Risks and benefits of research on children: developing an ethical framework to meet children's needs

Physicians are taking significant risks when they treat children with medications that may have not been adequately tested for their efficacy and safety during childhood. Such treatment decisions have to be taken in everyday clinical practice. They tend to be based on ‘trial and error’ from the physicians' personal experience, advice from colleagues, anecdotal reports from the literature and extrapolations from adult studies.

In addition medication errors are a constant hazard in paediatric clinical practice. Continuous changes of the dosage regime that are necessary during a child's growth and development make the calculation of the correct dose for each child difficult. The frequent use of off-label medicines with extemporaneous formulations or physician or nurse-made manipulations provide optimal conditions for these medication errors. ¹ Ingredients or excipients for improving solubility, sterility and the taste of children's medicines may also cause toxicity (e.g. benzyl alcohol and diethylene glycol).

Severe adverse drug reactions in children are not always fully reported. Some of the most dramatic examples of these are the apnoea caused by too large a dose of phenobarbitone, pethidine and prostaglandin, convulsions following the administration of theophylline and hepatic failure associated with high doses of paracetamol (acetaminophen).

Recognizing these significant risks in the care of their patients, practicing pediatricians, particularly in the USA pressed for changes in the regulation of medicines for children. In 1996, the American Academy of Pediatrics (AAP) ² reported that only a small fraction of all drugs and biological products marketed in the US at that time had had clinical trials performed in paediatric patients. A majority of marketed drugs are not labeled for use in paediatric patients. The AAP also pointed out that many drugs used in the treatment of both common childhood illnesses and more serious conditions carried little information in the labels about use in paediatric patients.

In order to address these inadequacies, the Food and Drug Administration (FDA) published regulations (see http://www.fda.gov/) which ensure that manufacturers specifically examine the drugs' effects on children if the medications were to have clinically significant use in children.

Paediatric research has since been encouraged by the paediatric exclusivity provision of the ensuing Food and Drug Administration Modernisation Act of 1997. This extended patent protection to give pharmaceutical companies an additional six months of marketing exclusivity if they do studies in children requested by the FDA. The FDA's ‘pediatric rule’ required paediatric studies under certain circumstances. ³

In January 1997 the National Institute of Health (NIH), a major funder of clinical research worldwide, developed the policy that children (defined as individuals under the age of 21 years) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

In the European Union, the Council resolved in 2000 to set their objectives for regulation on medicinal products for pediatric use, which aimed to stimulate research into and to increase the availability of medicines for children. ⁴ Draft regulations were consulted upon in 2004 which proposed the establishment of a European Paediatric Board with the European Medicines Evaluation Agency, that all new medicines should have a paediatric investigation plan with a six-month extension in patent term, and a new system of granting paediatric use marketing authorizations (PUMAs) for existing products. ⁵ These regulations came into effect in 2006 and already they have had a positive effect on promoting research in Europe (see http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/medchild_en.htm).

In 2007 the World Health Assembly adopted a resolution calling for a more rational use of and better medicines for children. The World Health Organization (WHO) noted that around 10 million children under the age of 5 years die every year. Many of these deaths are from treatable conditions, the most common of which is pneumonia. Others include diarrhoeas, malaria and HIV/AIDS. Few countries are on track to achieve the WHO Millennium Developmental Goals (MDGs), especially goal 4 which aims to reduce the mortality of children under 5 years old by two-thirds between 1990 and 2015.

Even though effective interventions exist, these may entail the use of ‘essential medicines’ which do not exist in dosage forms for children, particularly in low- and middle-income countries. Lack of the availability of these essential interventions has been identified as a major reason for countries not making adequate progress towards their MDGs. The WHO publication ‘Child Health Research – a foundation for improving child health’ ⁶ asserts that ‘Child health research must address the leading causes and determinants of morbidity and mortality at different stages of a child's development and identify and implement interventions that address these causes’.

Six main areas for research are identified:

Descriptive epidemiology and burden of disease: to describe the scale of the problem and identify the causes of child illness and death in different communities;

Aetiology and mechanisms of disease: to understand the determinants of childhood disease;

Development of interventions: to design the most appropriate strategies to improve child health;

Impact and evaluation of intervention: to measure the effect of the implemented strategies including new medications and raise new research questions;

Health systems: to increase the effectiveness of child health interventions and services;

Health policy: to analyse retrospectively and monitor prospectively the scaling up of child health and nutrition interventions.

In my view it has now become an ethical imperative, in the words of the Ethics Committee of the Conference of European Specialists in Paediatrics that ‘Children should share in the benefits from scientific research relevant to their individual age-related health needs’.

Though the FDA, the European Commission and WHO have brought a new emphasis on research on drug development for children, there remains a reluctance to include children in this research and especially in clinical trials. There are several reasons for this: firstly, children's increased vulnerability and therefore risks are increased both in the short and long term. There is an understandable parental reluctance to add any risk to their children's welfare.

