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Clinical Pharmacology: A Discipline Called to Action for Maternal and Child Health

2007; Wiley; Volume: 81; Issue: 4 Linguagem: Inglês

10.1038/sj.clpt.6100145

1532-6535

Gregory L. Kearns, W. A. Ritschel, John T. Wilson, Stephen P. Spielberg,

Ethics and Legal Issues in Pediatric Healthcare

Forty-three years ago, Harry Shirkey, the father of modern pediatric therapeutics, issued a clear call to action intended as one key solution to rescue children from the plight of being "therapeutic orphans."1 More than three decades later, John Wilson posed a critical question around this same call for accountability and responsibility regarding the study of drugs in children.2 Both admonishments were founded on the existence of insufficient information for pediatric prescribing, first assumed and then validated in 1975.3 Although it could be readily interpreted that children continue to be therapeutic orphans, the truth is that, through the recent efforts of many in the fields of pediatric clinical pharmacology and fetal-maternal medicine, much has changed, much new knowledge has been created, and much good has been wrought. Engagement of ethical and moral constructs to the application of fundamental scientific principles along the continuum of drug discovery, development, regulation, and utilization (DDRU), coupled with the diligence of a diverse group of biomedical professionals and in some instances politicians, has moved us away from the pediatric tragedy that in part precipitated creation of the modern Food and Drug Administration (FDA) to being squarely on the path toward an envisioned future of safe, effective, and individualized drug therapy for pregnant women, infants, and children. For the first time in the history of Clinical Pharmacology and Therapeutics, an issue is being devoted to the theme of clinical pharmacology pertaining to maternal and child health. The authors of this editorial, all linked in the past through educational affiliation and in the present by professional association in the discipline of clinical pharmacology, are honored to share perspectives and insights that are intended to magnify the significance of this issue and, more importantly, be an exposition of the important enabling role for clinical pharmacology in maternal and child health. Admittedly, these facts represent just the tip of the iceberg of concerns related to mothers and children; however, they illustrate several key points: First, although mothers and children represent a fundamentally important facet of society, they remain in many instances one of the most disadvantaged and vulnerable of populations whose plight is the result of circumstances beyond their control. Second, application of basic interventions (e.g., clean drinking water, sanitation, food, vaccines, essential medications) that are considered essential by Western standards could markedly improve maternal-child health. Third, to find effective solutions for problems of global proportions, those privileged to contemplate, develop, and deliver them must be driven by creativity and broad thinking. This includes all professionals across the spectrum of clinical pharmacology. "Maternal and child health" is not an established medical specialty in its own right, but is subsumed in the established disciplines of obstetrics, pediatrics, and family medicine. At present, does the information at hand justify a need for a separate discipline? The organisms involved, the mother on the one hand and the child—including the fetus prepartum—on the other, are two different individuals. Yet, at least prepartum, and in the case of breast feeding, postpartum, the fetus and the child, respectively, partake in the uptake, distribution, and elimination of any drug given to the mother. As such, they constitute the mother–fetus–infant continuum. However, these distinct organisms have unique anatomy, physiology, pharmacokinetics, and pharmacodynamics, all of which are continuously evolving. The inextricable link between infant and mother represents a continuum designed to perpetuate a species (Figure 1). Along this continuum are conditions that are "fixed" (e.g., genetic constitution) and thereby present across the entire spectrum of development. In contrast, other conditions are "variable" (e.g., environment, diet, socioeconomic conditions, disease and its treatment) and therefore have the potential to influence the dynamic of the continuum in an episodic fashion; this may produce consequences that are additive, synergistic, or antagonistic. When the context of therapeutic decision making for pregnant women, infants, and children is considered from a univariate perspective (e.g., trying to predict warfarin anticoagulant response using a monogenic approach), uncharacterized and frequently underrecognized variability can disable predictive accuracy8 and thereby limit utility by compromising drug safety, efficacy, or both. Thus, it is imperative that research conducted in pregnant women and pediatric patients consider the multiple determinants of drug disposition and effect so that generalization of knowledge and extrapolation to therapeutic recommendation(s) will be comprehensive and relevant to a desired outcome. The initial phase of human development represents a continuum with distinct facets associated with somatic growth, maturation, and psychosocial development. The net result is a physiologically mature human, capable of reproduction. A healthy continuum between mother and infant ensures perpetuation of the species. In the context of therapeutics, it must be recognized that genetic constitution, environment (including diet), concomitant disease state(s), and their treatment cut across the continuum of development in differential dimensions and as a result