Ethical Issues of Drug Research on Children. By: Tatiana Arzumanov

Transcription

1 Ethical Issues of Drug Research on Children By: Tatiana Arzumanov Today it is hard to imagine health care without medications. As a nation, Americans bought 3.1 billion prescriptions in the year of 2001 (averaging 10.9 prescriptions per person). (1) In addition, it is estimated that $18 billion are spent each year on Over the Counter products.(2) Medications save lives, make people stronger, relieve suffering, and give hope for the future. Times when medicines would be given to a person without any testing of their risks and benefits are way in the past. It is widely known and well expected that new medicinal agents be tested in laboratories and on animals before they can be given to humans. The Nuremberg Code, the Declaration of Helsinki, and the Belmond Report outlined basic ethical principles in medical research. The Nuremberg Code, developed in 1949 (four years after World War II ended), condemned the atrocities committed by Nazi physicians in human research. At that time, the civilized world agreed that medical research should be guided by high moral standards. (3) The World Medical Association Declaration of Helsinki addressed recommendations guiding medical doctors in biomedical research involving human subjects. This document was an expansion on the Nuremberg Code, calling for prior approval and ongoing monitoring of research by an independent ethical review committee.(4) These recommendations were set forward in recognition of the importance that the results of laboratory experiments be applied to humans to improve scientific knowledge and release human suffering. Among the basic principles outlined in the Declaration of Helsinki there is a statement that in any research on human beings, each potential subject must be adequately informed of the anticipated benefits and potential risks of the study and the subject s freely given informed consent, preferably in writing, should be obtained. In case of the subject being a minor, permission from a responsible parent or legal guardian is necessary. However, if a child is in fact able to give consent, the minor s consent must be obtained in addition to the consent of the legal guardian. (4)

2 The Belmont Report outlines three principles used as the framework for the protection of human subjects for biomedical and behavior research in the United States. These principles are respect for persons, beneficence, and justice. First of all, principle of autonomy should be applied to every individual and people with diminished autonomy should be protected. This means that the opinions and choices are to be respected. However, not every human being is capable of self-determination. This capacity matures together with the individual. Therefore, respecting of the immature may require their protection. It is recognized that not every immature requires the same level of protection. Thus, some minors need very extensive protection while others requires little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence. It is also recognized that the level of required protection should be reassessed periodically. Second of all, not only is it important to treat everybody in an ethical manner by respecting his/her decisions and protecting them from harm, but also to ensure everyone s well being. In other words, the principle of beneficence has to be applied to every person. This means do not harm and maximize possible benefits and minimize possible harms. The principle of do not harm was applied to the profession of medicine since the time of Hippocrates. Claude Bernard who states, "One should not injure one person regardless of the benefits that might come to others," introduced it to the medical research. However, it is necessary to know what harm is to avoid it. This means that it may be necessary to expose people to the risks of harm in order to learn what these risks are. Therefore, the concept of beneficence presents people with a dilemma. The question becomes when it is ethical to seek benefits despite the risks and when it is appropriate to go for the benefits despite of the risks. Finally, the principle of justice questions who should receive the benefits of the biomedical research and who should bear its burdens. The principle of justice implies that benefits and risks must be equally distributed. There are different ways the society might view this principle. Burdens and benefits can be distributed to each person equally, or according to individual need, or according to individual effort, or according to societal contribution, or, finally, according to merit. Historical background explains the importance of the principle of justice to the biomedical research. For example, during the 19 th and early 20 th centuries, research subjects were primarily poor people. During the same time rich patients would receive if the benefits of this research. In Nazi camps unwilling prisoners were used as research human subjects. In the United

