Children and adolescents represent about 25% of the European population. Yet there is a frightening lack of scientific data on the use of medicines in children, which has now reached the notice of national governments.

 Studies throughout Europe have shown that children receive medication not licensed for their use, or receive it at different doses, for different indications, or by different routes from those recommended.

 Because of the failure to recognize their needs and to perform appropriate research, children are denied access to safe and effective treatment that adults would demand as a fundamental right. 

Children have become therapeutic orphans, which is ironic, because the regulations about drug licensing were in many cases precipitated by accidents in children. In the United Kingdom, for example, laws were introduced after cases of drug toxicity in the developing fetus (thalidomide) and newborn infant (chloramphenicol-induced "grey baby" syndrome).

 In the United States, the Food and Drug Administration (FDA) was established in 1938 by the U.S. Food, Drug and Cosmetic Act after more than 100 children died following administration of a new antibiotic. It was not the sulfa drug itself that caused the deaths, but the solvent, diethylene glycol, used to prepare the pediatric formulation, which caused acute renal failure due to precipitation in the kidneys.

Licensing procedures worldwide demand that drugs for human use be effective, safe, and of high quality. But children are being treated daily with drugs for which those characteristics cannot be guaranteed. This has major implications both for their health and well-being and for drug manufacturers facing new proposals to limit their marketing of drugs untested in children. The desire to protect individual children from exposure to research risks may have the effect of harming children as a class by inhibiting research into pediatric health and disease. 

So why are children not more widely used in research into drugs and other treatments? I will discuss the ethical, legal, and practical obstacles and what it will take to surmount them. 

Children differ in many respects from adults. First, their diseases are different; there is no analogy to neonatal diseases in adults, and illnesses affect children and adults differently. For example, the mild infection of rubella in children is a major one in adults. Second, the effect of drugs can be different; phenobarbitone acts as a sedative in adults but can cause hyperactivity in children, and the association between aspirin and Reye's syndrome in children is not seen in adults. Third, children may not tolerate some treatments because of the taste or method of administration. 

Despite what we know about these differences, physicians prescribe medicines whose actions are poorly understood in children. In a survey conducted in five European countries, 67% of children received drugs prescribed in an unlicensed or off-label manner, and 39% of the prescriptions were off-label.

 mean that a drug is used in situations not covered by the manufacturer's product license or summary of product characteristics. This can mean that it is used at a different dose or frequency, in different clinical indications, in different age groups, by another route, or in a formulation not approved for children. Analgesics and bronchodilators were the drugs most frequently used off-label. Because most unlicensed drug use involves crushing adult tablets to form a suspension, the stability data for the tablets then become meaningless. The scale of off-label and off-license prescribing is unknown, but a retrospective analysis of prescriptions for children under 12 years old revealed that 20% of antibiotics (perhaps the most common medication given to children) were given at off-label doses, and one survey showed that 90% of drugs used in babies and neonates were off-label.

Off-label and off-license prescribing is not illegal. It is outside the terms of the product license, so the producing company has no product liability, but it can be done on the liability of the prescribing doctor. This is potentially dangerous because it increases the risk of adverse events

 and may be associated with lack of efficacy, but no cases of legal action being taken for harm so caused have been published. 

Children should have access to medicines with scientifically justified prescribing information that matches their needs. The vast majority of such information in use at present comes by extrapolation from data obtained from adults, an inherently unsafe practice. It can be difficult for a pediatrician to tell parents that a new treatment is unproven but potentially valuable, gain consent for a study, then explain that the child has been randomized to standard therapy, and yet still maintain the parents' trust. 

Safe and effective drug treatment for children requires age-appropriate formulations and trial data obtained from children across the age range. For many drugs already marketed, this would entail significant additional research, which would be difficult to justify and to design. The International Conference on Harmonisation (ICH) has produced guidelines for studies,

 and the European Agency for the Evaluation of Medicinal Products (EMEA) has published guidance on their use.

 These documents emphasize the need to obtain knowledge of the effects of medicines in pediatric patients without compromising their well-being. Pharmaceutical companies, regulatory authorities, health professionals, and society as a whole share responsibility for this effort. As a result it is expectedcertainly by the UK authoritiesthat pediatric development will be done for all new chemical entities where use in children is likely.

