Clinical research in pediatric population: Scientific and ethical aspects

Abstract

Children are a unique population with important differences in physical, physiological, and emotional differences from adults. Hence, research outcomes of studies conducted in adults cannot be extrapolated to pediatric population. However, there is scarcity of data on the safety and efficacy of new interventions in children, due to concerns about risks of research in children. It is vital to conduct scientifically robust and ethically sound observational noninterventional studies and interventional therapy clinical trials in children to provide supporting evidence for medical practices in the pediatric population, to advance understanding of diseases, and to provide quality health care. This is a brief review of scientific and ethical considerations in planning and conduct of clinical research in children.

INTRODUCTION

In India, children form 30% of population. Today’s healthy children are tomorrow’s healthy functional adults. Hence, research in health of children, who are a unique population with important differences in physical, physiological, and emotional differences from adults, deserves special attention. In many medical conditions, research outcomes of studies conducted in adults cannot be extrapolated to pediatric population. Hence, it is essential to conduct scientifically robust and ethically sound observational noninterventional studies and interventional therapy clinical trials, to provide supporting evidence for medical practices in pediatric population, to advance understanding of diseases, and to provide quality healthcare. Clinical trials in children are of vital importance in research and development of safe therapies, pediatric formulations, and medical interventions and are critical to improve the availability of age-specific, evidence-based medical treatments. However, concerns about risks of research in children, who are a vulnerable population, have discouraged the clinical research professionals from conducting research and undertaking trials of new therapies in pediatric population. Due to this, there is paucity of data on the safety and efficacy of new interventions in children, who may be exposed to ineffective or harmful therapies. This article discusses scientific and ethical considerations in planning and conduct of clinical research in children.

CLINICAL RESEARCH STUDIES

Clinical research includes interventional studies and observational noninterventional studies. These studies would include variety of studies depending on the purpose of research.

It is important to reflect on scientific aspects and ethical challenges prior to initiating clinical research in children.

SCIENTIFIC CONSIDERATIONS

Clinical trials of new therapy

Fundamental principle of drug development in children demands that they should not be recruited in a clinical trial of new therapy unless their participation is essential to fulfill an important pediatric health need. In planning development of a new therapy in children, important scientific aspects to be considered are: (1) rationale and timing of pediatric trials during drug development, (2) types of studies, (3) study design and population, (4) drug formulation and dosing, and (5) recruitment of children.[1,2,3,4,5]

Rationale and timing of pediatric trials during drug development

The overarching rationale for conducting clinical trials is to timely develop information on the proper use of pediatric formulations of medicinal products in children.[1] The objectives and purpose of the clinical trial in children are governed by the prevalence and seriousness of the condition to be treated in the pediatric population. A useful approach is to consider these aspects vis-à-vis adults.[1]

• Medicinal products for diseases predominantly or exclusively affecting pediatric patients, e.g., surfactant for respiratory distress syndrome in preterm infants or therapies targeted at metabolic or genetic diseases unique to the pediatric population

  • For such products, the entire clinical drug development program will be conducted in the pediatric population except for initial safety and tolerability data, which will usually be obtained in adults. If the risks are high and benefits in adults, it would be prudent to conduct clinical trials only in children.

• Medicinal products intended to treat serious or life-threatening diseases, occurring in both adults and pediatric patients, for which there are no or limited therapeutic options, e.g., infections

  • If a new therapy is likely to be a major advance, pediatric trials should be initiated urgently following evaluation of initial safety data and evidence of potential benefit.

• Medicinal products intended to treat other diseases and conditions, e.g., hypertension.

  • In such cases, there is less urgency for early initiation of pediatric studies. Clinical trials in children would begin during phase III of clinical development or after postmarketing experience in adults.

