Introduction
The purpose of this review is to discuss general issues that need to be taken into consideration when planning a pediatric study. A number of specific areas are covered, including the ethical considerations surrounding pediatric clinical trials and consent, and the performance of pediatric healthy volunteer studies. The respective roles of ethics committees in general and the European Group on Ethics in particular are covered, along with guidance from the General Medical Council of the United Kingdom. Finally, compassionate and innovative treatments in children and a proposal for an ethical framework for those treatments are discussed.
General Issues to be Taken into Consideration when Planning a Pediatric Study
The European Commissions regard identification and scientific validity of the study question to be pivotal considerations when planning a pediatric study [1]. There should be good justification for the study along with evidence of benefit as well as potential risks. The investigator(s) should be competent and appropriately trained, and the institution(s) should have a suitable infrastructure. Pre-clinical and clinical data, including information on safety and the investigator’s brochure, should be available. It is advisable to use (or develop) age-appropriate scales or measures of endpoints.
Informed consent should be comprehensive and assent understandable. There are certain special situations such as emergency trials (e.g. status epilepticus) when consent should be obtained from one or more designated individuals fully independent of the research team, and that consent from the parent/legal guardian and assent from the child are subsequently obtained. Obviously, it is not possible to obtain assent from pre-school children and neonates.
There are added considerations when considering the study of drugs in the neonate. An NIH/FDA panel has identified a number of criteria as being important for the investigation of drugs in the neonate [2]. The disease and the indication, including elements such as the potential for adverse outcomes, frequency in neonates, and the level of evidence for treatment of in this age group should be considered. In addition, the drug characteristics, including dosing, the availability or otherwise of age-appropriate formulations, clinically relevant drug-drug and drug-disease interactions, and drug disposition in neonates are important. The NIH/FDA panel notes that the ethical basis for a proposed neonatal study, including elements to address benefit or harm due to exposure to the study drug, study methodology, and benefit of the new treatment relative to established standard therapy, are important considerations.
The General Medical Council (GMC) of the United Kingdom has issued guidance surrounding pediatric clinical trials [3]. The GMC emphasis the importance of being able to assess the child’s capacity to decide whether or not to consent. A competent child should be able to understand the nature, purpose and possible consequences of the proposed investigation or treatment. The GMC notes that at age 16 a young person can be treated as an adult and can be presumed to have capacity to decide whilst those under the age of 16 years may have capacity to decide, depending on their ability to understand what is involved.
Ethics committees should have representation of pediatric expertise, both at the time of initial review and at the time of amendments. The committee has a duty to ensure protection of children, including minimization of risks, fear, pain and distress. There is also a European Group on Ethics in Science and New Technologies [4] which is a neutral, independent, pluralist and multidisciplinary body, composed of fifteen experts appointed by the Commission for their expertise and personal qualities. The task of the Group is to examine ethical questions arising from science and new technologies, and on this basis to issue opinions to the European Commission in connection with the preparation and implementation of European Union legislation or policies.
Insurance of child participants in the relevant country is necessary and indemnification may be a legal requirement. Continuation of trial medication after the completion of the study, whilst not a universal requirement, would likely be medically justified if such medication were shown to be of benefit. It is also a component which can enhance recruitment.
The ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use, chaired by the Commission services, has adopted recommendations on various ethical aspects of clinical trials performed in children [5]. These recommendations are designed to contribute to the protection of children who are the subject of clinical trials. The recommendations enshrine the principles of beneficence, justice and respect. Furthermore, the recommendations are intended to facilitate a harmonized application of rules on clinical trials across the European Union and thereby facilitate the conduct of clinical trials in the European Union.
Pediatric Healthy Volunteer Studies
Rollinson [6] asks: “It is very laudable to suggest that we test new investigational medicinal products on children but which parent would allow a child to take part in a Phase I healthy volunteer study (which look primarily at safety and tolerability of new medicinal products)? Rollinson notes that special care needs to be taken in obtaining both consent from the parents/guardians and assent from the children. This is a situation not involving a patient in whom a greater risk may be acceptable as a price to pay for a therapeutic benefit. A healthy volunteer does not stand to benefit but can potentially suffer an adverse reaction. Careful consideration needs to be taken of this risk, especially if payment is involved, and adequate indemnification needs to be in place in the event that compensation is required. Participation in volunteer studies should not be perceived as a money-making opportunity, especially in the case of children of less well- off parents.
The European Commission is relatively proscriptive in stating that, in principle, healthy children should not be enrolled as healthy volunteers and that studies should not be performed in children when they can be performed in adults [5]. However, there are notable exceptions such as immunogenicity studies and vaccine trials where the product is likely to be under development for otherwise healthy members of the population.
Compassionate and Innovative Treatments in Children
Brierley and Larcher propose an ethical framework for the special area of compassionate and innovative treatments in children [7]. On occasion, this form of intervention is incorporated in a “compassionate use” protocol. Brierley and Larcher state that there should be a clear clinical need and that there should be a realistic and reasonable scientific basis for what is proposed, which may be verified by an independent second opinion or review. There should be a realistic expectation of likely to benefit, for example some evidence from adult medicine, laboratory or animal research.
