安渡分享 | FDA人用处方药和生物制品说明书儿科资料指南摘要

• This guidance, issued March 2019, is intended to assist applicants in determining the appropriate placement and content of pediatric information in human prescription drug and biological product labeling as described in the regulations for the content and format of labeling for human prescription drug and biological products

• The goal of this guidance is to provide recommendations to help ensure that information on the use of prescription drugs in pediatric populations (whether positive, negative, or inconclusive) is consistently placed in the proper sections and subsections within labeling so that the information is clear and accessible to health care providers

A.  FDA Pediatric Labeling Initiatives

• Until the early 1990s, the majority of drug labeling contained minimal or no pediatric use information to guide safe and effective use in the pediatric population.  In 1994, the FDA began the first of several initiatives to improve pediatric use information in drug labeling by issuing a final rule revising the requirements for the Pediatric Use subsection of labeling

• This regulation was intended to promote the inclusion of pediatric information from new clinical studies, previously published pediatric studies, and case reports in an effort to provide pediatric dosing and monitoring information in labeling.  It also required drug manufacturers to examine existing data and determine whether those data were sufficient to support additional pediatric use information in a drug’s labeling

• Subsequent pediatric legislation included the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). The BPCA contains economic incentives for conducting pediatric studies of drugs and biological products, and PREA establishes requirements for studies of certain drugs and biological products that may be used in pediatric patients.  The BPCA and PREA were made permanent in 2012 with the passage of the Food and Drug Administration Safety and Innovation Act

• Data submitted in response to a written request under the BPCA and assessments submitted in response to a PREA study requirement must be described in labeling whether findings are positive, negative, or inconclusive. Pediatric information in the labeling must not be false or misleading in any particular

B. Pediatric Age Groups

• For prescription drug labeling, the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research generally define pediatric population(s) and pediatric patient(s) as ages birth to 16 years (i.e., younger than 17 years old), and these phrases include the subpopulation age groups of neonates, infants, children, and adolescents

• The FDA generally recommends using the phrases “pediatric patients X to Y years old,” “pediatric patients aged X to Y years,” or “pediatric patients aged X years and older” (or similar phrases) when describing a specific age group(s) or pediatric subpopulation in labeling

A.  Evidence Supports Safety and Effectiveness of a Drug for an Indication in Pediatric Patients (Scenario 1)

When data support the use of a drug for a pediatric indication, pediatric use information must be placed in relevant sections of labeling.

• INDICATIONS AND USAGE:  All approved pediatric indications should be included in the INDICATIONS AND USAGE section. If the drug is indicated for use in the entire pediatric population, the term pediatric patients or pediatric population should be incorporated into the indication statement

• If a drug’s pediatric indication is only for use in a specific pediatric age group, the indication statement should specify the ages of the indicated pediatric age group.

• DOSAGE AND ADMINISTRATION:  This section must include the recommended dosage in pediatric patients for all approved pediatric indications, preparation and administration instructions pertinent to pediatric use and storage conditions for stability of the prepared drug

• ADVERSE REACTIONS:  Details of pediatric adverse reaction data from clinical studies or postmarketing data must be included in the ADVERSE REACTIONS section.  Special attention should be given to highlighting adverse reactions that are novel or unique in pediatric patients or that occur at a different frequency or severity

• USE IN SPECIFIC POPULATIONS, Pediatric Use:  The Pediatric Use subsection must include a required regulatory statement or reasonable alternative  statement when a drug is approved in pediatric patients for an indication that is the same as an approved indication in adults

When a drug is approved for pediatric use based on adequate and well-controlled studies in adults with other information supporting pediatric use, this subsection must include a summary of the basis of approval

If a drug is approved in adults and also is approved in pediatric patients  based on adequate and well controlled studies in pediatric patients, the basis of approval can be included in this subsection with cross-references to the appropriate section(s) or subsection(s) of labeling that provide more detailed information

When a drug is approved for use only in pediatric patients, and not in adult patients, the entire labeling should provide information essential for the safe and effective use in pediatric patients

The Pediatric Use subsection must also include the following information, as applicable, when related to the safe and effective pediatric use of the drug and should include cross references to other sections or subsections of labeling as appropriate:

