Therapeutic Orphans Research Articles

Editorial Comment: Therapeutic Orphans

By an odd and unfortunate twist of fate, infants and children are becoming “therapeutic or pharmaceutical orphans.”1 Since 1962 they have been denied the use of many new drugs. The Drug Laws of 1962 had their inception following a pediatric tragedy—the thalidomide catastrophe. The laws of 1938 followed another which resulted from the use of a pediatric dosage form, “elixir” of sulfanilamide. By “legal” definition, drugs introduced since 1962 must be safe and efficacious, but only a small number of these have been studied in the pediatric age group. Certainly, there are some drugs which have an anticipated use only in adults; it would be unreasonable to ask for certification of these for use in infants and children. There are a small number of new drugs, released since 1962, which had an anticipated use for infants and children as well as for adults, and their applications for approval have been passed after the required studies in pediatric and adult patients. However, many of the drugs released since 1962 carry an “orphaning” clause, eg, “Not to be used in children … is not recommended for use in infants and young children since few studies … Address correspondence to Harry Shirkey, MD, Department of Pediatrics, Children's Hospital, Birmingham, AL.

Is Pediatric Labeling Really Necessary?

Labeling refers to the label on the drug container and all printed materials, including the package insert, that accompanies the product. Labeling of a drug indicates that there is substantial evidence from adequate and well controlled clinical trials for the safe and effective use of that drug. Labeling provides important information on clinical pharmacology, indications and usage, contraindications, precautions, adverse effects, dosage, and administration. Unfortunately for children, most drug labeling contains the precautionary disclaimer, because safety and efficacy in children have not been established. The availability of safe and effective drugs has been directly responsible for the improvement in health over the past 50 years. Children essentially have been excluded from the benefit of the many therapeutic advances that have marked pharmaceutic drug development. The failure to include children in clinical trials during drug development leads to delay in implementing potentially effective treatment. Most US food and Drug Administration-approved drugs lack approval for use in all children or are restricted to certain pediatric age groups, primarily older children.1 Only a few of the new drugs released in this country each year are approved for use in children. This lack of information on the safe and effective use of drugs in the most vulnerable patients, infants and neonates, is of greatest concern. Only five of the 80 most frequently used drugs have been approved for use in this population. Another problem is that most drugs are not available in suitable pediatric dosage forms. They are not available in appropriate dosage sizes, lack liquid formulation, and taste peculiar to the child, making compliance difficult. Pharmacies extemporaneously prepare many drugs in liquid dosage forms for use in children. These dosage forms are not sufficiently tested to determine stability, efficacy, or expiration dating. For solid dosage forms, parents often must divide adult tablets …

Therapeutic Orphans: European Perspective

There are several factors to be considered when facing the problem of therapeutic orphans. First, there is the scientific one. We are all convinced that there is much need for more data concerning the use of drugs in children, infants, and neonates. Second, there is a regulatory factor involving political and technical institutions. Finally, we have to consider the economic interest of the pharmaceutics industry in investing money in research that would hardly generate sufficient return. There is no need to stress here that improved research in pediatric clinical pharmacology is required. Despite the fact that the number of clinical trials in children has increased, in many cases the use of drugs still depends on extrapolation of data from adults, and adequate scientific documentation for their use in children is lacking. We need additional studies to optimize dosages at various ages throughout childhood, and we still need studies on clinical efficacy and tolerability of drugs in children. However, we must recognize that when the pharmaceutics industry has an economic interest in developing a drug for use in children, we generally have good clinical data and reasonably large studies. Just think of many studies on antibiotics or the many drugs used in the treatment of otitis media or pharyngitis. But in many cases, there is simply no economic advantage for the pharmaceutics industry to conduct studies in children. These studies would be time-consuming, often necessarily multicentered, and costly. This is true for a number of drugs. We also must consider that negative results in children could reflect unfavorably on the use of the same drug in adults and limit the profit of the industry. Performing such studies therefore would depend primarily on the economic support of nonprofit or governmental organizations. The example of the network of pediatric clinical pharmacology centers developed …

Off-Label Uses of Drugs in Children

As we approach the new millennium, very little has changed regarding the labeling of prescription drugs for use in infants and children. Along with pregnant women, infants and children remain therapeutic orphans. This condition is understandable because there are very few therapeutic indications that are unique to this patient population and the absolute quantities of drugs required by these patients remains relatively small. On an actuarial basis, humans spend only approximately 16 years as children, whereas they spend another 60 to 80 years as adults. As a result, there is very little incentive for pharmaceutics companies to develop drugs and drug dosing guidelines for infants and children. Careful review has revealed that >70% of all the Physicians' Desk Reference (PDR) entries have either no existing dosing information for pediatric patients or explicit statements that the safety and efficacy in children have not been determined. In the best of circumstances, there are age-specific admonitions because of lack of dosing information for infants and children. The resulting conundrum can be illustrated best by a case presentation. A 6-month-old infant, born 29 weeks premature, presents to a physician's office in respiratory distress. His medical history is significant for developing bronchopulmonary dysplasia as well as for prematurity. Vital signs are temperature: 37.7°C; pulse: 180; respiration: 72; blood pressure: 84/56; physical examination: intercostal retractions, increased anteroposterior diameter, bilateral diffuse expiratory wheezing, nasal flaring; treatment: albuterol 2.5 mg in 2 mL normal saline by nebulization. While receiving the aerosol, the patient's pulse rate climbs to 215 beats per minutes and he becomes cyanotic despite theo2 used to nebulize the drug. The physician is called by the nurse and witnesses the patient turn black with eyes rolled back. He then suffers a respiratory arrest. Resuscitation is unsuccessful. When confronted with a similar clinical emergency, most … Address correspondence to Jeffrey L. Blumer, PhD, MD, Pediatric Pharmacology and Critical Care, Rainbow Babies and Children Hospital, 11100 Euclid Ave, Cleveland, OH 44106.