 In diseases seen only in children, the full development program should now be carried out in children, and for serious or life-threatening diseases found in both adults and children, pediatric development can be started after initial proof of efficacy and safety in adults. For other diseases, trials in children should be started only after obtaining a large body of evidence from adult-only studies. 

 also encourages research in children as follows: 
Children represent a vulnerable population with developmental, physiological and psychological differences from adults, which make age- and development-related research important for their benefit. Medicinal products, including vaccines, for children need to be tested scientifically before widespread use. This can only be achieved by ensuring that medicinal products which are likely to be of significant value for children are fully studied.

But will this advice become reality? The evidence from the United States is that it will not unless penalties or inducements are offered to pharmaceutical companies. In 1994, FDA simplified the type of information needed to demonstrate drug safety and efficacy in children to encourage drug manufacturers to submit pediatric data voluntarily. The response was minimal; whereas in 1994 40% of drugs likely to be used in children had child-specific labeling, by 1997 it was only 33%.

 Most manufacturers went back to saying that safety and effectiveness had not been established for children.

 In 1997 the Food and Drug Administration Modernization Act (FDAMA) allowed the FDA to request labeling information on safe pediatric use for a new drug that would be commonly used in children. It also allowed them to request pediatric testing of drugs already on the market in certain circumstances where lack of data could pose significant risks. The Final Rule of 1998 (effective December 2000) was mandatory where a drug or biological agent offered a "meaningful therapeutic benefit" or there would be "substantial use"

 in children "and the absence of labeling poses a risk." It allowed the FDA to "require" studies to be submitted; if data were not provided, the sponsor company could be held in contempt of Congress for failure to comply with the requirement. This could result in criminal penalties against top executives and very large daily fines. (See box, Can FDA Require Pediatric Studies?) 

On 31 December 2001, FDAMA expired, and it was replaced by the Best Pharmaceuticals in Children Act (BPCA), signed into law by President Bush two days later. BPCA also grants six months'  exclusivity on a manufacturer's marketing license if the company "fairly" responds to the FDA's written request for pediatric studies. It also adds neonates to the requirement, and provides for funding studies in drugs that are no longer covered by marketing exclusivity. The National Institute of Child Health and Development is the authorized grantor for such studies. It is too soon to know if this new rule will be more effective in gaining information for safe pediatric prescribing, but indications are that more clinical studies are being conducted. 

Given that this research should be done, how can the researchers who carry out pediatric studies protect their subjects? There are issues of legal consent, ethics, risk/benefit balance, and practicalities. 

In most countries, children are the only people on whose behalf other individuals can give consent to medical procedures. (In other countries, adults unable to give consent can have that consent given for them by a relative or legal representative.) Consent given for a child is no different from adult consent; to be legally valid it must be freely given and informed, and in research terms implies accepting whichever treatment the child will receive in a randomized study. 

While consent to treatment is usually seen to be in the child's best interest, research may not be, because research generally benefits a population rather than the individual. The British Medical Association (BMA) advises that
It is now widely accepted that from an ethical perspective research can be carried out on children, when there is no expected benefit for them individually, provided there is minimum risk, strict safeguards and no objection from either the child or parents.

Those below the legal age of adulthood can consent to research if they can show that they understand medical advice and the pros and cons of receiving or refusing treatment. If a child of any age did not wish to receive a potentially life-saving experimental treatment, his or her refusal might well be overridden by parental consent, as the level for capacity needed could be claimed to be beyond that of a child. The guidance issued by the EMEA advises that this should be so.

 Conversely, hazardous experimentation authorized only by a child might actually be unlawful. 

Therefore, in most cases of research using child subjects, parental consent is necessary. Parental consent to something that might harm the child is not valid in law, so the fact that it has been given does not, of itself, justify the research. But guidelines from the Royal College of Physicians clarify the matter as follows:
The duty of the parent to act in the best interests of the child can reasonably be interpreted as an obligation not to do anything clearly against the interests of the child.