may modulate drug disposition, action, or both. A total of 133 new molecular entities (NMEs) were licensed to be marketed in the United States between 1998 and 2002. The number of these entities licensed for use in children increased in the 3 years after registration from 4% to 29%, primarily during the first 2 years after registration. Of the NMEs licensed for children, only 2% were for newborns (0–27 days), whereas most were for children aged 12 to 18 years.9 Interestingly, about 30% of the NMEs approved for marketing did not have a formulation suitable for pediatric use This is a surprising state of affairs for the twenty-first century and, in great measure, currently constrains the use of effective and potentially safe drugs in infants and young children. Historically, the importance of pharmaceutical formulation dates from the Greek physician Clarissimus Galenus (c. 129–200), who prepared his own prescriptions using specific ingredients called "Galenica" to formulate the medicament (delivery system).10 The concern about establishing the correct dose of a drug goes back to Philippus Aureolus Theophrastus Bombastus von Hohenheim, called Paracelsus (1493–1541), who is considered the "father of pharmacology"10 as demonstrated by his dictum, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."11 Some 40 years ago, the pediatrician and pharmacologist H.C. Shirkey expressed his concerns eloquently: "The dosage—right or wrong, is the final expression of diagnostic and therapeutic acumen".12 The potential price associated with therapeutic use of an inappropriate drug formulation and errant dosing is no better articulated than by an excerpt from a letter written by A.S. Calhoun (22 October 1937) in reference to the 1937 "elixir of sulfanilamide incident":13 But to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form. That realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive. I have known hours when death for me would be a welcome relief from this agony. As summarized by Roberts et al.,14 the marked expansion in the number of pediatric clinical trials conducted in the United States over the past decade has to a great extent focused on defining the age-appropriate pediatric dose for drug products approved for adults. In their summary paragraph, these authors (all of whom were working for the FDA at the time their review was published) concluded that "drugs used in children should be studied in accordance with sound ethical and scientific principles to define differences in efficacy, age-dependent changes in pharmacokinetics and/or pharmacodynamics, and to identify unique pediatric adverse events." This same sentiment—and challenge—could well be applied to the study of drugs during pregnancy. In any event, the only insurance policy sufficient to guard against the therapeutic misadventures born of the trial-and-error approaches documented in history is the prudent use of the tools of science, not simply to characterize the determinants of pharmacokinetics and pharmacodynamics in the pediatric patient or parturient, but to translate this knowledge into information of practical therapeutic utility—for example, the right dose for the right condition in the right patient. Although pediatric clinical drug trials have produced considerable new knowledge,15 much information has not been added to product labeling and thus is not widely disseminated to prescribers. As a result, medical practitioners remain challenged with appropriate prescribing for pediatric (and obstetric) patients. However, through expansion and augmentation of product labeling by the inclusion of all data from controlled clinical trials, marked improvements in pediatric and obstetric prescribing can be achieved. When this goal is accomplished, "off-label" and "off-knowledge" prescribing will not be synonymous, as is currently often the case for children and pregnant women. In this issue of CPT, Robert Ward and Ralph Kauffman16 recount the history of novel, landmark legislation in the United States that has fueled a renaissance in pediatric clinical pharmacology and therapeutics. Portions of the 1997 FDA Modernization Act (FDAMA), which provided an incentive (six months of extended marketing exclusivity) for the study of marketed drug products under the regulatory construct of the FDA, placed priority on children as part of the drug-development process. In the halls and boardrooms of many pharmaceutical companies, pediatric patients were accorded enhanced status, not simply from a financial value-added perspective but most importantly as a group of patients whose wide inclusion in the drug-development process has historically been impeded by the regulatory process. As a result, resources (e.g., finances, personnel, program development) were leveraged within companies not only to meet imposed regulatory demands but also to electively create opportunities to generate new knowledge squarely aimed at improving pediatric therapeutics. Despite vehement public rhetoric during the past decade that would intimate or possibly even declare that the legislative provisions for according extended marketing exclusivity to companies have produced a societal disadvantage by unnecessarily delaying the marketing of important generic drug products in the United States, there exists not a shard of objective evidence that the FDAMA or the Best Pharmaceuticals for Children Act (BPCA) has brought about anything but good. In fact, the BPCA and the companion Pediatric Research Equity Act (PREA) have served as a blueprint for legislation recently enacted by the European Union, which contains the important provisions of the BPCA and PREA and extends them in perpetuity to pediatric patients.17 Over the past 15 years, the National Institutes of Health (NIH) has also taken proactive steps to remedy the