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.
Pediatric Type of Studies, Data Extrapolation, Scenarios Warrants New Clinical Efficacy Studies in Pediatric Population (3)
Clinical Efficacy Studies can not be waived in pediatric populations is one or more of the following is different from the adult study:
- novel indication
- different disease process
- different therapy outcome
Pediatric Types of Studies, Pharmacokinetics Studies for
Adult vs Pediatric Specific Studies, Formulation Studies
Relative bioavailability comparison of formulations (i.e., pediatric vs adult oral formulation) should be conducted in:
Adult population
Pediatric Types of Studies, Pharmacokinetics Studies for
Adult vs Pediatric Specific Studies, Definitive Pharmacokinetic Parameter Studies
Definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients should be conducted in:
Pediatric population
Pediatric Types of Studies, Pharmacokinetics Studies in Pediatric Population, Studies with Pediatric Patients
Pros and Cons
Pharmacokinetic studies in pediatric population generally involves patients instead of healthy subjects.
Pros: better reflect clinical use
Cons: higher inter-subject variability
Pediatric Type of Studies, Product with Linear vs Nonlinear Pharmacokinetics in Adult
Linear Pharmacokinetics: Single-dose pharmacokinetic studies in pediatric population is sufficient, supported by sparse multi-dose sampling
Nonlinear Pharmacokinetics: Steady state multi-dose studies in the pediatric population is required
Pediatric Type of Studies, Dosing Measurement Calculation, Preferred in Pediatrics
Preferred: mg/kg
height, length, and body surfaces areas are more prone to errors particularly in children and infants
Pediatric Type of Studies, Practical considerations to facilitate pharmacokinetic Studies, Minimizing Blood Volume Withdrawn and associated Burdens (5)
IRB defines the maximum amount of blood (mL/kg or %Total), which can be minimized by:
- Use of sensitive assays for parent drugs and metabolites
- Use of experienced clinical labs for small volumes (i.e., PK, CBC, Blood Chemistries)
- Combine sample collection procedures (clinical and experimental samples)
- Use indewelling catheters
- Use models from optimal sampling theory (sparse sampling and population pharmacokinetics)
Pediatric Type of Studies, Minimizing Blood Volume Withdrawn and associated Burdens, Optimal Sampling Theory:
Sparse sampling
Each patients contributes as few as 2 to 4 observations at predetermined times to an overall “population AUC”.
Pediatric Type of Studies, Minimizing Blood Volume Withdrawn and associated Burdens, Optimal Sampling Theory:
Population pharmacokinetics
Uses the most useful sampling time points derived from modeling of adult data.
Pediatric Type of Studies, Efficacy, Pediatric Specific Considerations (Cannot Extrapolate), Examples (3)
Extrapolation of efficacy from adult or older age group facilitate but cannot replace efficacy studies in:
- subjective symptoms (different pain assessment)
- chronic disease (different duration and developmental outcome)
- preterm and newborn infants specific conditions
Pediatric Type of Studies, Safety, Opportunity of Unintended Exposure in Pediatric Patients
Unintended exposures to drugs (e.g. accidental ingestions) may provide opportunity to obtain safety and pharmacokinetic information, and to understand dose-related side effects.
Pediatric Type of Studies, Safety, Rationales for Special Safety Studies in Pediatric Population, Aspects (2)
- Developmental adverse events, which are not considered in adult studies
- Delayed adverse events, which only manifest later stage of growth and maturation.
Pediatric Type of Studies, Safety, Rationales for Special Safety Studies in Pediatric Population, Pediatric Specific Surveillance Areas Examples (5)
- Skeletal
- Behavioral
- Cognitive
- Sexual
- Immune
maturation and development should be assessed in long-term studies in pediatric patients.
Pediatric Type of Studies, Post-marketing Information
Pediatric patients require safety and efficacy information on growth and development from:
Post-marketing surveillance and long-term follow-up studies
Pediatric Type of Studies, Post-marketing Information
Pediatric patients require safety and efficacy information on growth and development from:
Post-marketing surveillance and long-term follow-up studies
Age Classification of Pediatric Patients (5), General and Arbitrary Classification
- Preterm newborn infants
- Term newborn infants (0 to 27 days)
- Infants and toddlers (28 days to 23 months)
- Children (2 to 11 years)
- Adolescents (12 to 16-18 years)
*Arbitrary but provide a basis for pediatric study design nonetheless.
Age Classification of Pediatric Patients, Flexible Approach,
General vs Categorical vs Continuous Variable
General: well-defined but arbitrary
Categorical: defined by safety and efficacy “break point (significant change)”
Continuous: not defined but more flexible and quantitative
Age Classification of Pediatric Patients, Preterm New Born Infants, Challenge Aspects (2)
Extrapolation of efficacy from studies in other age rarely possible due to unique:
- pathophysiology
- pharmacology
specific to preterm newborn, unless approved by neonatologist and neonatal pharmacologists.