Types of studies

The objectives of clinical studies in children would be to understand pharmacokinetics or assess efficacy and safety of pediatric formulation.[1]

• Pharmacokinetic study would be essential to support formulation development and determine pharmacokinetic parameters in children of different age groups to support dosing recommendations. Such studies are usually conducted in children with the disease. During the conduct of pharmacokinetic study, volume of blood withdrawn should be minimized by (1) use of sensitive assays for drugs, (2) use of laboratories experienced in micromethods for estimation, (3) synchronizing collection of clinical blood samples and pharmacokinetic samples, (4) use of population pharmacokinetics and sparse sampling, (5) use of scavenged samples – leftover samples after medical procedures,[2] and (6) decreasing discomfort by using indwelling catheters placed under topical anesthesia

• Efficacy studies in children are essential for supporting new indications of a medicinal product in pediatric patients, or when the disease course and outcome of therapy are likely to be different in adults and pediatric patients.[1] During planning of such studies, the influence of normal growth and development on physiologic processes relevant to drug administration, drug disposition, drug response, and the effect of development and disease should be considered.[2] The development and validation of different endpoints, which rely on self-report, e.g., pain, nausea, dizziness, visual, and auditory responses, would be necessary for specific age and developmental pediatric subgroups such as nonverbal and preschool.[1,2,3] Monitoring devices, e.g., blood pressure cuffs, should be appropriate for the age of the participant.[2] Assessment of quality-of-life outcomes requires consideration of whether to use proxy response by parents or response by the child or both as the responses could vary.[3] In children suffering from chronic diseases, the response to a therapy may vary among them because of the duration of the disease and its chronic effects and the developmental stage of the child. Uniqueness of diseases or manifestations in the preterm and term newborn infant may not allow extrapolation of efficacy from older pediatric patients and may require novel methods of outcome evaluation[1]

• Safety assessments are required as medicinal products may affect physical and cognitive growth and development, and the adverse event (AE) profile may differ in pediatric patients.[1] Some AEs and drug interactions that occur in children may not be detected in adult studies. Long-term studies or safety surveillance data, when paediatric patients are on chronic therapy or during the posttreatment period, may be needed to determine possible effects on skeletal, behavioral, cognitive, sexual, and immune maturation and development. Range of upper limit of normal for screening laboratory values, liver function, and biomarkers of inflammation varies with the age of the child.[2] Hence, age-appropriate lab ranges should be used in a pediatric trial. Postmarketing surveillance and/or long-term follow-up studies are important to determine the effects of therapy growth and development of pediatric patients.

Study design and population

Classification of the pediatric population into age categories is useful in design of the studies.[1] Following approach, based on consideration of developmental biology, pharmacology, and pharmacokinetics, would be appropriate in planning studies which are age-appropriate and product-specific.

• Preterm newborn infants

• Term newborn infants (0–27 days)

• Infants and toddlers (28 days to 23 months)

• Children (2–11 years)

• Adolescents (12 to 16–18 years).

Factors such as (1) smaller and heterogeneous population, (2) evaluation of clinically important outcomes, (3) rapidly changing dynamic disease process, and (4) movement of pediatric patients from one age category to another in long-term studies would impact study design, participant recruitment, and statistical plans.[1,4]

Drug formulation and dosing

During the planning of pediatric trials, the development of child-friendly and safe formulation of drug is fraught with major challenges. A variety of oral formulations, e.g., liquids, suspensions, chewable tablets, minitablets, and orodispersibles in different drug concentrations, may be necessary for children of different ages and weights.[1,2] Children’s preference for smell, taste, flavor, color, and texture could vary across age groups. Preparing a child-friendly, easy-to-swallow, palatable formulation would be difficult for clinical trials of herbal products. For injectable formulations, appropriate drug concentrations must be developed to ensure accurate and safe administration of the dose.[1]

Recruitment of children

In clinical trials of children, poor recruitment and difficulties during the conduct of the trial are most common reasons for trial discontinuation.[5] Of 559 trials registered between 2008 and 2010 on ClinicalTrials.gov, 104 (19%) were stopped early. Difficulty with the enrollment of children was the most common reason for termination.

