- Email: [email protected]
Clinical pharmacology research in the pediatric patient: the challenge continues
Progress in Pediatric Cardiology 12 Ž2000. 29᎐35
Clinical pharmacology research in the pediatric patient: the challenge continues U
Andrew P. Ten Eicka,b, Michael D. Reeda,b, a
Di¨ ision of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children’s Hospital, Cle¨ eland, OH 44106-6010, USA b Department of Pediatrics, School of Medicine, Case Western Reser¨ e Uni¨ ersity, Cle¨ eland, OH 44106, USA
Abstract For most of the 20th century, most drugs labeled by the United States Food and Drug Administration ŽUSFDA. have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk andror benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient’s caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts. 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pediatric research; Pharmacology; Pharmacokinetics; PPRU; Study methodology
U
Corresponding author. Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44106-6010, USA. Tel.: q1-216-844-3310; fax: q1-216-844-5122. E-mail address: [email protected] ŽM.D. Reed.. 1058-9813r00r$ - see front matter 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 5 8 - 9 8 1 3 Ž 0 0 . 0 0 0 5 6 - 4
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A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
1. Introduction Dozens of new drugs, new uses for old drugs and modifications of older formulations are made available to clinicians each year for the treatment of human disease. Unfortunately the focus of the vast majority of these innovations in healthcare is for the treatment of the adult patient w1᎐3x. This focus on the adult patient has unintentionally fostered the erroneous perception by innovators, investigators and legislators that the performance of rigorous clinical pharmacologic evaluations in infants, children and adolescents are extremely difficult, rarely completable and are unnecessary to undertake. A host of perceived obstacles continue to deter the pharmaceutical industry from providing the resources and collaboration necessary to meet their responsibility of partnering in advocating the advancement of pharmaceutical care for infants and children complimenting their ongoing efforts in adults w4,5x. This sad commentary is reflected by the small number of drugs which gain labeling for use in the pediatric patient by the United States Food and Drug Administration ŽFDA. each year w6x. This dearth of data is compounded by the even fewer number of petitions the FDA receives from innovators seeking labeling of medications for use in pediatrics for drugs already in clinical use with labeling for adults w6x. The clear differences which exist between pediatric and adult patients in drug dosing are important and indisputable. Nevertheless, few drugs are labeled by the US FDA with dosing recommendations for pediatric indications. In 1973, Wilson w1x surveyed one of the most frequently consulted books for dosing information, the Physicians Desk Reference ŽPDR., for the number of drugs that were FDA labeled for use in children. Seventy-eight percent of the 2000 drugs indexed in the 1973 PDR were found by Wilson to be without labeling for pediatrics or to provide insufficient data for application to the pediatric patient. Gilman and Gal w2x in a similar evaluation found 81% of the drugs in the 1991 PDR were without pediatric labeling information. More recently, Cote and colleagues w3x described the lack of pediatric labeling information in 71% of the new molecular entities that received FDA labeling between 1991 and 1994. This lack of labeling for so many drugs continues to effectively and persistently segregate infants and children in 1999 to being the ‘therapeutic orphans’ Shirkey described in 1968 w7x. The apparent lack of interest and commitment to the pediatric patient with respect to new chemical entities w3,6x sends an ominous message regarding a limited availability of potentially revolutionary new medications for the treatment of the pediatric patient. Once a drug receives approval by the FDA and is
marketed in the United States, a physician may prescribe the medication for any indication and any age group the physician deems appropriate. In an attempt to compensate for the lack of scientific-based drug dosing data in the pediatric patient, pediatric practitioners have routinely been forced to prescribe medications for their patients without sufficient data defining optimal dosing strategies, safety or efficacy experience. Numerous examples of this ‘off-label’ prescribing can be found in the literature w6x and is practiced in the clinic daily involving some of the most frequently prescribed medications for infants and children. For example, albuterol aerosol is not labeled by the FDA for use in children below the age of 4 years. Obviously the thought of withholding such a highly effective, relatively safe and potentially lifesaving medication as albuterol from infants and younger children is inconceivable. However, the offlabel use of medications in pediatric patients can sometimes causes devastating results which was described with administering large doses of chloramphenicol to neonates w8,9x and sulfonamide administration to premature neonates w10x. Clearly, the importance of performing the necessary studies to obtain the needed data to define optimal, age-appropriate dosing recommendations and document the safety profile for the proper and safe use of medications in patients of all ages cannot be overemphasized.