3 States, in the 1940 s rural black men were used in the Tuskegee syphilis study. They were denied effective treatments in order to complete the research. Today in the United States, the selection of research subjects is just. It is against the law to select research subjects simple because of their disadvantages, easy availability, and manipulability. Rather, the research subjects are to be selected for the reasons primary related to the problem studded. Moreover, benefits should not be distributed only to the people who can afford them. One of the applications of the Belmont Report is the Informed Consent. Every person participating in the biomedical research is given the opportunity to decide what should or should not happen to him/her. Thus the research subjects should now the research procedures, purposes, risks and benefits, as well as alternatives. They have to be able to ask questions and stop participating at any time during the research. It is also important that the subjects are able to understand the presented information. However, comprehension is a function of maturity. Another application of the Belmont Report is willingness to volunteer, meaning that every participant should be considered only if he/she gives a voluntary consent. In case of minors, it is very important to ensure that their choice is not under control of a relative or a guardian. However, ensuring voluntaries may be hard for the children population. As for the assessment of risks and benefits, the Belmont Report states that the risks should be minimized to the level necessary to meet the research purpose and that when vulnerable populations, such as children, are involved in research, the appropriateness of their involvement should be demonstrated. (5) Although medications save lives, make people stronger, relieve suffering, and give hope for the future, they can be very dangerous both for adults and children. Recently, there has been an increased interest in the safety of medicines used in children. There have been numerous studies of adverse drug reactions surveillance of children in hospital. One systematic review found that approximately 9% of children experience adverse drug reactions while in the hospital. Another study assessed the incidence of fatal adverse drug reactions in children. In order to determine the nature of drug related mortality in children, it retrospectively reviewed all suspected adverse drug reactions with a fatal outcome reported via the Yellow Card Scheme from 1964 until December 2000 to the Medical Control Agency in the UK. One of the objectives was to try to draw lessons regarding the safety of medicines used in children.

4 The study found that there were 390 deaths with 389 suspected drugs. The median age of children for whom reports were received was 5 years, with the greatest number of reports for infants in the first year of life. Different drugs were reported as being associated with children s deaths, such as anticonvulsants, cytotoxics, antibiotics, anaesthetics, corticosteroids, cardiovascular, lung surfactants, NSAIDs, immunosuppressants, muscle relaxants, bronchodilators, antihistamines, nasal decongestants, cough medicines, intravenous nutrition, antivirals, and insulin. The number of reported deaths has increased, with at least 10 deaths each year in the past decade. Most adverse drug reactions were attributed to hepatic failure, bone marrow suppression, sudden unexplained death, respiratory failure, asthma, pulmonary hemorrhage, and cardiac arrest. Drugs most frequently associated with fatalities were valproic acid, doxorubicin, propofol, carbamazepine, and halothane. (6) The broad range of suspected adverse drug reactions associated with fatalities has shown that pediatric patients are prone to adverse drug reactions that are traditionally thought of as being restricted to adults. It is very likely that the deaths associated with adverse drug reactions are significantly underreported. As of the most importance, this study demonstrated that the evaluation of toxicity in pediatric patients is essential in order to improve the clinical use of medicines in a section of the population, where scientific information is limited. Often it is unclear what dose is effective and safe for a child. A common approach has been to use data from adults and adjust the dose per child s weight. Experimenting over years with dose adjustments taught physicians how to use drugs in children effectively and without harm. However, this trial and error approach sometimes was tragic. For instance, in the 1950 s, chloramphenicol was widely used in adults to irradiate penicillin resistant bacteria. It was then tried on newborn babies (with good intent, of course). Many newborns died because their immature livers couldn t break down this antibiotic. (7) These deaths could have been avoided if chloramphenicol had been tested in this age group. This tragedy also told us that weight is not the only factor that needs to be considered when dosing medications for children. There are numerous reasons that pharmacokinetic data must be generated from studies in children rather than simply extrapolating from studies in adults. Metabolic processes in children are quit different comparing to adults. For example, children may have higher gastric PH and increased gastric and intestinal motility. Therefore, absorption of drugs from the gastrointestinal tract in children is different. Increased gastric ph slows the absorption of weak acids; conversely, weak bases are preferentially absorbed due to the effect of both ph and increased motility. Consistent with these theoretical considerations increased Phenobarbital absorption has been