Most commentators advocate also discussing the study with the child and obtaining the child's assent or acquiescence. A reasoned refusal might well be taken as evidence of competence and so respected, but even children unable to reason should be given the opportunity to object. A child's ability to consent will develop as he or she learns to make increasingly difficult and serious decisions, and during the course of a long study there may be a need to reexplain to a child and obtain assent on several occasions. Ability to assent may depend not just on age; many children with chronic disease and much experience of hospitals are more mature than their years. 

Children are perhaps the most vulnerable patient group, because they have fewer rights, may not be able to express their fears and needs, are easily bewildered, and may experience the most lasting benefits or harm from research. Recent guidelines on the conduct of medical research on children

 establish the following six principles of ethics:

Research on children is important for the benefit of all children. 

Children have unique interests and are not small adults. 

Research should be done on children only if the question cannot be answered by studying adults. 

Research that will not directly benefit the child subject is not necessarily unethical or illegal. 

All proposals should be submitted to a research ethics committee. 

Legally valid consent must be obtained, with additional agreement from school-age children if consent is by parents.

Medical research on children is important to promote child health and minimize safety risks from the use of untested drugs, but it is ethical only if there is a real prospect of benefit to children as a whole and the research is well designed and performed. This latter point excludes studies repeating known work or with insufficient statistical power to be meaningful. But a gray area exists where the previous work has been done in adults. If a drug has been shown to be efficacious in adults, some argue that equipoise no longer exists, and that to deny children an active drug is not ethical. Balanced against that is the possibility that the immature liver and enzymes may handle drugs very differently and so give a different effect. But if there is collective and genuine uncertainty about the best treatment among informed clinicians, then I believe that it is ethical to perform the research. 

Research ethics committees have a crucial role: their main function is to protect the patients, and child patients need maximal protection. Each ethics committee should include someone with a close practical knowledge and experience of sick children. Each study should ask an important question, the risks should be acceptable, and the research subject's autonomy should be respected. Protocols must be assessed for reasonableness and workability, and particularly for the monitoring of a child's wish to withdraw. 

There have been suggestions that the role of the ethics committee should be strengthened. Parents could be told that research projects were under way at the hospital, and they would not be required to give consent, but would be told if their child was about to be included in a study. They would be able to refuse entry, but under certain safeguards the researchers and the ethics committee would give assent.

 This would preserve the parents' autonomy but would remove the risk of them feeling pressured at a time of stress and vulnerability. 

In research a few subjects may face risk to benefit many, but when we seek to protect individual children from exposure to research risks, children as a class may be harmed due to lack of research into disease and the effect of drugs. 

To assess the potential benefit, one must consider the size and frequency of the problem and its severity. Is there truly a question that needs an answer, and if so, how likely is it that the answer will be obtained from a particular study? Will benefit be to one or many children? Potential harm, both physical and psychological, must be balanced against this. The latter is more difficult to assess because children vary, but researchers often underestimate the stress of short-term pain (such as blood sampling) in younger children. 

Risk in clinical research can be estimated as minimal, low, or high. Minimal risk is seen in studies where questioning, observing, or measuring forms the basis of the research. There is still a need for informed consent and for sensitivity, but the child is unlikely to be physically discomforted. Low-risk studies would include those where blood samples are taken, with brief pain and perhaps a little bruising. High-risk procedures include tissue biopsy and cardiac catheterization, and are not justified for research purposes alone, but only when research is done as part of treatment. All research in children, irrespective of risk, requires recognition of the need for psychological and social support for the children taking part, because their needs may differ from those of adults. 

But the risks of using drugs untested in children will always have greater potential for harm, given the figures for off-label and off-license use. When clinicians are exhorted to practice evidence-based care, the lack of evidence is at best confusing and at worst dangerous, yet neither doctors nor parents question the lack of pediatric dose information on commonly used drugs. The only area where children are well-served by drug trials is oncology, where, for example, most children with leukemia in the United Kingdom have been entered into Medical Research Council trials for many years.

One of the difficulties in assessing benefit is the relative rarity in children of some diseases common in adults. It can be hard to find sufficient numbers of children with the same condition, and statistical significance may not be reached in a trial. One could imagine pressure being placed on children with a chronic disease to enter a series of studies, simply because the target population is small, yet much research is needed. Such pressure would be unethical and unfair to the children. 

