4099fnl.pdf

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2000
Additional copies are available from: Office of Training and Communications Division of Communications Management (Internet) http://www.fda.gov/cder/guidance/index.htm Office of Communication, Training and Center for Biologics Evaluation and Research 1401 Rockville Pike, Rockville, MD 20852-1448 Internet: http://www.fda.gov/cber/guidelines.htm. Fax: 1-888-CBERFAX or 301-827-3844 Mail: the Voice Information System at 800-835-4709 or 301-827-1800 U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2000
Table of Contents
INTRODUCTION (1.).1
GUIDANCE (2).2
ISSUES WHEN INITIATING A PEDIATRIC MEDICINAL PRODUCT DEVELOPMENT PROGRAM (2.1) . 2 AGE CLASSIFICATION OF PEDIATRIC PATIENTS (2.5). 9 ETHICAL ISSUES IN PEDIATRIC STUDIES (2.6). 12 Guidance for Industry1
E11 Clinical Investigation of Medicinal Products
in the Pediatric Population
This guidance represents the Food and Drug Administration's current thinking on this topic. It doesnot create or confer any rights for or on any person and does not operate to bind FDA or the public.
An alternative approach may be used if such approach satisfies the requirements of the applicablestatutes and regulations.
INTRODUCTION (1.)
Objectives of the Guidance (1.1)
The number of medicinal products currently labeled for pediatric use is limited. Thisguidance is intended to encourage and facilitate timely pediatric medicinal productdevelopment internationally. The guidance provides an outline of critical issues in pediatricdrug development and approaches to the safe, efficient, and ethical study of medicinalproducts in the pediatric population.
Background (1.2)
Other ICH documents with relevant information affecting pediatric studies include: Structure and Content of Clinical Study Reports Dose-Response Information to Support Drug Registration Ethnic Factors in the Acceptability of Foreign ClinicalData Good Clinical Practice: Consolidated Guideline General Considerations for Clinical Trials Statistical Principles for Clinical Trials 1 This guidance was prepared under the auspices of the International Conference on Harmonisation of theTechnical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
E10: Choice of Control Group in Clinical TrialsM3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials forPharmaceuticals Scope of the Guidance (1.3.)
Specific clinical study issues addressed in this guidance include: 1. Considerations when initiating a pediatric program for a medicinal product;2. Timing of initiation of pediatric studies during medicinal product development;3. Types of studies (pharmacokinetic, pharmacokinetic/pharmacodynamic (PK/PD), 4. Age categories; and5. Ethics of pediatric clinical investigation.
This guidance is not intended to be comprehensive; other ICH guidances, as well asdocuments from regional regulatory authorities and pediatric societies, provide additionaldetail.
General Principles (1.4)
Pediatric patients should be given medicines that have been appropriately evaluated fortheir use in those populations. Safe and effective pharmacotherapy in pediatric patientsrequires the timely development of information on the proper use of medicinal products inpediatric patients of various ages and, often, the development of pediatric formulations ofthose products. Advances in formulation chemistry and in pediatric study design will helpfacilitate the development of medicinal products for pediatric use.
Drug development programs should usually include the pediatric patient population when aproduct is being developed for a disease or condition in adults and it is anticipated theproduct will be used in the pediatric population. Obtaining knowledge of the effects ofmedicinal products in pediatric patients is an important goal. However, this should be donewithout compromising the well-being of pediatric patients participating in clinical studies.
This responsibility is shared by companies, regulatory authorities, health professionals,and society as a whole.
GUIDANCE (2)
Issues When Initiating a Pediatric Medicinal Product Development
Program (2.1)
Data on the appropriate use of medicinal products in the pediatric population should begenerated unless the use of a specific medicinal product in pediatric patients is clearlyinappropriate. The timing of initiation of clinical studies in relation to studies conducted inadults, which may be influenced by regional public health and medical needs, is discussedin section II.C. Justification for the timing and the approach to the clinical program needs tobe clearly addressed with regulatory authorities at an early stage and then periodicallyduring the medicinal product development process. The pediatric development programshould not delay completion of adult studies and availability of a medicinal product foradults.