The Pediatric Pharmacology Research Unit (PPRU) Network and Its Role in Meeting Pediatric Labeling Needs

This meeting marks a milestone in the quest for solutions to the phenomenon referred to by Harry Shirkey in this country 3 decades ago as the problem of the therapeutic orphan.1 I know that the European colleagues who have come to share their knowledge and experience have long concerned themselves with ways of overcoming this same phenomenon in their respective countries. The person who has been attacking this issue for the longest time in the United States is Sumner Yaffe, the progenitor of this meeting and the man responsible for the development of the Network of Pediatric Pharmacology Research Units (PPRU) from his position as director of the Center for Research on Mothers and Children of the National Institute of Child Health and Human Development (NICHD). Iam indebted to Sumner for the opportunity to chair the PPRU Network Steering Committee and to Jeffrey L. Blumer, the principal investigator (PI) at the Cleveland PPRU site for planning today's watershed event. There have been numerous reasons given by pharmaceutics manufacturers over the years for their failure to sponsor tests that would provide data sufficient to result in approved labeling for pediatric use when new drugs were introduced (for the purposes of this talk, I'll speak to the issues that we face in the United States only, but I recognize that similar issues exist in virtually every country represented at this conference). The advances made in several spheres of endeavor and the creation of the PPRU Network have primarily eliminated virtually all the arguments that have been used over the years to avoid the development of labeling for the use of most drugs for pediatric indications. The most commonly used excuses for failure to provide the results of pediatric studies for labeling of new drugs, or for new pediatric indications for …

Common errors of drug administration in infants: causes and avoidance.

Drug administration errors are common in infants. Although the infant population has a high exposure to drugs, there are few data concerning pharmacokinetics or pharmacodynamics, or the influence of paediatric diseases on these processes. Children remain therapeutic orphans. Formulations are often suitable only for adults; in addition, the lack of maturation of drug elimination processes, alteration of body composition and influence of size render the calculation of drug doses complex in infants. The commonest drug administration error in infants is one of dose, and the commonest hospital site for this error is the intensive care unit. Drug errors are a consequence of system error, and preventive strategies are possible through system analysis. The goal of a zero drug error rate should be aggressively sought, with systems in place that aim to eliminate the effects of inevitable human error. This involves review of the entire system from drug manufacture to drug administration. The nuclear industry, telecommunications and air traffic control services all practise error reduction policies with zero error as a clear goal, not by finding fault in the individual, but by identifying faults in the system and building into that system mechanisms for picking up faults before they occur. Such policies could be adapted to medicine using interventions both specific (the production of formulations which are for children only and clearly labelled, regular audit by pharmacists, legible prescriptions, standardised dose tables) and general (paediatric drug trials, education programmes, nonpunitive error reporting) to reduce the number of errors made in giving medication to infants.

The Inhibitory Glycine Receptor: Prospects for a Therapeutic Orphan?

The inhibitory glycine receptor is a member of the ligand-gated ion channel superfamily. It mediates inhibitory synaptic transmission in mammalian spinal cord and brainstem. Structure and function of the receptor, as well as its chromosomal localization and genetic structure, have been extensively studied. While hereditary and acquired receptor dysfunctions can be identified, selective and specific modulation of receptor function is still lacking. The preponderance of current literature regarding the inhibitory glycine receptor raises the prospect that adequate methods for the treatment of glycine receptor-mediated disorders might be developed.

THE ETHICAL BOUNDARIES OF DRUG RESEARCH IN PEDIATRICS

Research abuses in the pediatric setting, mistakes, regulation, minimal investment, and professional misconceptions may contribute to children becoming therapeutic orphans. The moral imperative to expand pediatric pharmacology is urgent but the enterprise is not without risk. Pediatricians as experts in child care are privileged to be able to advocate for the expansion of this invaluable research while simultaneously advocating for the children who are to be involved. In the development of ethical drug research, children's well-being and empowerment can be realized. A shared commitment will help to ensure that in the future we will be better able to provide safe and effective medication and so greatly enhance the care of children.

Introduction: Drug Development for Infants and Children: Rescuing the Therapeutic Orphan

Introduction: Drug Development for Infants and Children: Rescuing the Therapeutic Orphan

Is the "Therapeutic Orphan" About to Be Adopted?