Another complication is the heterogeneity of children's disease. A childís response to illness varies with age; for example, a baby may be far more ill with a particular infection than an older child. This too can render statistical analysis difficult and perhaps inconclusive. 

Surrogate markers are often used in research, and although there is controversy over their reliability, their relevance has been established only in adults. Their value is unknown for children, and because diseases run different courses in children, it may be incorrect to use the same markers as for adults. Similarly, quality-of-life questionnaires to assess the impact of a disease or treatment on various aspects of a patient's life require validation before use, yet this is done only in adults, not children.

 It is self-evident that a child will be affected differently from an adult with the same disease, yet for toddlers and babies it is impossible to assess even pain other than by careful observation by a researcher, although observer rating scales exist.

A point often forgotten by authors of protocols is the small blood volume of children. A 600-g baby has only 50 mL of blood: those used to copious sampling from adults may inadvertently threaten the well-being of a child, because not more than 5% of the circulating volume can be taken without harm. 

I believe that most parents given a choice of medication would prefer one that had been tested in children, so in principle they would support the concept of children participating in research programs. But when asked to give consent for their child to take part in research, they may be worried about his or her well-being or feel pressured to decide quickly. They may have concerns about the consequences for their child's treatment if they refuse consent, so their consent would not truly be given without "coercion, undue influence or inducement, or intimidation."

In two studies involving babies, 71% of parents who were asked for consent early agreed, but only 43% of those asked later agreed.

 The authors of this study interpreted this to mean that longer reflection produces less agreement. Another report showed problems with competence and understanding in over 70% of parents, three times as often in an emergency study as in a more routine one.

 More than 96% of these parents believed it was right for them to give consent, but 64% believed their own child would benefit, despite randomization, and over 39% foresaw no risk or distress to their baby. This makes one question their understanding of what they had been told. In two other studies, when consent was sought by nurses, 30% of parents refused, compared with only 6.5% when consent was sought by doctors, suggesting that parents feel unable to refuse a doctor's request.

In a study of ventilation techniques in neonates at the North Staffordshire Hospital Trust,

 parental consent was sought when the infants were between two and four hours old. These babies were preterm and very sick, and some parents later claimed they were not told that their children would receive an experimental treatment. There is evidence that consent was sought in some cases,

 but one must question the capacity of parents to make rational choices at such a time, and therefore the validity of any consent given. 

In another study, parents who refused consent were better educated and more likely to have professional or administrative jobs than those who consented, suggesting that the more vulnerable parents consent.

 Because the essence of informed consent is that it is freely given, without pressure or inducement, and after as much discussion as needed by those consenting, all these results are a source of concern. 

Perhaps this varying level of understanding supports the suggestion that ethics committees should take a bigger role in consent, leaving the parents only the right of refusal. But ethics committees do not always challenge protocols as they should; in the North Staffordshire study, approval was given for using outcome scores that were not validated. 

Children are unique as a research group in that others give consent for them to take part. They have perhaps the most to gain and the most to risk, because any medical intervention could have long-lasting benefit or harm. Clinical research is an important means of promoting their well-being and health, particularly in ensuring they have effective and safe medication, and yet it is not done sufficiently often, despite the encouragement of ICH. The reasons for this are varied and include avoidance of harm, fear of litigation, and concerns about ethics. But the arguments for research in children being done responsibly are overwhelming, and there is good evidence from cancer studies that it can be done effectively and safely even in children with life-threatening illness. 

First and foremost, research should not be done in children if the results can be obtained from studying adults, but this is often not possible given the physiological differences. So, because research must be done in children, special consideration should be given to it. The research must be for their benefit, not for the financial or academic gain of the researcher; it must be balanced and well designed; and it must not duplicate previous work. 

Second, issues of consent must be improved. Some investigators seem to want to deny the rights of parents to consent, and evidence exists to show that consent is often not properly sought and the requirements that it be informed and voluntary are overlooked. In the Euricon study described earlier,

 44% of the doctors thought that parents should not be told all the risks to avoid alarming them. This is not surprising, because this study also showed that less than 5% of doctors had formal training in the issues and legality of informed consent. 

