ICH E11 Pediatric Research Flashcards
Pediatric Research, Objectives of the Guidance (2)
To encourage and facilitate timely pediatric medicinal product development internationally
Pediatric Research, Background ICH Documents, General (5)
E2: Clinical Safety Data Management
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E5: Ethnic Factors in the Acceptability of Foreign Clinical Data
E6: Good Clinical Practice: Consolidated Guideline
Pediatric Research, Background ICH Documents, Clinical Trials (3)
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group in Clinical Trials
Pediatric Research, Background ICH Documents, Nonclinical (4)
M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
Q1: Stability Testing
Q2: Validation of Analytical Procedures
Q3: Impurity Testing
Pediatric Research, Scope of the Guidance (5)
Specific clinical study issues to be addressed:
- considerations when initiating a pediatric program for a drug
- timing of initiation of pediatric studies during a drug development
- Types of studies (PK/PD, efficacy, safety)
- Age categories
- Ethic of pediatric clinical investigation
Pediatric Research, General Principles, Development Area and Requirement (2)
Safe and effective pharmacotherapy in pediatric patients requires the development of
- information on the proper use of drug in various ages, and very often
- the development of pediatric formulations of those products
Without compromising the well-being of pediatric patients.
Pediatric Research, Issues When Initiating a Pediatric Drug Development Program,
Pediatric Studies General Aspects (3)
- Drug development in pediatric patients should be considered, unless it is clearly inappropriate.
- Timing of pediatric vs adult development needs to be justified and addressed with authorities.
- Pediatric development should not delay the completion of adult studies
Pediatric Research, Issues When Initiating a Pediatric Drug Development Program,
Factors General (4)
- The prevalence of the condition in the pediatric population
- The seriousness of the condition
- The availability and suitability of alternative treatments (including efficacy and safety profile)
- Whether the drug is novel or one of a class
Pediatric Research, Issues When Initiating a Pediatric Drug Development Program,
Factors Pediatric Specific (5)
- Whether there are unique pediatric indications for the drug
- The need for the development of pediatric-specific endpoints
- The age range of pediatric patients anticipated.
- Unique pediatric or developmental safety concerns with the drug, including nonclinical safety issues
- Potential need for pediatric formulation development
Pediatric Research, Issues When Initiating a Pediatric Drug Development Program,
Factors for Urgent and Early Initiation
The presence of a serious/life-threatening disease for which the drug represents potentially a significant advance in therapy
Pediatric Research, Issues When Initiating a Pediatric Drug Development Program,
Relevant Source of Safety Data as Reference for Pediatric Study (2)
- Adult human exposure, most relevant
- Juvenile animal studies, relevant if developmental toxicology is indicated
Pediatric Research, Pediatric Formulations, Purpose (2)
Pediatric formulation permits:
- more accurate dosing
- enhanced patient compliance
(e.g, liquified or chewable drug with favors and colors)
Pediatric Research, Pediatric Formulations, Variation, Examples (4)
- Routes of administration (Oral vs Injectable)
- Active ingredient concentration (High vs low)
- Packaging dose for single-use vials (Large vs small volume)
- Dilution for excipients with toxicity (benzyl alcohol in preterm newborn).
Pediatric Research, Timing of Studies, Consideration Aspects (4)
Timing of pediatric studies depends on the
- drug
- disease
- safety
- alternative treatment (efficacy and safety)
Timing of Studies, Medicinal Products for Disease Predominantly or Exclusively Affecting Pediatric Patients (Pediatric-specific), Efficacy vs Safety Studies
In this case, the entire development program will be conducted in the pediatric population, except for initial safety and tolerability data, which will usually be obtained in adults.
With rare exceptions.
Timing of Studies, Medicinal Products for Disease Predominantly or Exclusively Affecting Pediatric Patients, Special Safety Studies in Pediatric Patients (Pediatric-specific), Examples (2)
Under these special cases, initial phase studies may be only reasonably studied in pediatric population, in which case the study in adult yields little useful information or poses inappropriate risk.
Examples:
- Surfactant for respiratory distress syndrome in preterm infant
- therapies targeted at metabolic or genetic disease unique to the pediatric population
Timing of Studies, Drug Intended to Treat Serious or Life-threatening Disease, Occurring in Both Adults and Pediatric Patients, for Which There are Currently No or Limited Therapeutic Options (Non-pediatric Specific but Serious)
For drugs representing significant advance in therapy for serious/life-threatening diseases:
Development should begin early in the pediatric population, following initial safety assessment and reasonable evidence of potential benefit.
Timing of Studies, Drugs Intended to Treat Other Diseases and Conditions (Non-pediatric specific and Non-serious)
Pediatric studies usually begin at later phase of clinical development (after II or III), or after substantial post-marketing experience in adults (if safety concern exists), unless the drug represent a significant advance in therapy for pediatric patients.
Pediatric Type Studies, Data Extrapolation, Regional Factors Impacting the Data Extrapolation, Examples (2)
Intrinsic and Extrinsic
Intrinsic: Pharmacogenetics
Extrinsic: Diet
Pediatric Type Studies, Data Extrapolation, Requirement for Extrapolating Adult Data for Pediatric Efficacy (3+2) to Waive Clinical Efficacy Studies
The following factors need to be the same:
- Approved indication
- Disease process
- Therapy outcome
- Blood level
- Dose-response (of safety or efficacy effects)
Pediatric Type Studies, Data Extrapolation, Principle for Extrapolating Adult Data for Pediatric Efficacy
Select pediatric doses that produces blood levels similar to those observed in adults: matching blood level (PK)
Efficacy estimates together with safety data, may be sufficient for pediatric use.
Pediatric Type Studies, Data Extrapolation, Principle for Extrapolating Data in Older Pediatric Group for Efficacy in Younger Pediatric Group
Select younger cohort doses that produces blood levels similar to those observed in older cohort doses: matching blood level (PK)
Efficacy estimates together with safety data, may be sufficient for use in younger pediatric group.
Pediatric Type Studies, Data Extrapolation, Principle for Extrapolating Adult Data for Pediatric Efficacy,
Pharmacodynamic Effect vs Clinical Efficacy
When disease, mechanism, and outcome are the same but blood levels in pediatric patients are not clear:
Use measurement of a pharmacodynamic effect related to clinical effectiveness as a surrogate to confirm expected efficacy (PK/PD).
Pediatric Type of Studies, Data Extrapolation, Approach for When Pharmacokinetics is Not Applicable (i.e., Topical Treatment), Efficacy and Safety Assessment
Efficacy Assessment: Pharmacodynamic endpoint or other surrogate approach
Safety Assessment: Local tolerability studies, combined with blood levels, and systemic effects.