The decision to proceed with a pediatric development program for a medicinal product,and the nature of that program, involve consideration of many factors, including: • The prevalence of the condition to be treated in the pediatric population • The seriousness of the condition to be treated • The availability and suitability of alternative treatments for the condition in the pediatric population, including the efficacy and the adverse event profile (includingany unique pediatric safety issues) of those treatments • Whether the medicinal product is novel or one of a class of compounds with known • Whether there are unique pediatric indications for the medicinal product • The need for the development of pediatric-specific endpoints • The age ranges of pediatric patients likely to be treated with the medicinal product • Unique pediatric (developmental) safety concerns with the medicinal product, • Potential need for pediatric formulation development Of these factors, the most important is the presence of a serious or life-threatening diseasefor which the medicinal product represents a potentially important advance in therapy. Thissituation suggests relatively urgent and early initiation of pediatric studies.
Information from nonclinical safety studies to support a pediatric clinical program isdiscussed in ICH M3. It should be noted that the most relevant safety data for pediatricstudies ordinarily come from adult human exposure. Repeated dose toxicity studies,reproduction toxicity studies, and genotoxicity tests would generally be available. The needfor juvenile animal studies should be considered on a case-by-case basis and be basedon developmental toxicology concerns.
Pediatric Formulations (2.2)
There is a need for pediatric formulations that permit accurate dosing and enhance patientcompliance. For oral administration, different types of formulations, flavors, and colors maybe more acceptable in one region than another. Several formulations, such as liquids,suspensions, and chewable tablets, may be needed or desirable for pediatric patients ofdifferent ages. Different drug concentrations in these various formulations may also be needed. Consideration should also be given to the development of alternative deliverysystems.
For injectable formulations, appropriate drug concentrations should be developed to allowaccurate and safe administration of the dose. For medicinal products supplied as single-use vials, consideration should be given to dose-appropriate single-dose packaging.
The toxicity of some excipients may vary across pediatric age groups and betweenpediatric and adult populations (e.g., benzyl alcohol is toxic in the preterm newborn).
Depending on the active substance and excipients, appropriate use of the medicinalproduct in the newborn may require a new formulation or appropriate information aboutdilution of an existing formulation. International harmonization on the acceptability offormulation excipients and of validation procedures would help ensure that appropriateformulations are available for the pediatric population everywhere.
Timing of Studies (2.3)
During clinical development, the timing of pediatric studies will depend on the medicinalproduct, the type of disease being treated, safety considerations, and the efficacy andsafety of alternative treatments. Since development of pediatric formulations can bedifficult and time consuming, it is important to consider the development of theseformulations early in medicinal product development.
Medicinal Products for Diseases Predominantly or ExclusivelyAffecting Pediatric Patients (2.3.1) In such cases, the entire development program will be conducted in the pediatricpopulation except for initial safety and tolerability data, which will usually be obtained inadults. Some products may reasonably be studied only in the pediatric population even inthe initial phases (e.g., when studies in adults would yield little useful information or exposethem to inappropriate risk). Examples include surfactant for respiratory distress syndromein preterm infants and therapies targeted at metabolic or genetic diseases unique to thepediatric population.
Medicinal Products Intended to Treat Serious or Life-ThreateningDiseases, Occurring in Both Adults and Pediatric Patients, forWhich There Are Currently No or Limited Therapeutic Options(2.3.2) The presence of a serious or life-threatening disease for which the product represents apotentially important advance in therapy suggests the need for relatively urgent and earlyinitiation of pediatric studies. In such cases, medicinal product development should beginearly in the pediatric population, following assessment of initial safety data and reasonableevidence of potential benefit. Pediatric study results should be part of the marketing application database. In circumstances where this has not been possible, lack of datashould be justified in detail.
Medicinal Products Intended to Treat Other Diseases andConditions (2.3.3) In such cases, although the medicinal product will be used in pediatric patients, there isless urgency than in previous cases, and studies would usually begin at later phases ofclinical development or, if a safety concern exists, even after substantial postmarketingexperience in adults. Companies should have a clear plan for pediatric studies andreasons for their timing. Testing of these medicinal products in the pediatric populationwould usually not begin until phase 2 or 3. In most cases, therefore, only limited pediatricdata would be available at the time of submission of the application, but more would beexpected after marketing. The development of many new chemical entities is discontinuedduring or following phase 1 and 2 studies in adults for lack of efficacy or an unacceptableside effect profile. Therefore, very early initiation of testing in pediatric patients mightneedlessly expose these patients to a compound that will be of no benefit.