relative dearth of new knowledge in the fields of pediatric and obstetric clinical pharmacology. Through the collective efforts of a group of eminent pediatric clinical pharmacologists from the United States and Canada, as well as concerted action by chief architects at the National Institute of Child Health and Human Development (NICHD), including Duane Alexander and Sumner J. Yaffe, the Pediatric Pharmacology Research Unit (PPRU) Network was inaugurated in 1994. The overarching goal of the PPRU Network was to provide a collective of expertise in pediatric clinical pharmacology and a premier clinical trial platform to facilitate the conduct of studies required to support pediatric drug labeling. Throughout the NIH, the PPRU Network was unique in comparison to other networks in that it represented a visionary public-private partnership in which core funding to units through a cooperative agreement was used to support necessary programmatic infrastructure (e.g., salary support for investigators, research nurses, technicians, and equipment costs), whereas patient-specific costs associated with a given study were provided by the pharmaceutical industry. Success and proof of concept for the PPRU Network were virtually immediate, with four multi-institutional clinical trials funded by the pharmaceutical industry conducted in its first year of existence. In the now 14th year of existence of this 13-member network, a total of 185 studies (primarily phase I and II) have been completed (personal communication, George Giacoia, 18 January 2007). In 2003, the NICHD used an analogous mechanism to foster conduct of basic, translational, and clinical research in pregnancy by creating the Obstetric Pharmacology Research Unit Network, a program summarized by the commentary from Zajicek and Giacoia18 in this issue. A view of the future of pediatric and obstetric therapeutics reveals major human resource gaps that could further disadvantage children as advances continue to be enjoyed in adult therapeutics. At present there is a shortage of scientists who have formal training in pediatric or obstetric clinical pharmacology. Although the National Institute of General Medical Sciences has a long and distinguished history of providing resources to institutions for the training of clinical pharmacologists, programs supported in the past by this institute have not included those in pediatric clinical pharmacology, which are generally smaller and less well established than their counterparts for adults. During the past decade, fewer than 20 individuals have completed fellowships in pediatric clinical pharmacology at academic institutions with formal training programs. This number is constrained not by restricted career opportunities in the field or available number of potential trainees but by availability of resources sufficient to appropriately support (e.g., salary and benefits costs, requisite research, and educational costs) physicians in their fourth through eighth years of postgraduate medical training. When such resources are available, they generally come from institutions (e.g., operational funds, individual grant funds); in some instances they are educational grants-in-aid from foundations. This shortage of support for training has been mitigated in small measure through innovative approaches (e.g., Mentored Individual Scientist Clinical Development awards) undertaken by the NICHD to support the delivery of training in clinical pharmacology to a limited number (seven over the past decade) of pediatricians and pediatric medical subspecialists. Nonetheless, the current demand for training both physicians and biomedical scientists in pediatric clinical pharmacology far outstrips the available opportunities—a situation that must find a remedy if the opportunities for therapeutic advancement afforded by the provisions of the BPCA, PREA, and similar global imperatives are to be fully realized. As with the success of the PPRU Network, a public-private partnership offers the best and most readily available solution for increasing support for postdoctoral fellowship training in pediatric and obstetric pharmacology. Appropriation of existing resources to this mission and the creation of new resources from the return-on-investment produced by the BPCA could do much to enable perpetuation of the renaissance in pediatric and obstetric clinical pharmacology by providing critical resources to support expanded educational opportunities. The articles in this issue of CPT, which pertain to pediatric and obstetric clinical pharmacology, span the spectrum of learned opinion, review the application of fundamental principles, expound creation of new information, and illustrate the application of the "new biology" as it relates to discovery of drug-related insult during normal development. In reality, this content will provide readers with only a sampling of what is now being done and what can be accomplished in the future. Proof of concept abounds for the value of integrating pharmacokinetics, pharmacodynamics, and pharmacogenetics as applied to the principles19 and practice20 of clinical pharmacology in pediatrics. We are witness to an evolving revelation of what must be done and why. Answers to these questions affect humanity in a perspective captured by Kofi Annan, former secretary-general of the United Nations: "Only as we move closer to realizing the rights of all children will countries move closer to their goals of development and peace." Children and pregnant women deserve the same rights to be the recipients of safe and effective drug therapy as does any other member of our society. The opinions expressed are solely those of the authors. We dedicate this editorial to the students we have been honored to teach and the infants and children we have been privileged to serve.