Secondly, because of children's age-specific needs, they have different physiological, psychological and pathogenic features occurring at the different ages and stages of their growth and development as well as sex and ethnicity, from the premature newborn infant through adolescence. Such factors increase the complexity and cost of research.

Thirdly, the high cost and low financial return have made pharmaceutical companies reluctant to invest.

And fourthly, outside North America, Europe and Japan there is a lack of universal ethical and regulatory guidance for researchers and sponsors upon which parental trust depends.

There are currently several layers of ‘protections’ for child subjects in clinical research:

the regulatory oversight available in each country;

specific guidance, e.g. ICH Good Clinical Practice without compliance with which most ‘ethical’ pharmaceutical companies will not conduct a clinical trial; ^4,7,8

professional ethical codes of practice such as the Declaration of Helsinki ⁹ provide the ‘external’ governance of medical researchers, who individually need to ‘internalize’ the principles to form their professional conscience – an essential ‘internal’ governance;

establishment of local research ethics committees and institutional review boards in the US provide essential ethical scrutiny;

and importantly, no clinical research project should go ahead without the informed consent of parents and consent/assent of the child.

The codes of professional ethics ^10,11 are underpinned in my view by seven core ethical principles, ¹² namely: Autonomy; Beneficence; Non-malfeasance; Fidelity; Truthfulness; Confidentiality; and Justice.

The Belmont Report ¹³ highlighted three of these – respect for persons (autonomy), beneficence and justice. But recent publicity about adverse events in clinical trials has revealed serious failures to address one or all four of the other listed principles.

Child subjects are indeed vulnerable and do need special protections beyond that provided by the World Medical Association's (WMA) Declaration of Helsinki ^9,14 particularly with regard to consent/assent, the assessment of risk and in research study designs.

To address this deficit, amendments to the section on research in the WMA's Declaration of Ottawa on the Right of a Child to Health Care have been suggested. ¹⁵

Each statement is self-standing but all are inter-related. They are that:

physicians should strive to attain the maximum achievable benefit and should avoid unnecessary risks, discomfort, stress or potential harm leading to physical, psychological, social or spiritual impairment;

biomedical studies involving children as research subjects should be focused on the knowledge of epidemiology, pathogenesis, diagnosis and treatment of diseases or conditions of childhood;

consent/assent;

children are minors who have not reached the age for self-responsible consent;

informed consent means the approval of the child's parents or legal representative for the participation of their child in a research study, following the provision of sufficient information to enable them to make an informed judgement;

informed assent means the acquiescence of the child to participate in the research, following information being provided in a form understandable to his/her age;

the refusal to participate in research – dissent – by an informed child must be respected;

consent of both parents should be sought prior to enrolling a child in a biomedical research project.

There must be no forced or undue influence, financial or otherwise, on the child's decision to participate in the research or on the parent's/legal representative's consent.

Risk

Risk assessment is a crucial step in evaluating a protocol and conducting a trial. Risk is defined as potential harm (real or theoretical) or potential consequence of an action. It may be physical, psychological or social, and may be immediate or delayed. It may vary according to age groups. Risk should be assessed in terms of probability, magnitude and duration.

Minimal risk involves procedures, questionnaires, observation and measurements carried out in a child-sensitive way.

Greater than minimal risk involves invasive procedures or therapies. These should be carried out only when:

the research is concerned with diagnosis and treatment and the expected benefits to the child participant outweigh the known or anticipated risks involved;

the research is likely to yield justifiable generalizable knowledge of vital importance about the child's disorder or condition, which is of vital importance for the understanding or amelioration of the disorder or condition;

the research presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children;

the research must provide the only opportunity to identify, prevent or alleviate a rare disease confined to childhood.

Study protocols

Study protocols and study designs must be child-specific. In addition to including the safeguards for adult subjects, they should justify the necessity of the research on children.

The preclinical safety and efficacy data are preconditions for the start of a paediatric clinical trial.

The study must be guaranteed to be conducted by experts competent in childhood diseases and disorders, who are empathetic and truly conversant with children, parents and the legal requirements where the interests of the child are paramount.

Privacy

The privacy of the child must be fully assured throughout the research project.

Research Ethics Committees (IRBs)

The interests of the child should always be represented by independent research ethics committees when research on children is being considered.

Further work needs to be done on these statements when they are sent out for consultation among the 80 national medical associations which are members of the WMA. They need to build on the fundamental ethical principles in the WMA's Declaration of Helsinki, which is being crafted to protect all ‘subjects’ who participate in clinical research worldwide. These statements should act as a reference to physicians throughout the world, from which each national medical association can derive its own culturally-sensitive guidelines. With the trust that is earned when medical researchers act in an ethical and transparent manner to prevent the ethical abuses of the past ¹⁵ and to plan for the future, ¹⁶ it is hoped that more parents will recognize the benefits that research on their children can bring to them and all children worldwide.