In cases of a nonserious disease where the medicinal product represents a majortherapeutic advance for the pediatric population, studies should begin early indevelopment, and pediatric data should be submitted in the application. Lack of datashould be justified in detail. Thus, it is important to carefully weigh benefit/risk andtherapeutic need in deciding when to start pediatric studies.
Types of Studies (2.4)
The principles outlined in ICH E4, E5, E6, and E10 apply to pediatric studies. Severalpediatric-specific issues are worth noting. When a medicinal product is studied inpediatric patients in one region, the intrinsic (e.g., pharmacogenetic) and extrinsic (e.g.,diet) factors2 that could affect the extrapolation of data to other regions should beconsidered.
When a medicinal product is to be used in the pediatric population for the sameindication(s) as those studied and approved in adults, the disease process is similar inadults and pediatric patients, and the outcome of therapy is likely to be comparable,extrapolation from adult efficacy data may be appropriate. In such cases, pharmacokineticstudies in all the age ranges of pediatric patients likely to receive the medicinal product,together with safety studies, may provide adequate information for use by allowingselection of pediatric doses that will produce blood levels similar to those observed in 2 In the ICH E5 guideline on Ethnic Factors in the Acceptance of Foreign Data, factors that may result indifferent drug responses to a drug in different populations are categorized as intrinsic ethnic factors orextrinsic ethnic factors. In this document, these categories are referred to as intrinsic factors and extrinsicfactors, respectively.
adults. If this approach is taken, adult pharmacokinetic data should be available to plan thepediatric studies.
When a medicinal product is to be used in younger pediatric patients for the sameindication(s) as those studied in older pediatric patients, the disease process is similar,and the outcome of therapy is likely to be comparable, extrapolation of efficacy from olderto younger pediatric patients may be possible. In such cases, pharmacokinetic studies inthe relevant age groups of pediatric patients likely to receive the medicinal product,together with safety studies, may be sufficient to provide adequate information for pediatricuse.
An approach based on pharmacokinetics is likely to be insufficient for medicinal productswhere blood levels are known or expected not to correspond with efficacy or where there isconcern that the concentration-response relationship may differ between the adult andpediatric populations. In such cases, studies of the clinical or the pharmacological effect ofthe medicinal product would usually be expected.
Where the comparability of the disease course or outcome of therapy in pediatric patientsis expected to be similar to adults, but the appropriate blood levels are not clear, it may bepossible to use measurements of a pharmacodynamic effect related to clinicaleffectiveness to confirm the expectations of effectiveness and to define the dose andconcentration needed to attain that pharmacodynamic effect. Such studies could provideincreased confidence that achieving a given exposure to the medicinal product in pediatricpatients would result in the desired therapeutic outcomes. Thus, a PK/PD approachcombined with safety and other relevant studies could avoid the need for clinical efficacystudies.
In other situations where a pharmacokinetic approach is not applicable, such as fortopically active products, extrapolation of efficacy from one patient population to anothercan be based on studies that include pharmacodynamic endpoints and/or appropriatealternative assessments. Local tolerability studies may be appropriate. It may beimportant to determine blood levels and systemic effects to assess safety.
When novel indications are being sought for the medicinal product in pediatric patients orwhen the disease course and outcome of therapy are likely to be different in adults andpediatric patients, clinical efficacy studies in the pediatric population are recommended.
Pharmacokinetic studies generally should be performed to support formulationdevelopment and determine pharmacokinetic parameters in different age groups tosupport dosing recommendations. Relative bioavailability comparisons of pediatricformulations with the adult oral formulation typically should be done in adults. Definitivepharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the medicinal product is likely to be used should be conducted in the pediatricpopulation.
Pharmacokinetic studies in the pediatric population should generally be conducted inpatients with the disease. This may lead to higher intersubject variability than studies innormal volunteers, but the data will better reflect clinical use.