Age Classification of Pediatric Patients, Preterm New Born Infants, Key Patient Features Considerations (8),
Physiological and Pathophysiological (5)
- gestational age at birth and adjusted age
- protein binding and displacement issues (bilirubin)
- unique neonatal disease states (respiratory and cardiovascular)
- unique susceptibilities of the preterm newborn (gastrointestinal, vascular, ocular)
- rapid and variable maturation of processes
Age Classification of Pediatric Patients, Preterm New Born Infants, Key Study Design Challenges (4)
- Weight and age stratification (i.e., gestational vs postnatal)
- Small blood volumes (e.g., 40mL blood in 500g infant)
- Sample size and variability (i.e., per center and across center)
- Outcome assessment challenges (e.g., compliance)
Age Classification of Pediatric Patients, Preterm New Born Infants, Key Patient Features Considerations (8),
Pharmacological (3)
- immaturity of renal and hepatic drug clearance mechanisms
- penetration of drug to CNS
- transdermal absorption of drugs and chemicals
Age Classification of Pediatric Patients, Term Newborn Infant (0-27 days), Special Considerations: Comparing to adult or older age groups (4)
Comparing to adult or older age groups:
- Drug distribution (body water/fat content, high body SA/Mass ratio)
- CNS penetration (BBB not fully matured) for drugs and endogenous substances (bilirubin)
- Oral absorption (variability)
- Hepatic and rental clearance (immature and rapidly changing)
Age Classification of Pediatric Patients, Term Newborn Infant (0-27 days), High vs Low Susceptibility, Examples
High susceptibility: chloramphenicol grey baby syndrome
Low susceptibility: amino-glycoside nephrotoxicity
Age Classification of Pediatric Patients, Infants and toddlers (28 days to 23 months), Special Considerations, Comparing to adult or older age groups (3)
- Rapid CNS, immune, and total body growth
- Improved oral absorption
- Hepatic and renal clearance start to surpass adult (on a mg/kg basis)
Considerable inter-individual variability in maturation.
Age Classification of Pediatric Patients, Children (2 to 11 years), Special Considerations, Comparing to adult or older age groups (3)
- Most hepatic and renal clearance pathways mature, often exceeding adult values.
- Psychomotor development could be affective by CNS-active drugs.
- Increased cognitive and motor skills
Age Classification of Pediatric Patients, Children (2 to 11 years), Common Developmental Evaluation Factors (4)
- Skeletal growth
- Weight gain
- School attendance
- School performance
Age Classification of Pediatric Patients, Children (2 to 11 years), Special Consideration for Puberty
In some cases, it may be appropriate to specifically assess the effect of puberty on drugs, by studying pre- and post-pubertal pediatric patients.
Age Classification of Pediatric Patients, Children (12 to 18 years), Special Considerations, Comparing to adult or older age groups
Physiological and behavioral (3+2)
- sexual maturation (drug impacts on sex hormones actions, development and pregnancy)
- rapid growth and neurocognitive development (drug impacts on course of development of body and mind)
- disease associated hormonal changes around puberty (diabetes, seizures, migraine, asthma)
- non-compliance (e.g., steroids affect appearance)
- recreational use of unprescribed drugs and agents
Ethical Issues in Pediatric Studies, General Expectation
In general, pediatric participants in clinical studies are expected to benefit from the clinical study.
Ethical Issues, IRB for pediatric studies, Required Member Expertise Areas (3)
IRB must have members/consultants who have expertise in the following aspects of pediatric research:
- ethical
- clinical
- psychosocial
Ethical Issues, Recruitment for Pediatric Subjects
Recruitment of study participants should occur in a manner free from inappropriate inducements (persuasion or influence) either to the legal guardian or the study participants.
Ethical Issues, Pediatric Study
Consent and Assent
Pediatric subject is legally unable to provide informed consent, as legal guardian assume full responsibility for their participation.
However, pediatric subject should assent, after being fully informed (and at appropriate age determined by IRB).
Ethical Issues, Pediatric Study
Requirement for Enrollment After Participants’s Dissent (2)
Participants’s wish to refuse or discontinue participation must be respected. However, legal guardian should be sufficient to allow participation if:
- therapeutic studies are for serious or life-threatening disease
- the welfare of the pediatric would be jeopardized without participation (in the opinion of both the investigator and the legal guardian)
Ethical Issues, Pediatric Study
General Principle for Enrollment, Relative Vulnerability
Whenever possible, enrollment should be obtained from less vulnerable population, as compared to those who are vulnerable or unable to provide consent.
Example: handicapped or institutionalized pediatric patients should be avoided if other pediatric patients are available to participate, unless the study require recruitment only from the handicapped or institutionalized population.
Ethical Issues, Pediatric Study, Minimizing Risk, Aspects (4)
The following aspects should be minimized to reduce risk:
- number of participates
- number of procedures
- uncertainties of toxicity
- response time to unexpected hazard
Ethical Issues, Pediatric Study, Minimizing Distress, Practical Consideration (4)
- Personnel: staffs who are knowledgeable and skilled in pediatrics
- Site-provision: furniture, play equipment, and food that are children friendly
- Site-setting: familiar environment such as home care or primary physicians clinic
- Technical approaches to minimize discomfort of procedures.
Ethical Issues, Pediatric Study, Technical approaches to minimize discomfort of procedures, Examples (3)
- Topical anesthesias to place IV catheters
- Indwelling catheters rather than repeated venipuncture for blood sampling
- Collection of protocol-specific blood sample from routine clinical samples when possible
Ethical Issues, Pediatric Study, Technical approaches to minimize discomfort of procedures, Blood Sample Collection, IRB specifications, Examples (2)
- number of venipuncture
- duration of cathether