Specific risks or safety concerns (hazards) associated with the use of the drug in pediatric patients   or in any specific pediatric age group (e.g., neonates) and/or the need for   specific monitoring

Any limitations on the pediatric indication.  If the approved indication(s) does not include all pediatric age groups, an appropriate pediatric use statement about the unapproved pediatric age groups mut be included

• CLINICAL PHARMACOLOGY:  Detailed descriptions of pediatric pharmacokinetic, pharmacodynamic, and/or pharmacogenomic study data; relevant data obtained from modeling, simulation, or bridging studies; and dose response information should be included in the CLINICAL PHARMACOLOGY section

• CLINICAL STUDIES:  Detailed descriptions of studies that provide substantial evidence of effectiveness for use in pediatric patients or populations (e.g., study design(s), population(s), endpoints, and results and limitations of the study design or evidence) should be provided in the CLINICAL STUDIES section

B. Evidence Does Not Support Safety and Effectiveness of a Drug for an Indication in Pediatric Patients (Scenario 2)

• When it is determined that available evidence regarding safety or effectiveness does not support a pediatric indication, relevant pediatric information related to the unapproved use that is included in labeling generally should be placed only in the Pediatric Use subsection

• Negative studies and inconclusive studies should be briefly summarized in this subsection, and not elsewhere in the labeling, to avoid the implication that a drug is safe and effective in pediatric patients

• An appropriate pediatric use statement must appear in the Pediatric Use subsection, before the summary of the available evidence, to clarify that safety and effectiveness in pediatric patients not been established for the unapproved indication discussed so that an unapproved indication or use is not implied or suggested

• If the use of the drug for an indication not approved in pediatric patients is associated with a risk or safety concern (hazard) in pediatric patients, the risk or safety concern must be described in the Pediatric Use subsection and must be stated in other sections of labeling as appropriate. A cross-reference from the Pediatric Use subsection to the applicable section or subsection that states the risk must be included

C. No Evidence to Support Safety and Effectiveness of a Drug for an Indication in Pediatric Patients (Scenario 3)

• When there is no evidence to support the safety and effectiveness of a drug for an indication in pediatric patients because studies have not been conducted or are ongoing, an appropriate pediatric use statement must be placed in the Pediatric Use subsection to state that safety and effectiveness in pediatric patients have not been established

• In addition to the pediatric use statement, if there is evidence strongly suggesting that a drug would be ineffective or unsafe the information must be included in the Pediatric Use subsection and if appropriate, must be stated in other sections of labeling

D. Contraindicated for Use in Pediatric Patients (Scenario 4)

• If a drug is contraindicated in all pediatric patients, in a specific pediatric age group(s), or in a subgroup of pediatric patients, the contraindication and reason for the contraindication should be stated first in the Pediatric Use subsection as well as in the CONTRAINDICATIONS section

• When a drug is contraindicated in all pediatric patients, the contraindication statement in the Pediatric Use subsection should be used as an alternative pediatric use statement instead of stating that safety and effectiveness have not been established in pediatric patients

• If the contraindication arose from a study conducted in pediatric patients, a brief description of the study should follow the contraindication statement in the Pediatric Use subsection

• The contraindicated use must be described in the CONTRAINDICATIONS section, and risk information associated with the contraindicated use should also be summarized in other sections of labeling as appropriate

• Nonclinical toxicity studies in juvenile animals can provide useful information concerning the safety profile of a drug in immature systems and a drug’s potential effects on the growth and development of pediatric patients. A concise summary of clinically relevant nonclinical toxicology studies in juvenile animal models should be described in the Pediatric Use subsection, following the information required in the Pediatric Use subsections  under the heading Juvenile Animal Toxicity Data. 

• Juvenile animal study data should only be summarized in the Pediatric Use subsection when the data suggest an adverse signal(s) that has not been previously assessed in a pediatric clinical study

Only information that may have clinical relevance should be summarized.  The summary should be discussed in clinically relevant terms, such as:

• Human equivalent dose exposures

• Ages of animals studied and how they correlate with approximate human ages
  

• Organ systems affected
  

• Duration of treatment of animals and relationship to clinical use 
  

• Reversibility of the adverse effect

• Developmental delay, if applicable