Third are issues of practicality. Because of their size, children have small blood volumes, so certain non-therapeutic adult studies such as pharmacokinetic studies with frequent blood sampling cannot be done, but there are alternatives. For example, by taking one sample from many children, population kinetics can be derived, which fulfill the requirements of understanding the metabolism of a drug and its effects on the body. If we continue to use drugs that have not been tested on children, we will inevitably see more cases like that of propofol. Propofol is a short-acting intravenous anesthetic, not licensed in children but used in intensive care units for their sedation. Many children who were given propofol developed metabolic acidosis, and 15 died.

 Regulatory agencies issued warning letters against its use in children, and it is still not licensed for them. But perhaps this tragedy could have been avoided by testing it on children in closely monitored clinical trials. 

For research in children to succeed, there must be partnership between the pharmaceutical industry (which funded 43% of randomized, controlled trials published in one pediatric journal over 15 years),

 researchers, ethics committees, and parents. It is not acceptable to put the lives of more children at risk by not having an evidence base for their use of medicines. 

1. House of Commons Health Committee, The Specific Health Needs of Children and Young People (House of Commons, London, 1997). 

2. Food and Drug Administration Modernization Act, Section 505A, Pediatric Exclusivity (FDA, Rockville, MD, 1997). The EU is also considering regulatory changes for the licensing of drugs to be used in children. 

3. S. Conroy, I. Choonara, P. Impicciatore, et al., "Survey of Unlicensed and Off-label Drug use in Paediatric Wards in European Countries," 

4. I. Choonara and J. Dunne, "Licensing of Medicines," 

5. R.R. Abood and D.B. Brushwood, Pharmacy Practices and the Law. (Aspen Publishers, Inc., Gaithersburg, Maryland, 1994). 

6. H.S. Boardman, "Pediatric Drug Development: Principles and Practice," International Journal of Pharmaceutical Medicine 15: 35-47 (2001), p. 36, quoting S. Conroy. 

7. S. Turner, A.J. Nunn, K. Fielding, and I. Choonara, "Adverse Drug Reactions to Unlicensed and Off-label Drugs on Paediatric Wards: A Prospective Study," 

8. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Topic E 11. 

9. Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population (CPMP/ICH/2711/99). 

10. H.S. Boardman, "Pediatric Drug Development: Principles and Practice," International Journal of Pharmaceutical Medicine 15: 35-47 (2001), p. 36, quoting J. Dunne of the U.K. Medicines Control Agency. 

11. European Union Clinical Trials Directive 2001/20/EC, Article 3. 

12. D. Murphy, "1999 Pediatric Initiatives," www.fda.gov/cder/present/dia-699/mu1-dia99/. 

13. T. Nordenberg, "Pediatric Drug Studies: Protecting Pint-sized Patients," 

 33 (3) (May-June 1999), www.fda.gov/fdac/features/1999/399_kids.html, quoting R. Roberts. 

14. Substantial use is classified as more than 50,000 patients for the labeled indication. 

15. British Medical Association, Consent, Rights and Choices in Health Care for Children and Young People. (BMJ Books, London, 2001), p. 202. 

16. Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population (CPMP/ICH/2711/99), p. 11, section 2.6.3. 

17. Royal College of Physicians, Research Involving Patients (Royal College of Physicians, London, 1990), section 7.43. 

18. Royal College of Paediatrics and Child Health: Ethics Advisory Committee, "Guidelines for the Ethical Conduct of Medical Research Involving Children," 

19. N. McIntosh, "Strengthen Ethical Committees' Role," 

20. J.M. Chessels, C. Bailey, and S.M. Richards, "Intensification of Treatment and Survival in All Children with Lymphoblastic Leukaemia: Results of UK Medical Research Council trial UKALL X," 

21. D.K. Pal, "Quality of Life Assessment in Children: A Review of Conceptual and Methodological Issues in Multidimensional Health Status Measures," 

Journal of Epidemiology and Community Health

22. Such as described in R.E. Grunau, T. Oberlander, L. Holsti, et al., "Bedside Application of the Neonatal Facial Coding System in Assessment of Premature Neonates," 

23. Council for International Organisations of Medical Sciences (CIOMS) and World Health Organization (WHO), International Ethical Guidelines for Biomedical Research involving Human Subjects (Geneva, 1993), p. 13. 