2. Historical overview of the importance of legislative efforts The foundation of the modern FDA was established in 1906 after the enactment of the Federal Food and Drug Act. This law was enacted after numerous American soldiers in Mexico died after receiving adulterated quinine. The focus of this legislation was to prohibit the interstate commerce of misbranded food, drink and drugs. Since this initial legislation, subsequent empowerments of the FDA by the US Congress have been in response to therapeutic misadventures occurring in the pediatric patient. Most of these misadventures could have been avoided with the proper information, proper data. In 1938 the Food, Drug and Cosmetic Act ŽFDCA. was enacted after 107 children died from receiving a sulfanilamide elixir which contained diethylene glycol as a solvent in compounding w11x. This new ‘wonder’ antibiotic was properly labeled as an elixir though it did not label the specific alcohol used. Passage of this Congressional Act mandated truthfulness in labeling and documented safety of the product. Furthermore, this law empowered the FDA with enforcement duties. In response to the thalidomide tragedy w12,13x of the
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
1960s, the Harris᎐Kefauver Amendment to the Food, Drug and Cosmetic Act of 1962 was enacted. This amendment dictated preclinical animal trials before clinical testing in humans could begin. This was the first time that the federal government mandated evidence that drugs marketed in the US be both efficacious and safe for the intended patient population. As commented above, both the 1938 and 1962 amendments to the FDCA were initiated in response to therapeutic tragedies occurring in the pediatric patient. These amendments were intended to increase the safety of medications used in humans in the US and to ensure that the available medications were efficacious for their stated intention. Although many felt that these laws would enhance research efforts involving medications for the pediatric patient, these amendments may have actually had the opposite effect w14x. Unfortunately, most pharmaceutical companies began to submit labeling recommendations for their drugs with the disclaimer ‘not recommend for use in children’ under a certain age or as not for use in children at all in response to these legislative efforts. The reasons for these restrictions by innovators are multifactorial including the erroneous perception by pharmaceutical manufacturers of the difficulty in performing rigorous dose-finding studies in infants and children, perceived ethical concerns for studying new or old medications in children w5,15x, a fear of ‘harming’ the child, and a perceived small market share and thus reduced profit margin to comment on just a few. Nevertheless, this posture by innovators actually stifled the provision of optimal drug therapy in infants, children and adolescents. Again, in response to this devastating lack of research focusing on the efficacy and safety of commonly prescribed medications in the pediatric patient, the FDA promulgated regulations which required specific pediatric doses of the medication to be included in the product labeling unless the requirement was waived. Implementation by the FDA of the 1994 Rule required pharmaceutical manufacturers to voluntarily determine and, if appropriate, submit a supplemental New Drug Application ŽSNDA. for drugs that have sufficient data for a pediatric indication. If insufficient data exists to support a pediatric indication, the package labeling is required to include the statement that the ‘safety and effectiveness in pediatric patients has not been established’. Unfortunately, few pharmaceutical manufacturers voluntarily provided adequate pediatric data in response to the 1994 Rule prompting the FDA to again re-examine their process and procedures as they pertain to the improvement of drug labeling for use in pediatrics. The continued poor success of previous legislative initiatives and the agency’s commitment to more forcefully encourage innovators to seek labeling for pediatrics of new and
31
previously approved drugs stimulated the Congress to enact the Food and Drug Administration Modernization Act ŽFDAMA. of 1997 w16x. This act is revolutionary in scope as it provides the manufacturer for the first time with a financial incentive for obtaining the necessary data to support labeling of their compound for use in pediatrics. This incentive to the sponsor can be substantial; a 6-month extension to the sponsor’srinnovator’s patent may be granted by the FDA if the data provided meet FDA requirements and ultimately result in product labeling for pediatrics. Supplementing FDAMA, the FDA Final Rule of 1997, which became effective 1 April 1999, mandated that pharmaceutical manufacturers, must Žno longer voluntarily. provide age appropriate pediatric data about formulations, dosing, efficacy and safety for the drugs which they manufacturer as long as these medications have a role in pediatric medicine w16x. The Final Rule of 1997 also expands the scope of the 1994 Rule to include new active moieties, new indications, new dosage forms, new dosing regimens, and new routes of administration. Recognizing that not all medications will have utility in pediatrics Žsee Table 1., the Final Rule appropriately permits the granting of waivers if the drug fulfills one or more of the following criteria: Ž1. the product does not represent a meaningful therapeutic benefit for pediatric patients; Ž2. if there is likely to be a very small number of pediatric patients Ži.e. defined as - 50 000 pediatric patients. for which the drug would be used; Ž3. the compound is unsafe for use in pediatrics; Ž4. if the necessary studies are impossible to conduct Ži.e. study criteria cannot be met, possible geographic restrictions .; or Ž5. it is impossible to prepare a product formulation appropriate for the pediatric patient w16x. Table 1 Adult medical conditions the United States Food and Drug Administration may grant waivers for pediatric drug studies a Alzheimer’s disease Age-related macular degeneration Amyotrophic lateral sclerosis Arteriosclerosis Basal cell and squamous cell cancer Breast cancer Endometrial cancer Hairy cell leukemia Infertility Lung cancer Non-germ cell ovarian cancer Osteoarthritis Pancreatic cancer Parkinson’s disease Prostate cancer Renal cell cancer Squamous cell cancers of the oropharynx Symptoms associated with menopause Uterine cancer Adapted from reference w16x.
a
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
32
Table 2 Pharmaceuticals that the United States Food and Drug Administration may require pharmacokinetic and efficacy data in pediatric subjects a Anesthesia drugs Anti-nausea drugs Anti-virals ŽHIV. Asthma agent Dermatological agents Žincluding acne agents. Hormones Neurological drug Non-steroidal anti-inflammatory agents Oncology drugs Pulmonary agents Adapted from reference w16x.
a
As discussed above, not all drugs approved by the FDA will be intended for use in infants and children Žsee Table 1.. The USFDA has defined, in the Final Rule, classes of medications that pharmaceutical manufacturers must supply pharmacokinetic and efficacy studies in age defined pediatric populations Žsee Table 2.. Not all medications intended for infants and children must proceed through the rigors of clinical efficacy trials Žsee Table 3. if the disease state in infants and children is thought to have similar pathology and time course as adults. Under the Final Rule, these medications administered to children will only have to undergo pharmacokinetic studies in age appropriate populations to be compliant with the USFDA’s rule. One of the most important aspects of the 1997 Final Rule is that the responsibility to provide evidence for exemption from this Rule is solely the responsibility of the manufacturer. If the FDA deems that a manufacturer has not met the requirements of the Final Rule, the agency could deem an already marketed drug product misbranded and as such, require the product to be removed from the US market w16x. With the creative incentives of the 1997 FDAMA combined with the potential ‘muscle’ of the Final Rule it is hoped that pediatric research endeavors will blossom. Hopefully by the next millennium, a large number of routinely prescribed medications as well as all new agents with pediatric use potential will be effectively studied and needed dosing, efficacy and safety data outlined clearly in the drug’s official label to the optimal benefit of the pediatric patient.
