Notice Number: NOT-HD-10-017

Key Dates
Release Date: May 26, 2010

Issued by
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov)

Purpose

The purpose of this RFI is to seek input from potential users regarding the data elements and information to be collected in a minimal and expanded Data Base of excipients that are used in pediatric formulations.

This is a time-sensitive Request for Information that will be used to obtain knowledge and information for project planning purposes only.This is a Request for Information (RFI), NOT a solicitation for proposals, applications, proposal abstracts, or quotations. This RFI should not be construed as an obligation in any way on the part of the United States (U.S.) Federal government.  The Federal Government will not pay for the preparation of any information submitted and/or for the government's use of that information. Additionally, the government cannot guarantee the confidentiality of the information provided.(See Confidentiality Section below).

Background

The Obstetric and Pediatric Pharmacology Branch (OPPB) within The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is involved with the planning and implementation of the Best Pharmaceuticals for Children Act (BPCA) 2007 (http://bpca.nichd.nih.gov/ ).  The BPCA 2007 authorizes the NICHD, in consultation with the U.S. FDA and experts in pediatric research, to identify therapeutic gaps in pediatric diseases, disorders or conditions in which more complete knowledge of treatment strategies, including drugs and biologics, may be beneficial to the pediatric population.  The lack of adequate pediatric formulations has been identified as a major obstacle for the study and use of drugs in children.

While concern has been focused on the medicinal component of the drug formulations administered, the history of drug toxicity in children has several examples of pediatric tragedies that have their origins in the excipients employed rather than the drugs used in the formulation preparation.

In 2006 NICHD created the United States Pediatric Formulations Initiative (US PFI) to address safety issues and problems associated with the lack of adequate pediatric formulations (Clin. Ther .2008;30 (11) 2097-2101). A similar Pediatric Formulation Initiative was created in 2008 in the European Union. (EU PFI).
The  US and EU-PFIs  are working together  to examine the risks of excipients in pediatrics, to identify gaps in safety information, and ultimately create and maintain a pediatric  excipients database that is available to drug  sponsors, scientists and the public.

For this purpose a joint EU-US PFIs Excipients Working Group has been formed to develop a strategy for conducting a high-level scientific literature review to evaluate acceptable excipients for children. The working group will determine a prioritization process for selected excipients based on: the strength of the literature evidence; broad applicability across the pharmaceutical industry; and potential for endorsement in Europe, US and worldwide following regulatory screening.

A number of issues have thus far emerged related to determination of how estimates have been made of acceptable recipient’s exposure, the availability of developmental toxicology information, and identification of gaps in information and knowledge.

The Specialized Information Services of the National Library of Medicine (NLM) has joined the pediatric excipients initiative as a co-sponsor, to provide advice about how best to structure the search of those items that are difficult to search, search for untapped sources of information, suggestion of toxicology experts, participate in the searching process and to discuss the availability of resources and support at NLM.

Development of an Excipients Database in Pediatrics: Minimal Data Base Elements

The joint EU-US PFIs Excipients Working Group has concluded that a simple search will not produce the needed information and that a clearly defined focus will yield meaningful information.  At this time the clinical consequences of excipient exposure in children are largely unknown. In addition, an accepted daily and cumulative intake of excipients have not been established in pediatrics.

A detailed review will be needed to define and establish the scope of knowledge gaps, update data on purported toxicities, and identify excipients that may impose a toxicity risk if included in pediatric formulations.

The data base structure will follow a modular model. Our initial approach would be to have a minimal database with the potential to expand with more information in later phases.  The data elements listed below would be included as a part of this initial minimal database.