24. M. Levene, I. Wright, and G. Griffiths, "Is Informed Consent in Neonatal Randomised Controlled Trials Ritual?" 

25. S.A. Mason and P.J. Allmark, "Obtaining Informed Consent to Neonatal Randomised Controlled Trials: Interviews with Parents and Clinicians in the Euricon Study," 

26. T.H.H.G. Koh, L. Collie, D. Budge, and P. Butow, "Informed Consent in Neonatal Randomised Trials," 

27. M.P. Samuels, J. Raine. T. Wright, et al., "Continuous Negative Extrathoracic Pressure in Neonatal Respiratory Failure," 

28. E. Hey and I. Chalmers, "Investigating Allegations of Research Misconduct: The Vital Need for Due Process," 

29. S.C. Harth and Y.H. Thong, "Sociodemographic and Motivational Characteristics of Parents who Volunteer their Children for Clinical Research: A Controlled Study," 

30. R.J. Bray, "Propofol Infusion Syndrome in Children," 

31. H. Campbell, S. Surry, and E. Royle, "A Review of Randomised Controlled Trials Published in Archives of Disease in Childhood from 1982-1996," 

Articles

Feature Article

Successful pediatric research requires partnership between the pharmaceutical industry, investigators, ethics committees, and parents.

Why Aren't More Pediatric Trials Performed?


The best way to think about participation in clinical trials would be: informed decision and consent to participate.

This assures that the patients or subjects have been educated about this aspect of their care, and after this information was presented, they decided to participate in the clinical trial. A little wordy perhaps, but it embodies the philosophy of how patients should make their decisions about participation in a clinical trial.

Research Department
Cancer Center of Santa Barbara
Santa Barbara, CA


I was under the impression that informed consent is a term with legal meanings and implications. Informed consent already implies that the subject was as fully informed as possible and agreed to participate. It is more important to focus on improving actual practices, not changing the terms used.


During a recent GCP course given in Virgina by the Association of Clinical Research Professionals (ACRP), one speaker stated, Nurses cannot dispense or administer study drugs. This was something neither I nor the other nurses in the room knew or understood. After all, drug administration occurs in hospitals, nursing homes, private duty, and doctors offices every day.

After a heated debate over the questions of administering drugs in hospitals, nursing homes, and private home care, the speaker said, You must check with your own state licensing board, as the law may be different with research in different states. For example, Florida has a provision that states, Nurses (RN, LPN) may administer study drugs.

After spending five days searching, I found someone in the know at the New York State Department of Professional Licensing Services. He told me it was true! Nurses (LPN, RN) cannot dispense or administer medication in clinical trials. 

How can such an important issue be so unknown and so un-enforced? When I asked the people at the state professional licensing department if they could provide me with a copy of this little-known law stating I could not perform this task, they told me that it is under pharmacy law, not nursing law. 

When I asked about the Delegation of Responsibility Signature page, found in every regulatory binder on which the physician investigator (PI) signs off, I was informed that MDs cannot delegate tasks that fall under the provision of their licenses, and that pharmacists, MDs, and nurse practitioners are the only ones licensed to dispense and administer. The official also said, Pharmacists should be the only ones dispensing study drugs and physicians should be the only ones giving them to subjects.

This is absurd. I have been a nurse for 30 years. For 30 years, I have dispensed and administered drugs under a physician license. Now, because Im in research, it changed? In a research setting, PIs do not have time to do it all. If they did, nurse coordinators would not exist. Additionally, consider the non-hospital and non-university private clinical sites that lack private pharmacists to dispense the unit dose research drugs received from the sponsor. Should a PI have to randomize, dispense, and administer every drug, for every subject, at every visit?

Worse yet, when I telephoned my nursing liability insurance carrier to ask if my LPN license covered me to administer medication, I was told, Youre covered. We cover you for everything that is allowed under your license description as stated by your individual state law. 

I have been working as a research nurse coordinator for seven years and have never been covered for liability or malpractice. Nobody seems to know about this law! I have checked with IRBs and pharmaceutical sponsors, but everyone appears to be in the dark.In the end, I wonder, why should any of them care? They wont lose their licenses in a lawsuit. 

Under this law, coordinators without a medical background are unllikely to be hurt professionally. However, if you are a nurse, trained to be a study coordinator, you stand to lose your livelihood!