For medicinal products that exhibit linear pharmacokinetics in adults, single-dosepharmacokinetic studies in the pediatric population may provide sufficient information fordosage selection. This can be corroborated, if indicated, by sparse sampling in multidoseclinical studies. Any nonlinearity in absorption, distribution, and elimination in adults andany difference in duration of effect between single and repeated dosing in adults wouldsuggest the need for steady state studies in the pediatric population. All these approachescan be facilitated by knowledge of adult pharmacokinetic parameters. Knowing thepathways of clearance (renal and metabolic) of the medicinal product and understandingthe age-related changes of those processes can often be helpful in planning pediatricstudies.
Dosing recommendations for most medicinal products used in the pediatric population areusually based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose.
While dosing based on mg/square meter body surface area might be preferred, clinicalexperience indicates that errors in measuring height or length (particularly in smallerchildren and infants) and calculation errors of body surface area from weight and height arecommon. For some medications (e.g., medications with a narrow therapeutic index, suchas those used in oncology), surface-area-guided dosing may be necessary, but extra careshould be taken to ensure proper dose calculation.
Practical considerations to facilitate pharmacokinetic studies
The volume of blood withdrawn should be minimized in pediatric studies. Blood volumesshould be justified in protocols. Institutional review boards/independent ethics committees(IRBs/IECs) review and may define the maximum amount of blood (usually on a milliliters(mL)/kg or percentage of total blood volume basis) that may be taken for investigationalpurposes. Several approaches can be used to minimize the amount of blood drawn and/orthe number of venipunctures.
• Sensitive assays for parent drugs and metabolites to decrease the volume of blood • Laboratories experienced in handling small volumes of blood for pharmacokinetic analyses and for laboratory safety studies (blood counts, clinical chemistry) • Collection of routine, clinical blood samples wherever possible at the same time as samples are obtained for pharmacokinetic analysis • The use of indwelling catheters, to minimize distress as discussed in section II.E.5.
• Use of population pharmacokinetics and sparse sampling based on optimal sampling theory to minimize the number of samples obtained from each patient. Techniquesinclude (1) sparse sampling approaches where each patient contributes as few as 2 to4 observations at predetermined times to an overall population area-under-the-curveand (2) population pharmacokinetic analysis using the most useful sampling time pointsderived from modeling of adult data.
The principles in study design, statistical considerations, and choice of control groupsdetailed in ICH E6, E9, and E10 generally apply to pediatric efficacy studies. There are,however, certain features unique to pediatric studies. The potential for extrapolation ofefficacy from studies in adults to pediatric patients or from older to younger pediatricpatients is discussed in section II.D. Where efficacy studies are going to be conducted,companies may want to develop, validate, and employ different endpoints for specific ageand developmental subgroups. Measurement of subjective symptoms, such as pain, callsfor different assessment instruments for patients of different ages. In pediatric patients withchronic diseases, the response to a medicinal product may vary among patients not onlybecause of the duration of the disease and its chronic effects but also because of thedevelopmental stage of the patient. Many diseases in the preterm and term newborn infantare unique or have unique manifestations precluding extrapolation of efficacy from olderpediatric patients and call for novel methods of outcome assessment.
ICH guidances on E2 topics and ICH E6, which describe adverse event reporting, apply topediatric studies. Age-appropriate, normal laboratory values and clinical measurementsshould be used in adverse event reporting. Unintended exposures to medicinal products(accidental ingestions) may provide the opportunity to obtain safety and pharmacokineticinformation and to maximize understanding of dose-related side effects.
Medicinal products may affect physical and cognitive growth and development, and theadverse event profile may differ in pediatric patients. Because developing systems mayrespond differently from matured adult organs, some adverse events and drug interactionsthat occur in pediatric patients may not be identified in adult studies. In addition, thedynamic processes of growth and development may not manifest an adverse event acutely,but at a later stage of growth and maturation. Long-term studies or surveillance data, eitherwhile patients are on chronic therapy or during the posttherapy period, may be needed todetermine possible effects on skeletal, behavioral, cognitive, sexual, and immunematuration and development.