3. Clinical drug research in children: unique needs and challenges An understanding of a drug’s pharmacokinetic profile, i.e. a detailed and specific description of the processes of absorption, distribution, metabolism and excretion, is essential to determining the optimal dose
of any medication. Clearly a number of important, patient-specific variables including underlying diseaseŽs., major organ functionrdysfunction and the possible use of extracorporal procedures all will influence a drug’s disposition profile and must be delineated before establishing dose recommendations. The most important patient-specific variable influencing drug disposition would appear to be age w4,17x. The normal maturational changes observed with increasing age will dramatically impact a drug’s disposition profile. The ontogeny of major organ function has been studied and is highly variable during the discrete phases of the fetal period, birth across a broad spectrum of gestational and postnatal ages, infancy and childhood, as well as through the later decades of adult life w4,17x. An understanding of the impact of these age-related maturational processes on a drug’s volume of distribution Ž Vd . allows for an accurate assessment of the individual dose to be administered whereas an appreciation of the influence of these changes on drug clearance permits an accurate assessment of the proper dosing interval. Thus, the validity of applying dosing recommendations obtained from traditional pharmacokinetic studies performed in healthy adult volunteers to ill infants and children is clearly questionable and underscores the importance of performing such evaluations in the pediatric population whom the drug will be prescribed. Conventional pharmacokinetic evaluations involve the administration of the study drug via the route interested Že.g. oral, rectal, intravenous. followed by the collection of multiple blood and urine samples over a specified time frame. The time frame for which sampling occurs should encompasses a minimum of three drug half-lives Ž t1r2 . for enhanced sensitivity. If this pharmacokinetic evaluation is the first study performed in a specific pediatric age group, the expected t1r2 would be estimated from adult andror animal data w17x, prospectively determined in the first few study subjects and the bloodrurine sampling strategy modified if necessary w18x. To fully characterize the drug’s disposition profile this same study design should be repeated again under multiple dose conditions Table 3 Medical conditions and pharmaceuticals that the United States Food and Drug Administration may require only pharmacokinetic data in pediatric subjects a Allergies Cardiovascular diseases GI disorders Hematology agents Infectious diseases Imaging agents Urological disorders Adapted from reference w16x.
a
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
Že.g. steady-state .. Quantitation of the drug and, if appropriate, any metabolites, in the biologic fluid samples obtained is performed and the concentration values plotted against time constructing a biologic fluid Že.g. plasma, serum. concentration᎐time curve. From this drug concentration᎐time curve calculations can be performed to determine important pharmacokinetic parameter estimates including area under the drug-concentration time curve ŽAUC., t1r2 , Vd and body Cl. An understanding of these variables and their interrelationships for a specific drug is the foundation to determining the optimal dose regimen for specific indications w17,18x. Although such studies are relatively easily performed in healthy adult volunteers, the performance of similar studies in infants and children are substantially more challenging. The performance of comprehensive pharmacokinetic evaluations in infants and children poses a number of practical challenges. The laboratory methodology must be sufficiently specific and sensitive to accommodate small sample volumes as the quantity of biologic fluid available from pediatric study patients is limited, directly related to patient age and underlying diseaseŽs.. Access to the systemic circulation, particularly for prolonged periods permitting repeated blood sampling can be difficult in children w19,20x. In addition, legitimate ethical concerns surround the performance of pharmacokinetic evaluations in infants and children. Recognizing the legitimate need for such studies to defining the safe and effective use of drugs in pediatrics has fostered the development of comprehensive ethical guidelines to the performance of drug evaluationrpharmacokinetic studies in pediatrics w21,22x. These issues and responsibilities are extremely important as the safety and well being of this population, which may be easily exploited, must always supersede any perceived gains. Prior to undertaking any clinical pharmacology study, the riskrbenefit for the child must be carefully scrutinized to prevent any undue harm. To address this important issue, the Department of Health and Human Services and the American Academy of Pediatrics have outlined four specific riskrbenefit categories for pediatric research Žsee Table 4. w22x. Assessing the risk should include all possible risks of the associated procedures Že.g. infection after venipuncture., drug therapy, effects on organ ontogeny, effect on growth and development and risks typically not considered with adult studies Že.g. pain, anxiety, separation anxiety, fear, volume to be delivered.. At no time do the potential or real benefits outweigh the risks nor should a child be enrolled to participate in a study that is poorly designed. All study investigators are obligated to determine associated risks to the patient who is participating in a drug study. The Institutional Review Board ŽIRB., another partner in
33
Table 4 Categories of riskrbenefit in pediatric research a Research not involving greater than minimal risk. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual. Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. Research not otherwise approved which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children. Adapted from reference w19,22x.