At this stage of my informal personal investigation, I contacted the ACRP and asked their help in researching this matter. I hoped the organization would assist in getting to the bottom of this question. But, it seems no one really knows the answer. I feel compelled to delve further into this issue, to spread the word to fellow nurses to inquire with their local governments and find out if they bear any liability. 

This law should be reviewed by professionals who understand the nature of research. If this is a gray area, lacking rules and guidance, then both must be clearly written to recognize the future of research growth. I look forward to any suggestions from the clinical trials community.


Having returned from the recent Computer Validation Workshop (Vienna, Austria, 2224 April, 2002) organized by the Drug Information Association, I could not refrain from writing you to make a pair of remarks regarding the question of whether email can be considered a safe means of information transfer in clinical trials.

One of the presentations contained the assertion that email cannot be considered a secure electronic document. Though this statement was made in the context of a lecture regarding good automated manufacturing practice (GAMP) forum in the Internet, it still provoked an uneasy feeling: email is widely used (and generally considered to be secure enough) for clinical-trial-related communication, which is quasi-confidential by definition.

According to FDA, the Internet is an open system, an environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system (21 Code of Federal Regulations 11, Definitions). This, however, does not preclude the use of email for transfer of important information provided that certain requirements are met.  Persons who use open system[s]shall employ proceduresSuch procedures and controls shall include [those] identified in 11.10, as appropriate, and additional measures such as document encryption and use of appropriate digital signature standards to ensure records authenticity, integrity, and confidentiality (21 Code of Federal Regulations 11, Sec. 11.30).

Logical security of email means that users have their own logins and passwords (at least within the mail system they use). Mail traffic should be directed through an encrypted channel, known as secure socket layer (SSL), which is regarded as protected for data transfer in electronic data capture, electronic subject diaries, and remote data entry systems andif we take an example without any relation to clinical trialsin credit cards data transfer within Internet-connected bank systems.

Physical security of email is in fact the same as that of the mail server and communication channels used for data transfer; and while communication security is usually ensured by the Internet service provider, the server (where the mail messages are stored upon their receipt or until dispatch) is, so to speak, under the jurisdiction of the interested party (email client). You can hardly find a company that would say its servers and communications are open and accessible to everybody. In fact, all the information is circulating within the companys intranet, whose physical and logical security are strictly regulated by SOPs of the information technologies department.

Creating an electronic signature [using Pretty Good Privacy (PGP) or SSL] does not pose any problems either.

Thus, in terms of security, a correctly configured and documented email system seems to be quite an acceptable means of information transfer in clinical trials. Are there any other opinions?

Manager, Information Technologies Dept.
InnoPharm Ltd.
Smolensk, Russia

Letters to the Editor

Readers respond to articles and editorials.

Letters to the editor

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 childrens 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.


In 1989, the United Nations General Assembly approved a Convention on the Rights of the Child.

 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 childs 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,

 and much pediatric therapeutic data is derived from studies in adults.

 In fact, children have been described as therapeutic orphans because of the deficit of appropriate studies in their age group.

 As a result of this deficit, about 50% of medications used in childrens hospitals are not properly licensed for use in children.

Many differences exist in physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults.

 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:

	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.


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 drugs 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.

 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.


No 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:

	respect for life, human dignity, and personal autonomy

From these ethical principles, general guidelines for good clinical practice in pediatric research can be derived.

 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).

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.


Once 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 Helsinki

 suggests that for a legally incompetent minor, the investigator must obtain informed consent from the childs 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 childrens 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.


Even 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 Childrens 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?


The 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 (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 1216 years in such trials?

Although encouraging efforts have been made to address these ethical issues in Europe and in the United States,

 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.

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, 

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), 

5.	C. Cote et al., Is the Therapeutic Orphan About to be Adopted? 

6.	S. Conroy et al., Survey of Unlicensed and Off-label Drug Use in Paediatric Wards in European Countries, 

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, 

11.	P.J.J. Sauer, Research in Children, Report on behalf of the Ethics Working Group of CESP, European Journal of Pediatrics 161: 15 (2002).