Normally the pediatric database is limited at the time of approval. Therefore,postmarketing surveillance is particularly important. In some cases, long-term follow-upstudies may be important to determine effects of certain medications on growth anddevelopment of pediatric patients. Postmarketing surveillance and/or long-term follow-upstudies may provide safety and/or efficacy information for subgroups within the pediatricpopulation or additional information for the entire pediatric population.
Age Classification of Pediatric Patients (2.5)
Any classification of the pediatric population into age categories is to some extentarbitrary, but a classification such as the one below provides a basis for thinking aboutstudy design in pediatric patients. Decisions on how to stratify studies and data by ageshould take into consideration developmental biology and pharmacology. Thus, a flexibleapproach is necessary to ensure that studies reflect current knowledge of pediatricpharmacology. The identification of which ages to study should be medicinal product-specific and justified.
If the clearance pathways of a medicinal product are well established and the ontogeny ofthe pathways is understood, age categories for pharmacokinetic evaluation might bechosen based on any break point where clearance is likely to change significantly.
Sometimes, it may be more appropriate to collect data over broad age ranges andexamine the effect of age as a continuous covariant. For efficacy, different endpoints maybe established for pediatric patients of different ages, and the age groups might notcorrespond to the categories presented below. Dividing the pediatric population into manyage groups might needlessly increase the number of patients required. In longer termstudies, pediatric patients may move from one age category to another; the study designand statistical plans should prospectively take into account changing numbers of patientswithin a given age category.
The following is one possible categorization. There is, however, considerable overlap indevelopmental (e.g., physical, cognitive, and psychosocial) issues across the agecategories. Ages are defined in completed days, months, or years.
• Infants and toddlers (28 days to 23 months) • Adolescents (12 to 16-18 years (dependent on region)) The study of medicinal products in preterm newborn infants presents special challengesbecause of the unique pathophysiology and responses to therapy in this population. Thecomplexity of and ethical considerations involved in studying preterm newborn infantssuggest the need for careful protocol development with expert input from neonatologists and neonatal pharmacologists. Only rarely will it be possible to extrapolate efficacy fromstudies in adults or even in older pediatric patients to the preterm newborn infant.
The category of preterm newborn infants is not a homogeneous group of patients. A 25-week gestation, 500-gram (g) newborn is very different from a 30-week gestation newbornweighing 1,500 g. A distinction should also be made for low-birth-weight babies as towhether they are immature or growth retarded. Important features that should beconsidered for these patients include: 1. gestational age at birth and age after birth (adjusted age);2. immaturity of renal and hepatic clearance mechanisms;3. protein binding and displacement issues (particularly bilirubin);4. penetration of medicinal products into the central nervous system (CNS);5. unique neonatal disease states (e.g., respiratory distress syndrome of the newborn, patent ductus arteriosus, primary pulmonary hypertension); 6. unique susceptibilities of the preterm newborn (e.g., necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity); 7. rapid and variable maturation of all physiologic and pharmacologic processes leading to different dosing regimens with chronic exposure; and 8. transdermal absorption of medicinal products and other chemicals.
Study design issues that should be considered include: 1. weight and age (gestational and postnatal) stratification;2. small blood volumes (a 500-g infant has 40 mL of blood);3. small numbers of patients at a given center and differences in care among centers; 4. difficulties in assessing outcomes.
Term Newborn Infants (0 to 27 days) (2.5.2) Although term newborn infants are developmentally more mature than preterm newborninfants, many of the physiologic and pharmacologic principles discussed above also applyto term infants. Volumes of distribution of medicinal products may be different from thosein older pediatric patients because of different body water and fat content and high body-surface-area-to-weight ratio. The blood-brain barrier is still not fully mature and medicinalproducts and endogenous substances (e.g., bilirubin) may gain access to the CNS withresultant toxicity. Oral absorption of medicinal products may be less predictable than inolder pediatric patients. Hepatic and renal clearance mechanisms are immature andrapidly changing; doses may need to be adjusted over the first weeks of life. Manyexamples of increased susceptibility to toxic effects of medicinal products result fromlimited clearance in these patients (e.g., chloramphenicol grey baby syndrome). On theother hand, term newborn infants may be less susceptible to some types of adverse effects(e.g., aminoglycoside nephrotoxicity) than are patients in older age groups.
