Practical and Ethical Issues in Pediatric Clinical Trials

As research subjects, children have special needs because of their vulnerabilities and developmental peculiarities. Doctors involved in research on children must respect the autonomy and the individuality of children, be aware of children’s apprehension about medical procedures, and acknowledge the fundamental biological differences between adults and children. In this article, we will review some of the ways in which pediatric trials differ from adult trials and discuss some of the practical and ethical issues that remain to be solved.

Consider, for example, that in the year 2000, the European Union had about 75 million children and 45,000 pediatricians, but only 12 clinical pediatric pharmacologists. Pediatricians have been informed of the problem of unlicensed and off-license pharmaceutical use, but such use is commonplace. In the United States, the Food and Drug Administration (FDA) Modernization Act and its successor, the Best Pharmaceuticals for Children Act, provide companies a six-month patent extension in recognition of adequately conducted pediatric trials.

A European conference held in Brussels in January 2002, co-hosted by the European Forum for Good Clinical Practice (EFGCP) and the Confederation of European Specialists in Paediatrics (CESP), addressed the ethical, scientific, and regulatory issues in pediatric research. Both authors of this article participated.

The need for pediatric researchIn 1989, the United Nations General Assembly approved a Convention on the Rights of the Child.¹ The following four principles articulated in this declaration are of fundamental importance in pharmaceutical studies:

• All human rights apply to children without exception.

• All interventions must have the child’s best interest as a primary consideration of the highest priority.

• Children have the right to the highest attainable level of health.

• Children have the right to obtain information and the right to respect of their opinion.

Optimal medical care is based on evidence-based intervention. There are, however, significant deficits in our current knowledge of the quality and efficacy of many therapeutic measures in children, ² and much pediatric therapeutic data is derived from studies in adults. ³ In fact, children have been described as “therapeutic orphans” because of the deficit of appropriate studies in their age group. ^{4, 5} As a result of this deficit, about 50% of medications used in children’s hospitals are not properly licensed for use in children. ⁶

Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults. ⁷ For example, in pharmacokinetics, there are differences in metabolic pathways, in organic functions, and in metabolic rates. In pharmacodynamics, differences exist in receptor functions, effector systems, and homeostatic mechanisms. Growth and development influence side effects, and the dose of medications is dependent on body weight or surface area. Finally, age influences severity of disease, pathological agents, and natural history. These differences imply that extrapolation of adult data on medicinal products for the child population is inappropriate.

Furthermore, childhood has several ages and stages. Studies must be performed on specific age groups such as premature newborns, full-term newborns, infants and toddlers, older children, and adolescents.

The FDA, EMEA, and other authorities state that research in children should be supported and encouraged. The Committee for Proprietary Medicinal Products (CPMP) recommends the following categorization of products to be studied in pediatric clinical trials: ⁷

• medicinal products for diseases affecting children exclusively, such as surfactant in neonates
• medicinal products intended to treat diseases that mainly affect children, or are of particular gravity in children, or have a different natural history in children
• medicinal products intended to treat diseases occurring in adults and children, for which there is currently no treatment
• medicinal products to treat a disease occurring in adults and children for which treatments exist, but where there is insufficient knowledge of efficacy or toxicity in children.

When should pediatric trials begin?One ethical issue pediatric researchers face is the fact that clinical research involves some risk to the subjects. Research procedures range from techniques involving minimal risk, such as questioning, observation, and measurement carried out sensitively, to techniques involving higher risk, such as chemotherapy and surgery. Risk is greatest in the early phases of clinical research. At what point in a drug’s development should research in children begin? The International Conference on Harmonization of Technical requirements for registration of Pharmaceuticals for Human Use (ICH) makes several suggestions regarding the inclusion of children in the development program of medicinal products. ⁸ For medicinal products for diseases affecting children exclusively or predominantly, the entire development program can be conducted in the pediatric population beginning with phase 1 or 2 trials. For products for serious diseases affecting both adults and children for which a sufficient treatment does not currently exist, the development program should be conducted early in the pediatric population after safety and tolerability data have been obtained in adults (phase 2 or 3). For other products for serious diseases, the product usually should not be tested in the pediatric population until phase 2 or 3, after substantial experience in adults.

In all cases, efficacy, pharmacokinetic, and safety studies must be performed first in animals, as is required for adult studies. Placebo-controlled trials are inappropriate in pediatrics when risk would be increased by withholding a proven, effective treatment. ⁹

Good clinical practice issuesNo child should participate in a study unless a benefit to children in general will result. The ICH notes that the benefit to the individual and the benefit to the group must be balanced, as follows:The ethical imperative to obtain knowledge of the effects of medicinal products in paediatric patients has to be balanced against the ethical imperative to protect the individual child in clinical studies and respect his/her integrity and personal dignity.Good clinical practice (GCP) helps maintain that balance by ensuring that subjects are properly protected in research studies; studies are based on good science, well designed and properly analyzed; and study procedures are properly undertaken and documented. If GCP is not followed, children who take part may be at risk, the data may be unreliable or unusable, and the study should be rejected by the ethics committee.

