of oncology products in pediatric patients Sharing scientific information Impact of sharing information

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Similarities: Common Goals

Recognition of urgent need for therapeutic options for pediatric patients with cancer.

Conduct of pediatric oncology studies early in product development.

Process transparency, sharing and timely dissemination of information resulting from conduct of these studies.

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Differences in Regulatory Approaches Initiation of Pediatric Oncology Studies

– EMEA: proof-of-concept from preclinical studies or from adult studies – FDA: proof-of-concept important but may proceed based on lack of therapeutic options for these serious and life-threatening diseases 4

Initiation of Pediatric Oncology Studies: Example

Written Request issued by FDA for study of an oncology product for treatment of brain stem gliomas.

EMEA: is there proof-of-concept and requested clarification from FDA regarding their rationale for issuing this WR.

FDA: limited treatment options for these patients; adult data available in related tumors and preclinical data may not be predictive of clinical response.

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Differences in Regulatory Approaches Indication

– EMEA: limited to adult indication if applicable to children – FDA: flexibility in pediatric indications studied permitted by our legislative incentive 6

Indication: Example

An oncology product – EMEA limited to study of the approved adult indication that was also applicable to children (i.e. nasopharyngeal carcinoma) – FDA requested studies in our Written Request for both nasopharyngeal carcinoma and other pediatric cancers (i.e. relapsed or refractory solid tumors).

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Differences in Regulatory Approaches Dosing regimen Example

– nasopharyngeal carcinoma:

FDA and EMEA: discussion of chemotherapeutic dosing regimen

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Differences in Regulatory Approaches Choice of Primary Efficacy Endpoint Example:

– Study of a rare pediatric tumor, nasopharyngeal carcinoma: FDA and EMEA: discussion of one primary endpoint- complete response; versus co-primary endpoints- complete response & survival 9

Scientific Information Exchanged Waivers:

– Full waiver: Necessary studies impossible or highly impractical (e.g. cancers not applicable to pediatrics or with low incidence in pediatrics); Strong evidence suggests that the product would be ineffective or unsafe; 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. 10

Scientific Information Exchanged Waivers (continued)

– Partial waiver: A subset of the pediatric population cannot be studied for any of the criteria specified for a full waiver (e.g. cancers that occur predominately in certain pediatric age groups) Reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

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Scientific Information Exchanged Efficacy

– discussion of preliminary lack of efficacy for an ongoing Phase 2 study for treatment of neuroblastoma.

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Scientific Information Exchanged Safety

– discussion of safety concerns related to: An oncology product for which a Phase 1 dose escalation and safety study was conducted under PREA in pediatric patients with relapsed or refractory solid tumors. FDA preliminary review: elevations in blood pressure and proteinuria were observed (labeled adverse events in adults); also, elevations in gonadotrophins observed in post menarchal girls. These parameters will be monitored in future clinical trials with this product. 13

Scientific Information Exchanged Safety

– discussion of safety concerns related to: An oncology product for which Phase 1/2 studies are ongoing in pediatric patients with solid and hematologic tumors, including neuroblastoma and clinical studies in adult patients with various tumors. FDA informed EMEA of the cardiac adverse events reported with this product. 14

Impact of Scientific Information Exchanged Goal:

sharing critical information may alter the conduct of a proposed or ongoing study or guide the conduct of future studies.

Examples:

– Oncology product for treatment of nasopharyngeal carcinoma: positive opinion rendered for this PIP by EMEA’s Paediatric Committee after discussion with FDA and further review; – Oncology product for treatment of solid and hematologic tumors, including neuroblastoma: FDA and EMEA agreed that there is need for careful cardiac monitoring in clinical studies with this product.

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Summary

FDA and EMEA share common goals regarding pediatric drug development Differences in regulatory approaches are discussed and we may agree to disagree or modify our approach. Scientific information is exchanged and consequently, we may alert each other to important information that may alter the conduct of ongoing studies or guide the conduct of future studies. 16