5 shown in older pediatric patients, while digoxin absorption is much less predictable and consistent in children compared to adults. Because the relative proportion of total body water, total extracellular water, and total fat is different and there is a difference in protein binding, distribution of the drugs is also different. Biotransformation of the drugs undergoes maturation during the pediatric period, and some pathways may be proportionally more active in children than in adults. This can result in different metabolic profiles for a particular drug in children and adults. Renal function increases over the first year of life; therefore elimination of the drugs changes with age. The pathophysiology of a particular disease may differ in children, which, in turn, affect the drug disposition. The well-documented difference in drug disposition secondary to an underlying disease occurs in children with cystic fibrosis. Drug clearance is faster in children with cystic fibrosis than in healthy children. Also, significant difference in dose-response may be seen in pediatric population due to the different sensitivity to the effects of the drugs. Therefore, dose-ranging studies and studies which address other important differences in drug disposition between children and adults are needed. (8) Finally, Pediatric studies are needed in order to develop a pediatric formulation of a drug, where younger pediatric populations cannot take the adult formulation. Lack of such studies may deny pediatric patients access to important new therapies, or may require children to take the drug in extemporaneous formulations that may be poorly or inconsistently bioavailable. The information coming out of those studies that were conducted in children proves the theoretical concerns about drug disposition in children. For example, with neurontin, a drug used to control seizures, research has shown that higher doses are needed in children younger than 5 to control seizures. With versed, one of the most commonly used medicines to sedate children undergoing surgery, researchers found that children with congenital heart disease and pulmonary hypertension need to start at a lower dose to prevent respiratory problems. Despite the fact that lack of biomedical research in children is recognized, researchers do not rush to proceed with such studies. A great majority of medications which are used for children have never been tested in this population. In fact, only 20 to 30% of the FDA approved drugs are labeled for pediatric use.(7) This means that the majority of medications are routinely given to children off label. Several reasons are thought to explain the lack of biomedical studies in children. One reason is that the drug companies consider pediatric market that would bring only small financial benefit. In fact, those drugs used for children

6 that bring a significant profit, such as vaccines and some antibiotics, are intensively studied in this population group. Another reason is that it is generally more difficult to conduct pediatric studies. These studies require age-appropriate equipment and medical techniques. For example, it takes more skill to draw blood or collect urine sample in children. However, the major reasons for inadequate pediatric studies are the ethical issues. For instance, children cannot give an informed consent because consent implies full understanding of potential risks and other considerations. It is possible that parents are very enthusiastic about a study, but the child says No! (7) Because effectiveness and safety data are absent for a lot of medications, doctors rely on their personal medical judgment to decide whether a particular drug is to be given to a child and at what dose. Pharmacists face similar dilemma: if a question is raised about a medication s efficacy or safety, they are left with their personal experience and theoretical extrapolations from adult studies. On one hand, there is a sick child who needs help. On the other hand, that very help may turn out to be very harmful, even fatal, because there were no studies done to learn about benefits and risks of the particular medication in children. Yet another side of the problem is that parents do not readily line up to enroll their children into biomedical studies (and who can blame them?). The health of children is a big concern in American society, but so is the extreme care taken to protect children from harm. Placing a child in a clinical trial is viewed unethical and contradicts parents responsibility to nurture and protect the child. Scientific society admits that too often and for too long children have been receiving medicines not tested in their age group, but scientists are faced with the same ethical dilemma: the knowledge of the appropriate use of medicines in children needs to be improved to minimize harm; at the same time, the risk of the biomedical research is to be minimized in this population. (9) Of all the moral principles outliner in the Belmont Report, the one that poses the most concern in children research is the informed consent. Not only cannot children provide this consent legally, but also the extent to which they are able to understand the purpose and all of the details of clinical studies, risks, and potential benefits of participating is limited and varies to the significant degree according to age and background. (9) It may be difficult even for an older child to understand such terms as randomization, trial, or placebo. Moreover, children and their parents may view drug treatment as the only hope regardless of the risks involved; they may also feel obligated to