There should be consensus in the team that there are no other reasonable or feasible or safer alternatives that might achieve the same result. The child’s family, and the child if competent or able to understand, needs to understand that the procedure/treatment is experimental and what the possible risks, benefits and alternatives are. Allowing for the pressures produced by the child’s clinical condition, there should be no coercion, and the family should be free to withdraw at any time. Brierley and Larcher conclude that the resources utilized by offering the intervention/treatment must be justified against likely success, and that the results must be reported, whatever the outcome.
Case Study on the Ethics of Performing Pediatric Clinical Trials: An Endocrine Example
During a clinical trial of recombinant growth hormone in a population of short stature but otherwise healthy children the following ethical problems were confronted [8]:
- What are the prospective benefits compared with the foreseeable risks associated with this therapy?
- Can the doctor really inform the parent and/or the child about the outcomes of the treatment?
- Who must make the decision about participation in the trial?
- From which age can the child himself decide about continuing or dropping out?
- Since the treatment requires frequent check-ups for years, to what extent does the child become psychologically dependent upon the medical profession?
- Given this possibility, is the child really free to withdraw from the treatment?
- Is there a conflict between the doctor's autonomy to propose the treatment and the patient's autonomy to decide about participation?
- Is there a clear threshold between life-threatening problems and minor, cosmetic problems?
Conclusions
On a general level, it needs to be decided at what stage in the development of a drug should pediatric trials actually start and when is it no longer ethical to conduct such trials in children. At the individual level, it needs to be decided whether or not a particular child or their parents/guardians are actually being given a choice or are they being compelled to allow participation in a trial. The most important elements to consider in performing pediatric clinical trials are consent/assent, the ethics committee and the competence/experience of the investigators. There are special situations which require special consideration, such as studies in the neonate, compassionate use studies and healthy volunteer studies. It is perhaps this last situation, that of the healthy volunteer study involving the pediatric population, that requires the deepest ethical consideration, out of respect for the altruism being demonstrated by the child.
Helpful Documents
- United Nations: Convention on the Rights of the Child (1989).
- Council of Europe: Convention on Human Rights and Biomedicine (1997).
- Declaration of Helsinki.
- Guidelines for the ethical conduct of medical research involving children. David Hull. Arch Dis Child 2000; 82: 177-182.
- European Parliament and of the Council: Directive 2001/20/EC.
- Council for International Organizations of Medical Sciences (CIOMS): International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002).
References
- Ethical Considerations for Clinical Trials Performed in Children, 6th October 2006: http://ec.europa.eu/health/files/pediatrics/docs/paeds_ethics_consultation20060929_en.pdf
- Ward RM, Benitz WE, Benjamin DK Jr, Blackmon L, Giacoia GP, Hudak M, lasky T, Rodriguez W, Selen A. Criteria supporting the TRIALSstudy of drugs in the newborn. Clinical Therapeutics 2006; 28: 1385-1398.
- 0-18 years: guidance for all doctors: http://www.gmc-uk.org/guidance/ethical_guidance/children_guidance_index.asp
- European Group on Ethics in Science and New Technologies: http://ec.europa.eu/european_group_ethics/index_en.htm
- Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Pediatric Population. Recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. 2008: http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf
- Rollinson CM. Who will volunteer their children? BMJ 2004; 329: 818.
- Brierley J, Larcher V. Compassionate and innovative treatments in children: Proposal for an ethical framework. Arch Dis Child 2009; 94: 651-654.
- Pilpel D. Leavitt FJ. Elizur-Leiberman E. Ethical and cross cultural questions concerning pediatric clinical trials. Controlled Clinical Trials 1996; 17: 201-208.
Dr E. David G. McIntosh is an Australian pediatrician, vaccinologist and infectious disease specialist. In Novartis Vaccines he is the Global Scientific Affairs Senior Expert. In September 2010 David became an Honorary Professor within the Scientific Center for Children's Health in the Russian Academy of Medical Science.
Previously, in Wyeth, David worked on the 7- and 13-valent pneumococcal conjugate vaccines, the intra-nasal cold-adapted influenza vaccine, the antibiotics tigecycline and piperacillin-tazobactam, and the anti-parasitic agent moxidectin, under development for the treatment of River Blindness in Africa. He originally trained as a medical doctor in Sydney, Australia, and specialised in paediatric infectious diseases. He has worked in Papua New Guinea, the Northern Territory of Australia, Peru and Argentina, New Zealand and throughout Europe, the Middle East and Africa. He studied early-onset Group B streptococcal infection at the King George V Hospital for Mothers and Babies in Sydney.
His MPH treatise involved the study of chronic suppurative otitis media in Australian Aborigines and his Ph.D. thesis described the molecular epidemiology of hepatitis B virus in recent immigrant families in Australia. He co-authored the landmark 50-year follow-up of the original congenital rubella syndrome patient cohort. His post-doctoral work was on gene therapy for hepatitis, in the Department of Medicine at Imperial College in London. Along with others, he performed a study entitled: "The epidemiological burden of influenza in infants and young children in East London".
David completed a four-year Higher Medical Training period in Pharmaceutical Medicine at the Royal College of Physicians, London, and is on the Specialist Register of the UK as a Pharmaceutical Physician and a Paediatrician. He has written chapters on pneumococcal vaccination, paediatric clinical pharmacology, and post-infectious sequelae/long-term consequences of infectious diseases. He is currently enrolled as a post-graduate student in a Master's degree in Medical Law and Ethics.