a
clinical research, is charged with the responsibility of assuring that all studies comply with Federal and International guidelines including the ethical treatment of study subjects. Since infants and children have limited ability to make well-informed decisions concerning their own health and welfare it is of the utmost importance that the IRB recognizes and prevents the child from being exposed to undue risks. Consistent with the ethical treatment of research subjects, the individual must be informed of the particular study and it’s associated risks andror benefits w19,22x. Since infants and children are not cognitively ready nor legally able to make independent decisions concerning their health and well-being, consent to participate in a study must be cautiously gained from parents or the child’s guardian w22x. As stated above, most studies in children are performed in sick children therefore parents or guardians must be thoroughly aware of potential benefit and risks to the patient. Parents of a sick child may feel that the experimental treatment is the child’s last hope for improvement and they may not fully consider the associated risks. Therefore the investigator must thoroughly explain the study and it’s possible risks in language understood by parents or guardian. Depending upon the educational background, emotional and physical state of the parents or guardian the investigator or their agent may need to repeatedly explain the study and associated risks. Parent or guardian consent should be obtained before discussing the study with the child. It is generally agreed that consent to participate should be obtained from children G 13 years of age and children G 7 years of age should provide their assent to participate w22x. If at anytime, consent or assent from the parent, guardian, or child is withdrawn the child should be removed from the study and no further data collected w22x. Traditionally most clinical pharmacokinetic studies require obtaining blood and possibly other biological fluids. Procedures such as venipuncture for blood
34
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
collection, cerebral spinal fluid aspirates, and bronchoscopies should all be performed in a manner that minimizes the child’s fear and discomfort. Repeated sampling raises ethical, physiological and practical limitations in children. The emotional and physical well-being of a child, even though they may not interpret or verbalize the experience or pain in a manner similar to adults, should be continuously addressed. The application of EMLA cream at the site of venipuncture may alleviate much of the discomfort associated with venipuncture and catheter insertion. The use of an indwelling venous cannula to obtain repeated blood samples should also increase the comfort of the patient. The determination of the number and quantity of biological fluid samples is multifactorial w21x. As discussed above, the analytical technique performed to quantitate drug concentration will dictate the minimum amount of the biological sample that is necessary to accurately perform the assay. The method employed must be precise, reproducible, rapid, and readily adaptable w15x. The use of micro-analytical techniques can dramatically reduce the volume of biological fluid necessary to obtain accurate results and allows the investigator to expand the number of samples obtained enhancing spectrum and precision of the data. Considering the limited quantity of blood that may be removed from young infants and children an increasing number of investigators are incorporating the principles of optimal sampling theory into the design of their pediatric pharmacokinetic studies w21x. Briefly, optimal sampling strategy incorporates mathematical models to define the optimal times to obtain biologic fluid samples over a dosing interval which will provide the most robust pharmacokinetic analysis. This approach allows the investigator to design their sampling strategy to include the most ‘information rich’ portion of the concentration᎐time curve and obtain all of the needed information while collecting the least number of samples. Numerous examples confirm the appropriateness of such a sampling strategy and the validity of the results applied to patient care. w21x Although the detailed processes outlined above are challenging, they serve as the foundation for the performance of needed pharmacokinetic data in pediatric patients of all ages. Numerous highly experienced and talented pediatric pharmacology research centers exist in the US and throughout the world. As a stimulus to foster continued, creative collaborative research among such experienced centers that focuses on the obtaining the needed data to permit labeling of drugs for use in pediatrics the National Institutes of Health through the National Institute of Child Health and Human Development established the Pediatric Pharmacology Research Unit network w5x. To-
day, 13 such experienced centers work closely together in an integrated network, together and with other experienced centers, clinicians and industry partners, in addressing these important, needed issues all focused on providing the necessary data for the safe and efficacious use of medications in pediatrics. The knowledge and capabilities to optimally perform such research studies in pediatric patients of all ages is readily available and must be utilized.
4. Conclusion In contrast to the technological marvels of the past few decades which declared their Y2K compliance on 1 January 2000, it may be many years into the next millennium before we know if our pediatric research efforts are compliant with the needs and expectations of our patients. Although it is disturbing that much of the impetus for generating the necessary data for proper labeling of medications for the pediatric patient has been stimulated by government initiatives and financial incentive, it would appear that the FDA’s Final rule and similar efforts around the globe are on track for finally dispelling the inappropriate label of a ‘therapeutic orphan’.
Acknowledgements Support for this work was provided in part by Pediatric Pharmacology Research Unit grant HD 31323-02. References w1x Wilson JT. Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women. Basic and therapeutic aspects of perinatal pharmacology. New York, NY: Raven Press, 1975:411᎐421. w2x Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. Clin Pharmacokinet 1992;23:1᎐9. w3x Cote CJ, Kauffman RE, Troendle GJ, Lambert GH. Is the ‘therapeutic orphan’ about to be adopted?. Pediatrics 1995;95:229᎐237. w4x Christensen ML, Helms RA, Chesney RW. Is pediatric labeling really necessary?. Pediatrics 1999;104Ž3.:593᎐597. w5x Cohen SN. The pediatric pharmacology research unit ŽPPRU. network and its role in meeting pediatric labeling needs. Pediatrics 1999;104Ž3.:644᎐645. w6x Wilson JT. An update on the therapeutic orphan. Pediatrics 1999;104Ž3.:585᎐590. w7x Shirkey HC. Therapeutic orphans. J Pediatr 1968;2:119᎐120. w8x Burns LE, Hodgman JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. New Engl J Med 1959;261:13118᎐13121. w9x Sutherland JM. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. Am J Dis Child 1959;97:761.
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35 w10x Silverman WA, Anderson DH, Blanc WA, Crozier DN. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:614. w11x Anonymous. Deaths due to elixir of sulfanilamide-massengill: report of the Secretary of Agriculture submitted to House Resolution 352 of November 19, 1937 and Senate Resolution of November 16, 1937. J Am Med Assoc 1937;109:1985᎐1988. w12x Lenz W. A study of the German outbreak of phocomelia. Lancet 1962;2:1332. w13x Taussig H. A study of the German outbreak of phocomelia. J Am Med Assoc 1962;198:1106᎐1114. w14x Connor JD. A look at the future of pediatric therapeutics: an investigator’s perspective of the new pediatric rule. Pediatrics 1999;104Ž3.:610᎐613. w15x Kauffman RE, Kearns GL. Pharmacokinetic studies in paediatric patients: clinical and ethical considerations. Clin Pharmacokinet 1992;23:10᎐29. w16x Anonymous. Regulations requiring manufactures to assess the safety and effectiveness of new drugs and biological
w17x
w18x
w19x w20x
w21x
w22x
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products in pediatric patients; Final rule. Fed Reg 1998; 63Ž231.:66631᎐66672. Reed MD, Besunder JB. Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am 1989;36:1053᎐1074. Wilson JT, Kearns GL, Murphy D, Yaffe SJ. Paediatric labelling requirements: implications for pharmacokinetic studies. Clin Pharmacokinet 1994;26:308᎐325. Janofsky J, Starfield B. Assessment of risk in research on children. J Pediatr 1998;98:842᎐846. Saeed MA, Gatens PF. Anterior interosseous nerve syndrome: unusual etiologies. Arch Phys Med Rehabil 1983; 64:182. Reed MD. Optimal sampling theory: an overview of its application to pharmacokinetic studies in infants and children. Pediatrics 1999;104Ž3.:627᎐632. Anonymous. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1995;95:286᎐294.