Good clinical practice follows the general principles of medical ethics: ¹⁰

• respect for life, human dignity, and personal autonomy
• beneficence (do some good)
• non-maleficence (do no harm)
• justice.

From these ethical principles, general guidelines for good clinical practice in pediatric research can be derived. ^{8, 11, 12} Trials should focus on the knowledge, cure, relief, or prevention of diseases of children. Biomedical studies must be devoted to reducing suffering and improving the prognosis of diseases. Expected benefit must exceed recognizable risks. Serious predictable risks should be avoided. Only well-designed studies are ethically appropriate. Study protocols must be evaluated by ethics committees (institutional review boards) and reviewed by experts in pediatric issues. Informed consent or assent must be obtained from the child participant and informed consent from the legal representative, according to national law.

Detailed operational guidelines for clinical investigations of medicinal products in the pediatric childhood population are provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ⁸

It is imperative that pediatric studies be performed by medical and scientific personnel who are familiar with good GCP guidelines and are capable of a trusting relationship and communication with the child and parents. Studies should be performed in institutions that provide a child-friendly atmosphere with a pediatric infrastructure and personnel.

Ethics committees are an effective instrument to protect subjects from inadequate research. An ethics committee that is going to review pediatric research should have members experienced in working with children. A European study (1998) showed that local committees usually review pediatric studies, because there are only a few national committees examining research projects in children. CESP recommended in 1998 that all national pediatric specialties establish Ethics Committees and that the interests of children should be represented on these committees. ^{14, 15}

Informed consent and assentOnce the ethics committee has approved a properly designed study, the problem of obtaining consent or assent from children and their parents arises. The latest version of the Declaration of Helsinki¹³ suggests that for a legally incompetent minor, the investigator must obtain informed consent from the child’s legally authorized representative in accordance with applicable law. Even a legally incompetent minor may be able to give assent to decisions about participation in research, and in such cases the investigator must obtain that assent in addition to the consent of a legally authorized representative.

The Ethics Working Group of CESP gives several recommendations on this subject. The informed consent and assent process for including children in biomedical research should include all the information and consideration generally accepted for seeking informed consent of competent adults. Investigators should not place any coercion or undue influence to participate on the children’s parents. Dignity, privacy, and confidentiality of the child and family must be ensured. Information provided to children should conform to their intellectual capacity to understand the reason for the research and the risks therein. The family should be given sufficient time and information to consider the pros and cons of their involvement. Separate age-appropriate information sheets and consent or assent forms should be developed for the parents or legal representatives and for the child. A child should be able to withdraw willingly from any research project without detriment. In general the consent of both parents should be sought prior to enrolling a child in a biomedical research project. However, in some countries the consent of one parent is deemed adequate.

Recruitment issuesEven if sponsors are eager to perform studies in children, and the trial protocol has been carefully designed to meet their needs, recruiting pediatric subjects may be difficult. Parents seem to be becoming increasingly reluctant to enroll their children in basic research with no perceivable immediate benefit. As with adult trials, it is easiest to recruit children into trials when the standard therapies are unsatisfactory and the illness is inevitably lethal, as in cystic fibrosis and leukemia. Many parents have difficulty understanding placebo-controlled trials, and when they do understand them, they often have reservations about enrolling their children in them. An increasing number of antibiotic clinical trials are conducted in developing countries because it is easy to recruit subjects there, a trend that has raised ethical concerns.

In our experience, parents commonly raise several objections to enrolling their children in trials. Fear of harming or hurting children, especially by extensive blood sampling, objections to using children as “guinea pigs,” misconceptions regarding the need for placebos, and the increasing complexity of information sheets all contribute to parents’ reluctance.

Children themselves may be less reluctant than their parents. In 2001, an unpublished study of 30 families performed in Children’s Hospital in Dublin showed that 23% of parents would allow their child to participate in a clinical trial of an antibiotic with a license for adults, whereas 45% of children would be willing to take part.

However, the issue of childhood assent is contentious. An intellectual age of seven years has arbitrarily been recommended for including children in the assent process. One of the authors concluded from a small study that children under 10 years old did not fully understand the complexities of clinical trials and what they were being asked to assent to. Although parents are expected to sign the consent documents, should the verbal assent of children suffice, or should they be asked to sign something saying that they had been informed of the risks and assented, or did not dissent?