7 researchers and believe that refusal to enter the trial may compromise their child s health care. (10) The principle of beneficence also poses an ethical problem especially if studies present more than minimal risk without immediate benefit to the children involved. There are people who say that such research is highly immoral, but there are also people who point out that, if such clinical studies are outlawed, much research promising great benefits to children in the future will be lost.(5) The US FDA addressed the problem of biomedical research in children. Voluntary measures to encourage pediatric studies were implemented in the early 1990s. The voluntary nature of these measures left many drugs, age groups, and indications unstudied. Due to the fact that manufacturers are limited in their resources, they elected to conduct these studies preferentially on those drugs for which the sales are large. For the same reasons, there are fewer pediatric studies conducted on drugs for neonates and infants. The younger populations are more difficult to study. They may require special techniques, equipment, and formulations making it more expensive to care them out.(10) Because these voluntary measures were, for the most part, unsuccessful, in 1997, the FDA proposed a regulation that required all manufactures of the new drugs to care out pediatric studies in certain situations. This regulation was finalized in 1998 and is now known as Pediatric Rule. Pediatric Rule was designed to ensure that new drugs have adequate pediatric labeling for the approved indications at the time, or soon after, approval. It is presumed that all new drugs will be tested in pediatric patients. However, manufacturers can obtain a waiver of this requirement if the product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used in children. This law requires pharmaceutical companies to test their products on children under some circumstances. Pediatric studies are required if there is likelihood that the particular drug will be used in a great number of children, has therapeutic benefits, poses risks to children in the absence of labeling, or used in different pediatric groups. (11) As a result, about 30 studies have been started on cancer drugs. In fact, most children receive their cancer therapy as part of a clinical trial. Hopefully these studies will give physicians new cancer therapies for children. However, this new regulation raises additional ethical questions. For example, it is unclear in what phase of a drug development should pediatric studies begin or what trial design is optimal. (7) Introduction of Pediatric Rule generated vigorous public response. The FDA receives numerous comments from pediatricians, professional societies,

8 parents, members of the pharmaceutical industry, and patient groups. Some comments, primarily from pediatricians, professional societies, parents, and patient groups, support this regulation. They describe the problems faced by the pediatric community and parents resulting from inadequate pediatric labeling and the absence of pediatric formulations. However, some comments, primarily those from pharmaceutical industry, oppose a pediatric study requirement, arguing that voluntary measures were sufficient to ensure adequate pediatric labeling. (10) Unfortunately, a law cannot resolve an ethical issue. No law can in itself lead to a greater number of children being enrolled in drug trials or deal with the difficulty in obtaining informed consent. As of today, the majority of drugs are used in children without any experimental proof that they are effective and safe in pediatric population. It is well known that pharmacokinetic profile of some of these drugs is different in this group. Not always is it possible to extrapolate pharmacokinetics from adults; therefore, pediatric studies are essential. However, clinical studies in this particular population group are especially difficult to care out due to ethical consideration. Being a pharmacy student and a parent, I can fully appreciate the complexity of this ethical dilemma. As millions of other parents, I raise a question of efficacy and, most importantly, safety every time I fill a measuring cup with a medication which label stated, Under age of 5, consult your physician for dosage information. I understand that it means that the dosage information is lacking because there were no clinical studies done to address efficacy and safety of this medication in children. During these moments I truly hope that our pediatrician is experienced enough to give us an advice that will help and not harm. Things become even more complicated when the medicine is new and the doctor may not have had enough experience with this agent. It is during these moments I wish there were pediatric tests performed for all medications used in children. On the other hand, I would not want any experiments done on my daughter and I understand that very few parents, if any, would volunteer their children for the biomedical research. As a future pharmacist, I realize that there will be situations when I will have to make a clinical judgment call and decide whether a drug not tested in pediatric population should be administered to a child. I also may be responsible for conduction of a clinical trial in children. I have to admit it is a hard ethical dilemma and the decision is not easy to make. I think that the most appropriate solution is to use those medications that are licensed if these medications are among my options. If, however, the information about efficacy and/or safety of the particular medication were not

9 available, I would choose a medication, which is accepted on the bases of high possibility of benefit by my colleagues. I believe that prospective clinical trials are not the only option to assess efficacy and safety in children. Retrospective studies can be particularly useful in pediatric population. Whenever possible retrospective data on efficacy and safety of medications in children should be collected and analyzed. In addition, pharmacokinetic and pharmacodynamic properties of the drugs should be extrapolated from the studies in adults if it is theoretically reasonable. However, I understand that sometimes extrapolation of data from adults to children will not work simple because children have different pharmacokinetic characteristics. Thus child s age affects drug absorption, distribution, metabolism, and elimination. Therefore, it may be necessary to conduct biomedical studies in pediatric population to prevent unnecessary harm. If I were ever to participate in biomedical research on children, I would strictly adhere to the moral principles outlined in the Belmont Report. References:

10 1. Accessed on Accessed on Accessed on Accessed on Accessed on Clarkson A, Choonara I. Surveillance for fatal suspected adverse drug reactions in the UK. Arch Dis Child 2002;87: Meadows M. Drug Research and Children. FDA Consumer Magazine Accessed Accessed on Sutcliffe A. Testing New Pharmaceutical Products in Children. BMJ 2003;326:64-65