Clinical pharmacology research in the pediatric patient: the challenge continues U
Andrew P. Ten Eicka,b, Michael D. Reeda,b, a
Di¨ ision of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children’s Hospital, Cle¨ eland, OH 44106-6010, USA b Department of Pediatrics, School of Medicine, Case Western Reser¨ e Uni¨ ersity, Cle¨ eland, OH 44106, USA
Abstract For most of the 20th century, most drugs labeled by the United States Food and Drug Administration ŽUSFDA. have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk andror benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient’s caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts. 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pediatric research; Pharmacology; Pharmacokinetics; PPRU; Study methodology
U
Corresponding author. Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44106-6010, USA. Tel.: q1-216-844-3310; fax: q1-216-844-5122. E-mail address: [email protected] ŽM.D. Reed.. 1058-9813r00r$ - see front matter 䊚 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 5 8 - 9 8 1 3 Ž 0 0 . 0 0 0 5 6 - 4
30
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
1. Introduction Dozens of new drugs, new uses for old drugs and modifications of older formulations are made available to clinicians each year for the treatment of human disease. Unfortunately the focus of the vast majority of these innovations in healthcare is for the treatment of the adult patient w1᎐3x. This focus on the adult patient has unintentionally fostered the erroneous perception by innovators, investigators and legislators that the performance of rigorous clinical pharmacologic evaluations in infants, children and adolescents are extremely difficult, rarely completable and are unnecessary to undertake. A host of perceived obstacles continue to deter the pharmaceutical industry from providing the resources and collaboration necessary to meet their responsibility of partnering in advocating the advancement of pharmaceutical care for infants and children complimenting their ongoing efforts in adults w4,5x. This sad commentary is reflected by the small number of drugs which gain labeling for use in the pediatric patient by the United States Food and Drug Administration ŽFDA. each year w6x. This dearth of data is compounded by the even fewer number of petitions the FDA receives from innovators seeking labeling of medications for use in pediatrics for drugs already in clinical use with labeling for adults w6x. The clear differences which exist between pediatric and adult patients in drug dosing are important and indisputable. Nevertheless, few drugs are labeled by the US FDA with dosing recommendations for pediatric indications. In 1973, Wilson w1x surveyed one of the most frequently consulted books for dosing information, the Physicians Desk Reference ŽPDR., for the number of drugs that were FDA labeled for use in children. Seventy-eight percent of the 2000 drugs indexed in the 1973 PDR were found by Wilson to be without labeling for pediatrics or to provide insufficient data for application to the pediatric patient. Gilman and Gal w2x in a similar evaluation found 81% of the drugs in the 1991 PDR were without pediatric labeling information. More recently, Cote and colleagues w3x described the lack of pediatric labeling information in 71% of the new molecular entities that received FDA labeling between 1991 and 1994. This lack of labeling for so many drugs continues to effectively and persistently segregate infants and children in 1999 to being the ‘therapeutic orphans’ Shirkey described in 1968 w7x. The apparent lack of interest and commitment to the pediatric patient with respect to new chemical entities w3,6x sends an ominous message regarding a limited availability of potentially revolutionary new medications for the treatment of the pediatric patient. Once a drug receives approval by the FDA and is
marketed in the United States, a physician may prescribe the medication for any indication and any age group the physician deems appropriate. In an attempt to compensate for the lack of scientific-based drug dosing data in the pediatric patient, pediatric practitioners have routinely been forced to prescribe medications for their patients without sufficient data defining optimal dosing strategies, safety or efficacy experience. Numerous examples of this ‘off-label’ prescribing can be found in the literature w6x and is practiced in the clinic daily involving some of the most frequently prescribed medications for infants and children. For example, albuterol aerosol is not labeled by the FDA for use in children below the age of 4 years. Obviously the thought of withholding such a highly effective, relatively safe and potentially lifesaving medication as albuterol from infants and younger children is inconceivable. However, the offlabel use of medications in pediatric patients can sometimes causes devastating results which was described with administering large doses of chloramphenicol to neonates w8,9x and sulfonamide administration to premature neonates w10x. Clearly, the importance of performing the necessary studies to obtain the needed data to define optimal, age-appropriate dosing recommendations and document the safety profile for the proper and safe use of medications in patients of all ages cannot be overemphasized.