Other ethical issuesThe age at which children should become involved in the assent or consent process is just one question that must be studied and defined more clearly. Other ethical questions also constantly arise when sponsors consider pediatric trials. For example, can healthy children participate in taste tests of pediatric liquid formulations? How does one define “minimum risk” in terms of venipuncture and sample collection? Should currently well children with cystic fibrosis participate in pharmacokinetic studies of inhaled aerosolized antibiotics? How should investigators handle the need for contraceptives for adolescents involved in therapeutic trials where teratogenesis may be of concern, such as trials of new antiepileptics? What are the standards for off-license, off-label drug use in very low birth weight infants (under 1 kg)? Do we need placebo-controlled trials when there is no existing comparator, as in the case of antiviral agents?

The case of aerosolized inhaled insulin demonstrates how many ethical gray areas there still are in pediatric trials. An adult study of this therapy has demonstrated effect, but has not established long-term efficacy or safety. A person on 40 units insulin daily by injection would require 400 units insulin by inhalation. Insulin-dependent diabetes mellitus is primarily a disease of children. The desire of most children with diabetes is to be rid of insulin injections. Should children with diabetes be allowed to participate in trials of inhaled insulin, or must they await adult studies? The following are just some of the ethical issues that would arise in such a trial:

• What are the pharmacokinetics and pharmacodynamics of such a dose? Insulin distribution and metabolism would have to be studied.
• Assuming only about 10% of an inhaled dose is absorbed, would radio-isotope labeled studies of insulin deposition be required?
• Are there potential deleterious effects of such a large dose, such as antibody formation?
• Children with diabetes of five to ten years’ duration would be very willing to participate. They would likely have a good appreciation of the issues involved. They would probably be willing to risk potential side effects in exchange for perceived benefit (absence of injections!). Would it be appropriate to include children aged 12–16 years in such trials?

Although encouraging efforts have been made to address these ethical issues in Europe and in the United States, ^16,17 much remains to be discussed, as this one example shows. It will require the combined efforts of pediatricians, pharmacologists, researchers, manufacturers, and medical societies to move pediatric trials forward with the necessary speed and care.

References 1. General Assembly of the United Nations, Convention on the Rights of the Child, 20 November 1989, www.unicef.org/crc/crc.htm.

2. R.L. Smyth and A.M. Weindling, “Research in Children: Ethical and Scientific Aspects,” Paediatrics 354: 21–24 (1999).

3. National Institutes of Health, NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, grants.nih.gov/grants guide/notice-files/not98-014.html (1998).

4. T.L. Chambers and R. Kurz, “Ethical Overview of Paediatric Research and Practice in Europe from the Ethical Working Group of the Conference of European Specialists in Paediatrics (CESP),” European Paediatrics 158: 537–540 (1999).

5. C. Cote et al., “Is the Therapeutic Orphan About to be Adopted?” Paediatrics 98: 118–123 (1996).

6. S. Conroy et al., “Survey of Unlicensed and Off-label Drug Use in Paediatric Wards in European Countries,” British Medical Journal 320: 79–82 (2000).

7. Committee for Proprietary Medicinal Products (CPMP), “Note for Guidance on Clinical Investigations of Medicinal Products in Children,” CPMP/EWP 462 (1995).

8. Directive 2001/20/EC of the European Parliament and the Council on the Approximation of the Law, Regulations and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use, 4 April, 2001, www.eortc.be/Services/Doc/clinical-EU-directive-04-April-01.pdf.

9. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population. ICH, Topic 11, www.ich.org (2000).

10. T. Chambers, “Seven Questions about Paediatric Research,” Journal of the Royal Society of Medicine 93: 320–321 (2000).

11. P.J.J. Sauer, “Research in Children,” Report on behalf of the Ethics Working Group of CESP, European Journal of Pediatrics 161: 1–5 (2002).

12. Royal College of Paediatrics and Child Health, Ethics Advisory Committee, “Guidelines for the Ethical Conduct of Medical Research Involving Children,” Archives of Disease in Childhood 82: 177–182 (2000).

13. World Medical Association Recommendations Guiding Physicians in Biochemical Research Involving Human Subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, and amended by the 29th World Medical Assembly, 1975; 35th World Medical Assembly, 1983; 41st World Medical Assembly, 1989; the 48th General Assembly, 1996; and the 52nd World Medical Assembly, Edinburgh, Scotland, October 2000 (The World Medical Association, Inc., PO Box 63, 01212 Ferney-Voltaire Cedex, France; www.wma.net/e/policy/17-c html ).

14. World Health Organization, Operational Guidelines for Ethics Committees that Review Biomedical Research, www.who.int/tdr/publications/publications/ethics.htm (2000).

15. R. Kurz, “The Role of European Ethics Committees in Paediatrics,” Good Clinical Practice Journal 7: 22–25 (2000).

16. J. Wechsler. “Science, Pediatric Studies, and Surrogates,” Applied Clinical Trials, June 1999, 28–33.

17. J. Wechsler, “Ethics, Kids, and Sex,” Applied Clinical Trials, August 2001, 15–17.