Important factors relevant to participation of children in clinical trials could be:[2,3]

• Parents’ fears and concerns about risks of clinical trial

• Investigator team’s efforts to explain trial procedures to parents and in age-appropriate manner to child

• Child-friendly clinic environment to provide an enjoyable experience for the child

• Timing of trial during school or holidays

• Requirements of fasting, dietary restrictions

• Requirements and timing of blood collections

• Time for clinic visits – early morning, school time.

These aspects require special attention in organizing pediatric clinical trials.

Clinical trials of traditional medicine treatments

Traditional medicine therapies include:

• Herbal drugs

• Nondrug treatments, e.g., panchakarma.

These clinical trials would be considered traditional, except phytopharmaceuticals, which are new drugs as per New Drugs and Clinical Trials Rules 2019 of India.[6,7]

Prior to embarking on clinical trials of traditional medicine treatments, critical issues to be considered are:[8]

1. Rationale of trials in children – Unmet medical need in children

2. Disease – Prior human use-experience

3. Selection of treatment – Single or multiple plants, classical or patent, and proprietary

4. Types of studies – Objective outcomes of efficacy and safety

5. Study design – Placebo, randomization, and blinding

6. Drug formulation – Quality, palatability, and ease of administration

7. Dose optimization – Extrapolation from whole plant to extract, pediatric dose

8. Duration of trial – Adequate to judge efficacy on clinically relevant outcome measures.

Observational studies

Observational studies are conducted in real-world settings and can provide useful information on (a) natural history of disease – prevalence and incidence, (b) unmet medical need in population, (c) safety surveillance of prescribed drugs, and (d) comparison of effectiveness of marketed drugs in real life.[9] In contrast to interventional clinical trials, observational studies are conducted without administering any intervention or drug to the patients.

The design of studies could be:

• Retrospective design – Based on available medical records on patients, e.g., case–control study

• Prospective design – Based on planned collection of medical data of patients, e.g., registry and cross-sectional survey.

ETHICAL CONSIDERATIONS

Interventional clinical trials

The conduct of pediatric clinical trials of any therapeutic modality raises many ethical concerns in children, as they represent a vulnerable group. The children are not able to make autonomous decisions regarding participation in clinical research.[1,10] Children lack the cognitive and emotional level of maturity and the legal status to give voluntary consent for participation in clinical trials on their own behalf. They have increased likelihood of suffering greater harm in research compared to adults. Hence, special measures are necessary to ensure the protection of the rights, safety, and well-being of children and to shield them from unjustified risk.[1,10]

Clinical trials in the pediatric population require a robust ethical review by ethics committee (EC), with a special emphasis on the informed consent process.

Ethics committee review procedure

The ECs have a major responsibility in safeguarding rights, safety, and well-being of pediatric participants. The EC members or experts consulted by the committee should be knowledgeable in pediatric ethical, clinical, and psychosocial issues.[1,10]

The EC should thoroughly examine trials in neonates, as they are the most vulnerable group within the pediatric population. The EC should have an advisory member with expertise in neonatal research or neonatal care for review of such studies.

The EC should critically review the fundamental ethical issues [Table 1].

Table 1.

Fundamental ethical considerations for paediatric clinical trials

Scientific validity

Type of study

Rationale

Design

Population age group

Investigator competence

Qualification

Experience in pediatric research

Training in the conduct of trial

Risks assessment

Age and developmental status

Underlying disease

Trial formulation of therapy

Invasive protocol procedures, e.g., blood collection

Inconvenience of complying with study visits

Benefits

Evaluation of the potential direct benefits of the therapy

Indirect benefits such as better medical care and the availability of free investigations for participation

Safety

Procedures to monitor and minimize risks and ensure participant safety

Autonomy

Consent process

Assent procedures

Additional protection for vulnerable groups

Confidentiality

Measures to ensure the privacy of participants

Procedures to maintain the confidentiality of data

Compensation

Influence of payments for participation

Compensation for serious adverse event

Informed consent process

Obtaining appropriate informed consent from the vulnerable population – children – and parents/guardians is a complex issue. As children lack legal and intellectual capacity to understand risks of taking part in a clinical trial, the parents or legal guardians give consent and authorize the participation of the child. In addition, the clinical investigator should seek assent and agreement from children about research participation.