Infants and Toddlers (28 days to 23 months) (2.5.3) This is a period of rapid CNS maturation, immune system development, and total bodygrowth. Oral absorption becomes more reliable. Hepatic and renal clearance pathwayscontinue to mature rapidly. By 1 to 2 years of age, clearance of many drugs on a mg/kgbasis may exceed adult values. The developmental pattern of maturation is dependent onspecific pathways of clearance. There is often considerable inter-individual variability inmaturation.
Most pathways of drug clearance (hepatic and renal) are mature, with clearance oftenexceeding adult values. Changes in clearance of a drug may be dependent on maturationof specific metabolic pathways.
Specific strategies should be addressed in protocols to ascertain any effects of themedicinal product on growth and development. Children achieve several importantmilestones of psychomotor development that could be adversely affected by CNS-activedrugs. Entry into school and increased cognitive and motor skills may affect a child’sability to participate in some types of efficacy studies. Factors useful in measuring theeffects of a medicinal product on children include skeletal growth, weight gain, schoolattendance, and school performance. Recruitment of patients should ensure adequaterepresentation across the age range in this category, as it is important to ensure asufficient number of younger patients for evaluation. Stratification by age within thiscategory is often unnecessary, but it may be appropriate to stratify patients based onpharmacokinetic and/or efficacy endpoint considerations.
The onset of puberty is highly variable and occurs earlier in girls, in whom normal onset ofpuberty may occur as early as 9 years of age. Puberty can affect the apparent activity ofenzymes that metabolize drugs, and dose requirements for some medicinal products on amg/kg basis may decrease dramatically (e.g., theophylline). In some cases, it may beappropriate to specifically assess the effect of puberty on a medicinal product by studyingpre- and postpubertal pediatric patients. In other cases, it may be appropriate to recordTanner stages of pubertal development or obtain biological markers of puberty andexamine data for any potential influence of pubertal changes.
Adolescents (12 to 16-18 years (dependent on region)) (2.5.5) This is a period of sexual maturation; medicinal products may interfere with the actions ofsex hormones and impede development. In certain studies, pregnancy testing and reviewof sexual activity and contraceptive use may be appropriate.
This is also a period of rapid growth and continued neurocognitive development.
Medicinal products and illnesses that delay or accelerate the onset of puberty can have aprofound effect on the pubertal growth spurt and, by changing the pattern of growth, may affect final height. Evolving cognitive and emotional changes could potentially influence theoutcome of clinical studies.
Many diseases are also influenced by the hormonal changes around puberty (e.g.,increases in insulin resistance in diabetes mellitus, recurrence of seizures aroundmenarche, changes in the frequency and severity of migraine attacks and asthmaexacerbations). Hormonal changes may thus influence the results of clinical studies.
Within this age group, adolescents are assuming responsibility for their own health andmedication. Noncompliance is a special problem, particularly when medicinal products(for example, steroids) affect appearance. In clinical studies compliance checks areimportant. Recreational use of unprescribed drugs, alcohol, and tobacco should bespecifically considered.
The upper age limit varies among regions. It may be possible to include older adolescentsin adult studies, although issues of compliance may present problems. Given some of theunique challenges of adolescence, it may be appropriate to consider studying adolescentpatients (whether they are to be included in adult or separate protocols) in centersknowledgeable and skilled in the care of this special population.
Ethical Issues in Pediatric Studies (2.6)
The pediatric population represents a vulnerable subgroup. Therefore, special measuresare needed to protect the rights of pediatric study participants and to shield them fromundue risk. The purpose of this section is to provide a framework to ensure that pediatricstudies are conducted ethically.
To be of benefit to those participating in a clinical study, as well as to the rest of thepediatric population, a clinical study must be properly designed to ensure the quality andinterpretability of the data obtained. In addition, participants in clinical studies shouldbenefit from the clinical study except under the special circumstances discussed in ICH E6.