12. Royal College of Paediatrics and Child Health, Ethics Advisory Committee, Guidelines for the Ethical Conduct of Medical Research Involving Children, 

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, 

16.	J. Wechsler. Science, Pediatric Studies, and Surrogates, 

Both the pharmaceutical industry and regulatory authorities worldwide have recognized the need for more clinical studies in children. A recent European conference addressed the issues.

Practical and Ethical Issues in Pediatric Clinical Trials

Over the past decade, Washington policy makers have adopted a range of initiatives to encourage testing of pharmaceuticals in children in order to obtain better information on effectiveness and appropriate dosing. After years of trying to pressure sponsors to develop needed data, policy makers succeeded by offering a fat, juicy carrotextended exclusivity on products providing pediatric labeling information requested by the Food and Drug Administration. At the same time, FDA waved a big sticka rule requiring sponsors to include pediatric populations in clinical trials for all new drugs likely to be prescribed for young patients. 

Separately, in 1998 the National Institutes of Health adopted a policy requiring all research proposals applying for NIH funding to include children in studies and to follow standards to ensure ethical treatment of young study subjects. 

These actions have vastly increased the number of clinical trials and the number of young participants involved in clinical studies. Such developments have raised a host of ethical and operational issues related to clinical trial procedures and policies that continue to challenge policy makers.


By most counts, the pediatric exclusivity policy established by the FDA Modernization Act of 1997 (FDAMA) has been a major success. As of March 2002, FDA had received 300 proposed pediatric study requests from manufacturers and had issued 241 written requests for such studies, which FDA says could potentially involve more than 32,000 children. As a result of reports from these studies, the agency granted exclusivity to 56 drugs and gained pediatric labeling for 31 of them. FDA considers 9 of the 31 pediatric labels to provide significant changes for dosing, safety, or use. In addition, studies show that certain products are not recommended for pediatric use. 

To continue the program past its five-year sunset date at the end of last year, Congress approved the Best Pharmaceuticals for Children Act (BPCA), which was signed into law in January 2002. It extends the program until 2007 and contains numerous initiatives to further encourage pediatric research. A key provision permits FDA to collect user fees for reviewing pediatric supplements, which will allow the agency to consider these priority supplements that merit speedy assessment. 

The BPCA also authorizes the federal government to fund pediatric studies for drugs and other medical products that lack patent protection or sufficient sales to prompt private sector research. A major shortcoming of the voluntary pediatric program is that many therapiesantibiotics, off-patent products, orphan drugsoffer little financial incentive for a sponsor to conduct additional studies on children. The legislation provides $200 million to support research on such therapies by NIH and calls for FDA to develop a list of approved drugs that could benefit from additional pediatric studies that industry is unlikely to undertake. 

The legislation also calls for FDA to establish a new Office of Pediatric Therapeutics in the Commissioners office to coordinate all FDA pediatric issues and activities. This office will oversee the Office of Pediatric Drug Development and Special Initiatives in the Center for Drug Evaluation and Research (CDER), which was established last September. Dianne Murphy, who formerly headed CDERs pediatric team, directs the current CDER office, which will have more resources from user fees to oversee an expanding number of pediatric clinical trials. 

Other provisions in the bill aim to facilitate pediatric studies by calling for sponsors to submit to FDA plans for conducting pediatric research during the IND (investigational new drug) study phase. The legislation creates a Pediatric Pharmacology Advisory Committee and adds language to encourage studies on neonates and on minority groups. Congress also includes provisions in BPCA to encourage research on cancer therapies for children, building on FDAMA provisions that FDA clarified in a guidance published in June 2000. BPCA calls on the National Cancer Institute to develop preclinical models for evaluating pediatric cancer therapies and to coordinate NIH research in this area. FDA and NIH will report to Congress next January on how these and other initiatives further patient access to new pediatric cancer therapies. 

Sponsors are underwriting more studies of children, but controversy continues over the need for FDA?s pediatric rule and the impact of extended exclusivity on generics.

Applied Clinical Trials-07-01-2002

Why Aren't More Pediatric Trials Performed?

Letters to the editor

Practical and Ethical Issues in Pediatric Clinical Trials

FDA, Congress Spur Pediatric Drug Development

Pediatric Clinical Studies in Japan: Regulations and Current Status

No Orphans Among European Children?

Ron Keeney