Informed consent document

This document should provide adequate information about the clinical trial in clear and simple language. For industry-sponsored clinical trials for obtaining regulatory approval of new therapies, the informed consent document should include explanations as per Indian drug regulations and Good Clinical Practice guideline.[7,11]

The parents or LAR should be given above information in simple and unambiguous local vernacular language, which they understand. For clinical trials, which have academic research purpose, the informed consent document(ICD) should be adapted to include ethical issues, e.g., period of storage of the sample/data, use of data for secondary purposes appropriate for the objectives of the clinical study.[10]

Assent form document

The type and extent of information in the assent document should be simplified as per the child’s cognitive and age-related level. The essential information should include the following items:[10]

1. What the study is about and how it might help

2. What will happen and when

3. What discomfort the child may suffer

4. What will be done to minimize discomfort

5. Who will answer the child’s questions during the study

6. Whether the child has an option to say “no” to participation in the study.

The assent form should be short and easy to understand for children, and appropriate for the child’s age and reading ability.[10] An 8-year-old should be explained what exactly she/he is going to experience, although she/he may not understand the concept of clinical research. They can understand the practical aspects of protocol. For a 15-year-old child, the assent process should be similar to the informed consent process.

Documentation of consent and assent

Obtaining informed consent and assent is a process. The investigator should give time and opportunities for the parents and child to ask questions on the study protocol and should explain the study details in clear terms to ensure that the parents and child understand the clinical trial procedures. The process should be audio-video recorded. The child should be told that she/he may withdraw her/his assent at any time during the study. Child’s dissent or refusal to participate in clinical trial should be respected.

Assent should be obtained in age-appropriate manner[10] as follows:

• Children between 7 and 11 years of age, oral assent in the presence of parent or LAR

• Children between 12 and 18 years of age, written assent in the presence of parent or LAR.

EC should decide whether consent of one or both parents would be required for participation of a child in the study.[10] As clinical trials of new therapies would be considered high risk, consent from both parents may have to be obtained. One parent’s consent is acceptable when the other parent is deceased, not known, not competent to consent, or not available, or when only one parent is legally responsible for the care and custody of the child.

The consent and assent should be documented by the parents or LAR and the investigator by signing and dating the informed consent form.

If the parents or LAR are not literate and not able to read or sign the consent form, they should put thumb impression. In this case, the process of obtaining consent should be conducted in the presence of an impartial witness who should sign and date the document.

If a child wants to withdraw from a therapeutic study for serious or life-threatening diseases, but if the investigator and parents or LAR feel that the well-being of the child would be put at risk by his/her failure to participate, continued parental or legal guardian consent should be adequate to continue the trial.[1]

Clinical trial in emergency, when the parents or LAR may not be in a state to give consent, deferred consent may be considered.[10]

Reconsent

In some situations, reconsent would be required in case of:

1. Change in therapy

2. Change in study procedures

3. Long-term follow-up

4. Participant becoming conscious or mentally competent

5. Child attaining 18 years of age

6. Change in LAR

7. Availability of new information.[10]

Observational studies

The noninterventional observational studies would be considered minimum risk level research as harm to the child would be very slight and temporary.[10] For observational studies – retrospective or prospective – EC should review the fundamental ethical issues highlighted in Table 1.

In retrospective studies, which are based on available medical records and where the participants are de-identified or cannot be contacted, the EC may waive the requirements for informed consent.[10]

For prospective studies, the informed consent process should be similar to the process for interventional clinical trials.

CONCLUSIONS

Children form in important part of the Indian population. It is imperative to conduct clinical research and perform clinical trials to investigate the unique health care needs and provide age-appropriate therapy in pediatric pollution. Successful planning and conduct of clinical research studies requires use of robust state-of-the-art scientific designs and compliance to special ethical requirements of the vulnerable population.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.