Institutional Review Board/Independent Ethics Committee (IRB/IEC)(2.6.1) The roles and responsibilities of IRBs and IECs, as detailed in ICH E6, are critical to theprotection of study participants. When protocols involving the pediatric population arereviewed, there should be IRB/IEC members or experts consulted by the IRB/IEC who areknowledgeable in pediatric ethical, clinical, and psychosocial issues.
Recruitment of study participants should occur in a manner free from inappropriateinducements either to the parent(s)or legal guardian or the study participant.
Reimbursement and subsistence costs may be covered in the context of a pediatric clinicalstudy. Any compensation should be reviewed by the IRB/IEC.
When studies are conducted in the pediatric population, an attempt should be made toinclude individuals representing the demographics of the region and the disease beingstudied, unless there is a valid reason for restricting enrollment.
As a rule, a pediatric subject is legally unable to provide informed consent. Thereforepediatric study participants are dependent on their parent(s) or legal guardian to assumeresponsibility for their participation in clinical studies. Fully informed consent should beobtained from the legal guardian in accordance with regional laws or regulations. Allparticipants should be informed to the fullest extent possible about the study in languageand terms they are able to understand. Where appropriate, participants should assent toenroll in a study (age of assent may be determined by IRBs and IECs or be consistent withlocal legal requirements). Participants of appropriate intellectual maturity should personallysign and date either a separately designed, written assent form, or the written informedconsent. In all cases, participants should be made aware of their rights to decline toparticipate or to withdraw from the study at any time. Attention should be paid to signs ofundue distress in patients who are unable to clearly articulate their distress. Although aparticipant’s wish to withdraw from a study must be respected, there may becircumstances in therapeutic studies for serious or life-threatening diseases in which, in theopinion of the investigator and parent(s) or legal guardian, the welfare of a pediatric patientwould be jeopardized by his or her failing to participate in the study. In such a situation,continued parental or legal guardian consent should be sufficient to allow participation inthe study. Emancipated or mature minors (defined by local laws) may be capable of givingautonomous consent.
Information that can be obtained in a less vulnerable, consenting population should not beobtained in a more vulnerable population or one in which the patients are unable to provideindividual consent. Studies in handicapped or institutionalized pediatric populationsshould be limited to diseases or conditions found principally or exclusively in thesepopulations, or situations in which the disease or condition in these pediatric patientswould be expected to alter the disposition or pharmacodynamic effects of a medicinalproduct.
However important a study may be to prove or disprove the value of a treatment,participants may suffer injury as a result of inclusion in a study, even if the whole communitybenefits. Every effort should be made to anticipate and reduce known hazards.
Investigators should be fully aware before the start of a clinical study of all relevantpreclinical and clinical toxicity of the medicinal product. To minimize risk in pediatricclinical studies, those conducting the study should be properly trained and experienced in studying the pediatric population, including the evaluation and management of potentialpediatric adverse events.
In designing studies, every attempt should be made to minimize the number of participantsand of procedures, consistent with good study design. Mechanisms should be in place toensure that a study can be rapidly terminated should an unexpected hazard be identified.
Repeated invasive procedures may be painful or frightening. Discomfort can be minimizedif studies are designed and conducted by investigators experienced in the treatment ofpediatric patients.
Protocols and investigations should be designed specifically for the pediatric population(not simply re-worked from adult protocols) and approved by an IRB or IEC as described insection II.F.1.
Practical considerations to ensure that participants’ experiences in clinical studies arepositive and to minimize discomfort and distress include the following: • Personnel knowledgeable and skilled in dealing with the pediatric population and its age-appropriate needs, including skill in performing pediatric procedures • A physical setting with furniture, play equipment, activities, and food appropriate for • The conduct of studies in a familiar environment such as the hospital or clinic where • Approaches to minimize discomfort of procedures, such as (1) topical anesthesia to place IV catheters, (2) indwelling catheters rather than repeated venipunctures forblood sampling, and (3) collection of some protocol-specified blood samples whenroutine clinical samples are obtained.
IRBs and IECs should consider how many venipunctures are acceptable in an attempt toobtain blood samples for a protocol and ensure a clear understanding of procedures if anindwelling catheter fails to function over time. The participant’s right to refuse furtherinvestigational procedures should always be respected except as noted in section II.F.3.

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