In this issue of Pediatrics, the Committee on Drugs (COD) has examined the continued problem of the "unapproved" use of "approved" medications in pediatrics.1 This commentary will expand on the issues that have restricted drug research in children and describe current initiatives to facilitate and encourage such research to achieve the necessary drug labeling to reduce unapproved uses of medications in children. BACKGROUND Physicians who treat infants and children frequently prescribe medications that have never been approved by the Food and Drug Administration (FDA) for pediatric patients; unfortunately, many drugs are released without labels for pediatric use and often with pediatric disclaimers.

Clinical Perspective Paediatric clinical pharmacology: Reclaiming the therapeutic orphan

The current lack of adequate paediatric drug labelling information has placed children at undue risk because physicians caring for these patients are forced to decide between withholding potentially useful therapies or using drugs outside of the labelling recommendations. The importance of specific drug labelling information for infants and children rests on the frequent observation of substantial age-related differences in drug action and disposition. Because of these observations, the American Academy of Pediatrics has repeatedly called for increased paediatric drug research to support drug labelling information. Recently, the United States Food and Drug Administration has proposed new guidelines to promote paediatric dosing information for drugs which may be used in children. Also, to improve paediatric drug labelling and encourage collaboration between established academic centres and the pharmaceutical industry, the National Institutes of Child Health and Human Development established the Pediatric P...

Pediatric Pharmacology: The Path Clears for a Noble Mission

Unlabeled use of drugs in children occurs frequently and contributes to the therapeutic orphan dilemma. This situation can no longer be condoned; few acceptable reasons still exist for not evaluating potentially effective drug therapy in children. An apparent lack of research funds is not one of these reasons; only allocation of these funds to pediatric pharmacology is found wanting. Availability of clinical pharmacology programs, pediatric pharmacology manpower, sensitive analytical techniques, and acceptable ethical approaches to pediatric research reveal that drug evaluation is feasible in children. Studies readily include the required therapeutic indication for drug use in pediatrics. Efforts of academia, government and industry are now converging to show that the path for the noble mission of pediatric pharmacology--rational use of FDA approved drugs for children--is now clear for action.

Therapeutic Orphans

In Reply.— We agree with Drs Darling and Lambert that children are “therapeutic orphans” and that precious little data exist concerning the safety and efficacy of many of the drugs used in pediatric practice. Although Drs Darling and Lambert believe that we, in “academia,” have a“responsibility” to study these drugs, they have not offered any suggestions of how to do this. These are very difficult studies to design,with soft end points, that must

Clinical Pharmacology in Obstetrics

Pregnancy is a therapeutic orphan, says Dr Peter Lewis, the editor of this book. While there have been profound changes and rapid growth in the fields of pharmacology and obstetrics in the last three decades, there has been an understandable reluctance on the part of drug companies to endorse trials of their drugs in pregnant patients. This book looks at the cutting edge of drug therapy in pregnancy today. The first three chapters, which are written by Dr Lewis himself, deal with the effect of drugs on the mother and on the fetus. The pharmacokinetics of drugs in a two-compartment (mother and fetus) system are discussed and diagramed. A careful reading of these chapters may help someone to understand why the fetus may have a higher concentration of the drug in its system than the mother. The remaining 22 chapters of the book are handled by 27 contributing editors who

Pediatric Drug Testing: Is It at Risk?

H arry Shirkey could not have guessed what he started when, in 1963, he first coined the phrase therapeutic orphans to describe the plight of a population for whose use few drugs had been tested and approved. His expression drew attention to pediatric therapeutics, a field not merely neglected but until then virtually ignored. Physicians were often forced to guess at drug dosages for children on the basis of a percentage of adult body weight. A breakthrough came when pediatric pharmacologists such as Dr. Shirkey pointed to skin surface area as a more rational way to calculate pediatric doses. Unfortunately, that method did not work for all drugs either: some drugs were absorbed and metabolized more efficiently in children than in adults, others stayed in the blood stream for longer periods of time and had longer half lives than in adults, and still others produced in children responses quite different from those in adults. In the mid-1960s pharmacologists realized that drugs would have to be adequately tested in children from the beginning, as if children were another species, before appropriate directions could be given for their use.

Pediatric Clinical Pharmacology and the "Therapeutic Orphan"

Pediatric Clinical Pharmacology and the "Therapeutic Orphan"

Surveillance of pediatric adverse drug reactions: A neglected health care program

Dr. Alan K. Done, Director of Pediatric Pharmacology for the Food and Drug Administration, has recently secured a commitment from the pharmaceutical industry to complete preclinical studies of the many drugs which have not as yet been tested in young animals and are therefore not currently available for use in children. Once accomplished, this action and others already taken by the agency should help solve the problem of "therapeutic orphans."1 On the other hand, young children continue to be exposed to a large number of drugs which are already on the market and which are being given without adequate medical supervision or monitoring for adverse reactions.

Therapeutic Orphans—Everybody's Business

Therapeutic Orphans—Everybody's Business