2. Historical overview of the importance of legislative efforts The foundation of the modern FDA was established in 1906 after the enactment of the Federal Food and Drug Act. This law was enacted after numerous American soldiers in Mexico died after receiving adulterated quinine. The focus of this legislation was to prohibit the interstate commerce of misbranded food, drink and drugs. Since this initial legislation, subsequent empowerments of the FDA by the US Congress have been in response to therapeutic misadventures occurring in the pediatric patient. Most of these misadventures could have been avoided with the proper information, proper data. In 1938 the Food, Drug and Cosmetic Act ŽFDCA. was enacted after 107 children died from receiving a sulfanilamide elixir which contained diethylene glycol as a solvent in compounding w11x. This new ‘wonder’ antibiotic was properly labeled as an elixir though it did not label the specific alcohol used. Passage of this Congressional Act mandated truthfulness in labeling and documented safety of the product. Furthermore, this law empowered the FDA with enforcement duties. In response to the thalidomide tragedy w12,13x of the
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
1960s, the Harris᎐Kefauver Amendment to the Food, Drug and Cosmetic Act of 1962 was enacted. This amendment dictated preclinical animal trials before clinical testing in humans could begin. This was the first time that the federal government mandated evidence that drugs marketed in the US be both efficacious and safe for the intended patient population. As commented above, both the 1938 and 1962 amendments to the FDCA were initiated in response to therapeutic tragedies occurring in the pediatric patient. These amendments were intended to increase the safety of medications used in humans in the US and to ensure that the available medications were efficacious for their stated intention. Although many felt that these laws would enhance research efforts involving medications for the pediatric patient, these amendments may have actually had the opposite effect w14x. Unfortunately, most pharmaceutical companies began to submit labeling recommendations for their drugs with the disclaimer ‘not recommend for use in children’ under a certain age or as not for use in children at all in response to these legislative efforts. The reasons for these restrictions by innovators are multifactorial including the erroneous perception by pharmaceutical manufacturers of the difficulty in performing rigorous dose-finding studies in infants and children, perceived ethical concerns for studying new or old medications in children w5,15x, a fear of ‘harming’ the child, and a perceived small market share and thus reduced profit margin to comment on just a few. Nevertheless, this posture by innovators actually stifled the provision of optimal drug therapy in infants, children and adolescents. Again, in response to this devastating lack of research focusing on the efficacy and safety of commonly prescribed medications in the pediatric patient, the FDA promulgated regulations which required specific pediatric doses of the medication to be included in the product labeling unless the requirement was waived. Implementation by the FDA of the 1994 Rule required pharmaceutical manufacturers to voluntarily determine and, if appropriate, submit a supplemental New Drug Application ŽSNDA. for drugs that have sufficient data for a pediatric indication. If insufficient data exists to support a pediatric indication, the package labeling is required to include the statement that the ‘safety and effectiveness in pediatric patients has not been established’. Unfortunately, few pharmaceutical manufacturers voluntarily provided adequate pediatric data in response to the 1994 Rule prompting the FDA to again re-examine their process and procedures as they pertain to the improvement of drug labeling for use in pediatrics. The continued poor success of previous legislative initiatives and the agency’s commitment to more forcefully encourage innovators to seek labeling for pediatrics of new and
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previously approved drugs stimulated the Congress to enact the Food and Drug Administration Modernization Act ŽFDAMA. of 1997 w16x. This act is revolutionary in scope as it provides the manufacturer for the first time with a financial incentive for obtaining the necessary data to support labeling of their compound for use in pediatrics. This incentive to the sponsor can be substantial; a 6-month extension to the sponsor’srinnovator’s patent may be granted by the FDA if the data provided meet FDA requirements and ultimately result in product labeling for pediatrics. Supplementing FDAMA, the FDA Final Rule of 1997, which became effective 1 April 1999, mandated that pharmaceutical manufacturers, must Žno longer voluntarily. provide age appropriate pediatric data about formulations, dosing, efficacy and safety for the drugs which they manufacturer as long as these medications have a role in pediatric medicine w16x. The Final Rule of 1997 also expands the scope of the 1994 Rule to include new active moieties, new indications, new dosage forms, new dosing regimens, and new routes of administration. Recognizing that not all medications will have utility in pediatrics Žsee Table 1., the Final Rule appropriately permits the granting of waivers if the drug fulfills one or more of the following criteria: Ž1. the product does not represent a meaningful therapeutic benefit for pediatric patients; Ž2. if there is likely to be a very small number of pediatric patients Ži.e. defined as - 50 000 pediatric patients. for which the drug would be used; Ž3. the compound is unsafe for use in pediatrics; Ž4. if the necessary studies are impossible to conduct Ži.e. study criteria cannot be met, possible geographic restrictions .; or Ž5. it is impossible to prepare a product formulation appropriate for the pediatric patient w16x. Table 1 Adult medical conditions the United States Food and Drug Administration may grant waivers for pediatric drug studies a Alzheimer’s disease Age-related macular degeneration Amyotrophic lateral sclerosis Arteriosclerosis Basal cell and squamous cell cancer Breast cancer Endometrial cancer Hairy cell leukemia Infertility Lung cancer Non-germ cell ovarian cancer Osteoarthritis Pancreatic cancer Parkinson’s disease Prostate cancer Renal cell cancer Squamous cell cancers of the oropharynx Symptoms associated with menopause Uterine cancer Adapted from reference w16x.
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Table 2 Pharmaceuticals that the United States Food and Drug Administration may require pharmacokinetic and efficacy data in pediatric subjects a Anesthesia drugs Anti-nausea drugs Anti-virals ŽHIV. Asthma agent Dermatological agents Žincluding acne agents. Hormones Neurological drug Non-steroidal anti-inflammatory agents Oncology drugs Pulmonary agents Adapted from reference w16x.
a
As discussed above, not all drugs approved by the FDA will be intended for use in infants and children Žsee Table 1.. The USFDA has defined, in the Final Rule, classes of medications that pharmaceutical manufacturers must supply pharmacokinetic and efficacy studies in age defined pediatric populations Žsee Table 2.. Not all medications intended for infants and children must proceed through the rigors of clinical efficacy trials Žsee Table 3. if the disease state in infants and children is thought to have similar pathology and time course as adults. Under the Final Rule, these medications administered to children will only have to undergo pharmacokinetic studies in age appropriate populations to be compliant with the USFDA’s rule. One of the most important aspects of the 1997 Final Rule is that the responsibility to provide evidence for exemption from this Rule is solely the responsibility of the manufacturer. If the FDA deems that a manufacturer has not met the requirements of the Final Rule, the agency could deem an already marketed drug product misbranded and as such, require the product to be removed from the US market w16x. With the creative incentives of the 1997 FDAMA combined with the potential ‘muscle’ of the Final Rule it is hoped that pediatric research endeavors will blossom. Hopefully by the next millennium, a large number of routinely prescribed medications as well as all new agents with pediatric use potential will be effectively studied and needed dosing, efficacy and safety data outlined clearly in the drug’s official label to the optimal benefit of the pediatric patient.