GENERAL INFORMATION
CAS No
Synonyms
Physicochemical excipient characterization
Pharmacopoeial status
Regulatory status
Functional classification

HUMAN FIELDS
Demographic (age, gender etc)
Administration/Exposure (E.g., Route, dose, concentration, duration etc)
Safety/Tolerability/Adverse effects findings by organ/system (e.g. GI, CVS, respiratory, etc.)
Pharmacokinetics/ADME
PK/PD relationship
Acceptable daily intake

NON HUMAN FIELDS
Age. Juvenile/Adult) Species (e.g. rat, mouse, dog, non human primates.)
Administration/Exposure (e.g. Route, dose, concentration, duration etc)
Toxicity findings by organ/system (eg. Genotoxicity, hepatotoxicity etc,)
Toxicokinetics
Dose information (Eg., MTD, LD, NOEL, NOAEL)
In Vitro Data

Overall Purpose of the Excipients Database In Pediatrics

• To characterize the prevalence and spectrum of symptoms and/or laboratory findings of clinically significant toxicity.
• To identify knowledge gaps and needed studies or providing the basis for the development of  hypothesis-driven safety or toxicity studies.
• To conduct a high-level scientific literature review of the pharmacology, toxicology and safety data of a selected group of excipients used in pediatric formulations.
• To identify developmental pharmacology/toxicology findings of clinical significance.
• To determine the relationship between exposure and evidence of clinically significance toxicity in the pediatric age group as a whole, or in pediatric subpopulations.

Information Requested

The NIH is especially interested in concrete and relevant suggestions in order to determine the pediatric excipient database structure that best satisfies the needs of potential users, and therefore requests the following information:

• What type of specific information should be included in these categories as part of a pediatric excipients minimal data set?
• What data/information elements should be part of an expanded data base?
• What type of information on excipients used in pediatric formulations is difficult to obtain or not available from existing sources?
• What format should the information in the proposed database be used?  Should the database contain free flowing text (literature citation with text summarizing the article) with basic search facility, or should it be set up in a structured/tabular format with advanced search facility (e.g.,query builder)?
• How should users of the data base participate in the development of a single online source? By joining US PFI work or ad hoc groups? By offering help in populating the database( e.g., sponsors  sharing or donating unpublished/in-house data)? Or by participating in any future database expansion?

Issued by How to Submit a Response

Please provide your response to this Request for Information (RFI) no later than June 30, 2010.  Responses should be submitted as an e-mail attachment in PDF format. Please limit responses to 10 pages or less.  E mails should be sent to Sara Kistler at skistler@circlesolutions.com  Please indicate “NICHD PFI” as the subject line for your email.

When responding to this RFI, please identify:

• The kind organization that you represent (e.g., Government, Industry, Academia, Healthcare).
• Your role in that organization (e.g. Formulation Scientist, Toxicologist, Clinical trial investigator, Drug Safety/Pharmacovigilance Officer, Health care worker, Librarian, Information specialist. Regulatory affairs Officer, etc.).
• How often you and other individuals performing the role/function(s) in that group would need access to excipients toxicity and safety information?

NICHD will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder’s submission. However, responses to the RFI submitted may be reflected in future solicitation(s). NICHD reserves the right to contact any responder that responds to this RFI for the sole purpose of enhancing NICHDs understanding of your RFI submission. The collected information will be analyzed and may appear in reports.

This notice does not obligate the Government to award a contract or otherwise pay for the information provided in response. The Government reserves the right to use information provided by respondents for any purpose deemed necessary and legally appropriate. Any organization responding to this notice should ensure that its response is complete and sufficiently detailed. Information provided will be used to assess tradeoffs and alternatives available for the potential requirement and may lead to the development of a solicitation. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted.

Any solicitation resulting from the analysis of information obtained will be announced to the public in Federal Business Opportunities in accordance with the FAR Part 5. However, responses to this notice will not be considered adequate responses to a solicitation.
No proprietary, classified, confidential, or sensitive information should be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).”

Inquiries

Specific questions about this RFI should be directed to the following individual:

George P. Giacoia M.D.
Obstetric and Pediatric Pharmacology Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Center for Research for Mothers and Children
6100 Executive Boulevard, Room 4AO1C
Bethesda, Maryland  20892-7510
(Rockville, Maryland 20852 for non USPS/courier service)
E mail: gg65m@nih.gov

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