3. Clinical drug research in children: unique needs and challenges An understanding of a drug’s pharmacokinetic profile, i.e. a detailed and specific description of the processes of absorption, distribution, metabolism and excretion, is essential to determining the optimal dose
of any medication. Clearly a number of important, patient-specific variables including underlying diseaseŽs., major organ functionrdysfunction and the possible use of extracorporal procedures all will influence a drug’s disposition profile and must be delineated before establishing dose recommendations. The most important patient-specific variable influencing drug disposition would appear to be age w4,17x. The normal maturational changes observed with increasing age will dramatically impact a drug’s disposition profile. The ontogeny of major organ function has been studied and is highly variable during the discrete phases of the fetal period, birth across a broad spectrum of gestational and postnatal ages, infancy and childhood, as well as through the later decades of adult life w4,17x. An understanding of the impact of these age-related maturational processes on a drug’s volume of distribution Ž Vd . allows for an accurate assessment of the individual dose to be administered whereas an appreciation of the influence of these changes on drug clearance permits an accurate assessment of the proper dosing interval. Thus, the validity of applying dosing recommendations obtained from traditional pharmacokinetic studies performed in healthy adult volunteers to ill infants and children is clearly questionable and underscores the importance of performing such evaluations in the pediatric population whom the drug will be prescribed. Conventional pharmacokinetic evaluations involve the administration of the study drug via the route interested Že.g. oral, rectal, intravenous. followed by the collection of multiple blood and urine samples over a specified time frame. The time frame for which sampling occurs should encompasses a minimum of three drug half-lives Ž t1r2 . for enhanced sensitivity. If this pharmacokinetic evaluation is the first study performed in a specific pediatric age group, the expected t1r2 would be estimated from adult andror animal data w17x, prospectively determined in the first few study subjects and the bloodrurine sampling strategy modified if necessary w18x. To fully characterize the drug’s disposition profile this same study design should be repeated again under multiple dose conditions Table 3 Medical conditions and pharmaceuticals that the United States Food and Drug Administration may require only pharmacokinetic data in pediatric subjects a Allergies Cardiovascular diseases GI disorders Hematology agents Infectious diseases Imaging agents Urological disorders Adapted from reference w16x.
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A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
Že.g. steady-state .. Quantitation of the drug and, if appropriate, any metabolites, in the biologic fluid samples obtained is performed and the concentration values plotted against time constructing a biologic fluid Že.g. plasma, serum. concentration᎐time curve. From this drug concentration᎐time curve calculations can be performed to determine important pharmacokinetic parameter estimates including area under the drug-concentration time curve ŽAUC., t1r2 , Vd and body Cl. An understanding of these variables and their interrelationships for a specific drug is the foundation to determining the optimal dose regimen for specific indications w17,18x. Although such studies are relatively easily performed in healthy adult volunteers, the performance of similar studies in infants and children are substantially more challenging. The performance of comprehensive pharmacokinetic evaluations in infants and children poses a number of practical challenges. The laboratory methodology must be sufficiently specific and sensitive to accommodate small sample volumes as the quantity of biologic fluid available from pediatric study patients is limited, directly related to patient age and underlying diseaseŽs.. Access to the systemic circulation, particularly for prolonged periods permitting repeated blood sampling can be difficult in children w19,20x. In addition, legitimate ethical concerns surround the performance of pharmacokinetic evaluations in infants and children. Recognizing the legitimate need for such studies to defining the safe and effective use of drugs in pediatrics has fostered the development of comprehensive ethical guidelines to the performance of drug evaluationrpharmacokinetic studies in pediatrics w21,22x. These issues and responsibilities are extremely important as the safety and well being of this population, which may be easily exploited, must always supersede any perceived gains. Prior to undertaking any clinical pharmacology study, the riskrbenefit for the child must be carefully scrutinized to prevent any undue harm. To address this important issue, the Department of Health and Human Services and the American Academy of Pediatrics have outlined four specific riskrbenefit categories for pediatric research Žsee Table 4. w22x. Assessing the risk should include all possible risks of the associated procedures Že.g. infection after venipuncture., drug therapy, effects on organ ontogeny, effect on growth and development and risks typically not considered with adult studies Že.g. pain, anxiety, separation anxiety, fear, volume to be delivered.. At no time do the potential or real benefits outweigh the risks nor should a child be enrolled to participate in a study that is poorly designed. All study investigators are obligated to determine associated risks to the patient who is participating in a drug study. The Institutional Review Board ŽIRB., another partner in
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Table 4 Categories of riskrbenefit in pediatric research a Research not involving greater than minimal risk. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual. Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. Research not otherwise approved which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children. Adapted from reference w19,22x.
a
clinical research, is charged with the responsibility of assuring that all studies comply with Federal and International guidelines including the ethical treatment of study subjects. Since infants and children have limited ability to make well-informed decisions concerning their own health and welfare it is of the utmost importance that the IRB recognizes and prevents the child from being exposed to undue risks. Consistent with the ethical treatment of research subjects, the individual must be informed of the particular study and it’s associated risks andror benefits w19,22x. Since infants and children are not cognitively ready nor legally able to make independent decisions concerning their health and well-being, consent to participate in a study must be cautiously gained from parents or the child’s guardian w22x. As stated above, most studies in children are performed in sick children therefore parents or guardians must be thoroughly aware of potential benefit and risks to the patient. Parents of a sick child may feel that the experimental treatment is the child’s last hope for improvement and they may not fully consider the associated risks. Therefore the investigator must thoroughly explain the study and it’s possible risks in language understood by parents or guardian. Depending upon the educational background, emotional and physical state of the parents or guardian the investigator or their agent may need to repeatedly explain the study and associated risks. Parent or guardian consent should be obtained before discussing the study with the child. It is generally agreed that consent to participate should be obtained from children G 13 years of age and children G 7 years of age should provide their assent to participate w22x. If at anytime, consent or assent from the parent, guardian, or child is withdrawn the child should be removed from the study and no further data collected w22x. Traditionally most clinical pharmacokinetic studies require obtaining blood and possibly other biological fluids. Procedures such as venipuncture for blood
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A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35
collection, cerebral spinal fluid aspirates, and bronchoscopies should all be performed in a manner that minimizes the child’s fear and discomfort. Repeated sampling raises ethical, physiological and practical limitations in children. The emotional and physical well-being of a child, even though they may not interpret or verbalize the experience or pain in a manner similar to adults, should be continuously addressed. The application of EMLA cream at the site of venipuncture may alleviate much of the discomfort associated with venipuncture and catheter insertion. The use of an indwelling venous cannula to obtain repeated blood samples should also increase the comfort of the patient. The determination of the number and quantity of biological fluid samples is multifactorial w21x. As discussed above, the analytical technique performed to quantitate drug concentration will dictate the minimum amount of the biological sample that is necessary to accurately perform the assay. The method employed must be precise, reproducible, rapid, and readily adaptable w15x. The use of micro-analytical techniques can dramatically reduce the volume of biological fluid necessary to obtain accurate results and allows the investigator to expand the number of samples obtained enhancing spectrum and precision of the data. Considering the limited quantity of blood that may be removed from young infants and children an increasing number of investigators are incorporating the principles of optimal sampling theory into the design of their pediatric pharmacokinetic studies w21x. Briefly, optimal sampling strategy incorporates mathematical models to define the optimal times to obtain biologic fluid samples over a dosing interval which will provide the most robust pharmacokinetic analysis. This approach allows the investigator to design their sampling strategy to include the most ‘information rich’ portion of the concentration᎐time curve and obtain all of the needed information while collecting the least number of samples. Numerous examples confirm the appropriateness of such a sampling strategy and the validity of the results applied to patient care. w21x Although the detailed processes outlined above are challenging, they serve as the foundation for the performance of needed pharmacokinetic data in pediatric patients of all ages. Numerous highly experienced and talented pediatric pharmacology research centers exist in the US and throughout the world. As a stimulus to foster continued, creative collaborative research among such experienced centers that focuses on the obtaining the needed data to permit labeling of drugs for use in pediatrics the National Institutes of Health through the National Institute of Child Health and Human Development established the Pediatric Pharmacology Research Unit network w5x. To-
day, 13 such experienced centers work closely together in an integrated network, together and with other experienced centers, clinicians and industry partners, in addressing these important, needed issues all focused on providing the necessary data for the safe and efficacious use of medications in pediatrics. The knowledge and capabilities to optimally perform such research studies in pediatric patients of all ages is readily available and must be utilized.
4. Conclusion In contrast to the technological marvels of the past few decades which declared their Y2K compliance on 1 January 2000, it may be many years into the next millennium before we know if our pediatric research efforts are compliant with the needs and expectations of our patients. Although it is disturbing that much of the impetus for generating the necessary data for proper labeling of medications for the pediatric patient has been stimulated by government initiatives and financial incentive, it would appear that the FDA’s Final rule and similar efforts around the globe are on track for finally dispelling the inappropriate label of a ‘therapeutic orphan’.
Acknowledgements Support for this work was provided in part by Pediatric Pharmacology Research Unit grant HD 31323-02. References w1x Wilson JT. Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women. Basic and therapeutic aspects of perinatal pharmacology. New York, NY: Raven Press, 1975:411᎐421. w2x Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. Clin Pharmacokinet 1992;23:1᎐9. w3x Cote CJ, Kauffman RE, Troendle GJ, Lambert GH. Is the ‘therapeutic orphan’ about to be adopted?. Pediatrics 1995;95:229᎐237. w4x Christensen ML, Helms RA, Chesney RW. Is pediatric labeling really necessary?. Pediatrics 1999;104Ž3.:593᎐597. w5x Cohen SN. The pediatric pharmacology research unit ŽPPRU. network and its role in meeting pediatric labeling needs. Pediatrics 1999;104Ž3.:644᎐645. w6x Wilson JT. An update on the therapeutic orphan. Pediatrics 1999;104Ž3.:585᎐590. w7x Shirkey HC. Therapeutic orphans. J Pediatr 1968;2:119᎐120. w8x Burns LE, Hodgman JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. New Engl J Med 1959;261:13118᎐13121. w9x Sutherland JM. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. Am J Dis Child 1959;97:761.
A.P. Ten Eick, M.D. Reed r Progress in Pediatric Cardiology 12 (2000) 29᎐35 w10x Silverman WA, Anderson DH, Blanc WA, Crozier DN. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:614. w11x Anonymous. Deaths due to elixir of sulfanilamide-massengill: report of the Secretary of Agriculture submitted to House Resolution 352 of November 19, 1937 and Senate Resolution of November 16, 1937. J Am Med Assoc 1937;109:1985᎐1988. w12x Lenz W. A study of the German outbreak of phocomelia. Lancet 1962;2:1332. w13x Taussig H. A study of the German outbreak of phocomelia. J Am Med Assoc 1962;198:1106᎐1114. w14x Connor JD. A look at the future of pediatric therapeutics: an investigator’s perspective of the new pediatric rule. Pediatrics 1999;104Ž3.:610᎐613. w15x Kauffman RE, Kearns GL. Pharmacokinetic studies in paediatric patients: clinical and ethical considerations. Clin Pharmacokinet 1992;23:10᎐29. w16x Anonymous. Regulations requiring manufactures to assess the safety and effectiveness of new drugs and biological
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products in pediatric patients; Final rule. Fed Reg 1998; 63Ž231.:66631᎐66672. Reed MD, Besunder JB. Developmental pharmacology: ontogenic basis of drug disposition. Pediatr Clin North Am 1989;36:1053᎐1074. Wilson JT, Kearns GL, Murphy D, Yaffe SJ. Paediatric labelling requirements: implications for pharmacokinetic studies. Clin Pharmacokinet 1994;26:308᎐325. Janofsky J, Starfield B. Assessment of risk in research on children. J Pediatr 1998;98:842᎐846. Saeed MA, Gatens PF. Anterior interosseous nerve syndrome: unusual etiologies. Arch Phys Med Rehabil 1983; 64:182. Reed MD. Optimal sampling theory: an overview of its application to pharmacokinetic studies in infants and children. Pediatrics 1999;104Ž3.:627᎐632. Anonymous. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1995;95:286᎐294.