6

BPCA, PREA, and Drug
Studies with Neonates

Chapter 2 discussed how children differ from adults in their response to medications and how neonates, in particular, differ not only from adults but also from older infants and children. As an example of unexpected responses in neonates, it cited the belated discovery in the 1950s of the toxic effects of chloramphenicol when it was used to treat infections in neonates. At roughly the same time, doctors learned that another treatment (penicillin and sulfisoxazole) that had come into use without controlled testing was associated with an increased risk of death attributed to kernicterus (brain injury from elevated bilirubin) (Robertson, 2003a, b). Not long after that, yet another anti-infective (novobiocin) was discovered to pose similar risks to neonates, but this discovery, based on clinical surveillance, came while the product’s use was still limited. As described later in this chapter, anti-infectives lead the list of drugs with labeling changes made on the basis of neonatal studies requested under the Best Pharmaceuticals for Children Act (BPCA) and required under the Pediatric Research Equity Act (PREA).

Despite substantial advances in the understanding of neonatal pharmacology, improved resources for neonatal clinical studies, and explicit inclusion of neonates as a relevant age group for studies conducted under BPCA, the limited testing of medications in this vulnerable age group is a continuing concern. One of the tasks for the Institute of Medicine (IOM) committee was to examine the use of neonatal assessment tools in studies conducted under BPCA and PREA or predecessor policies. This chapter begins by highlighting the challenges of conducting studies with this age group and reviewing data on the extensive off-label use of medications for



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6 BPCA, PREA, and Drug Studies with Neonates C hapter 2 discussed how children differ from adults in their response to medications and how neonates, in particular, differ not only from adults but also from older infants and children. As an example of unexpected responses in neonates, it cited the belated discovery in the 1950s of the toxic effects of chloramphenicol when it was used to treat in- fections in neonates. At roughly the same time, doctors learned that another treatment (penicillin and sulfisoxazole) that had come into use without controlled testing was associated with an increased risk of death attributed to kernicterus (brain injury from elevated bilirubin) (Robertson, 2003a,b). Not long after that, yet another anti-infective (novobiocin) was discovered to pose similar risks to neonates, but this discovery, based on clinical sur- veillance, came while the product’s use was still limited. As described later in this chapter, anti-infectives lead the list of drugs with labeling changes made on the basis of neonatal studies requested under the Best Pharmaceu- ticals for Children Act (BPCA) and required under the Pediatric Research Equity Act (PREA). Despite substantial advances in the understanding of neonatal phar- macology, improved resources for neonatal clinical studies, and explicit inclusion of neonates as a relevant age group for studies conducted under BPCA, the limited testing of medications in this vulnerable age group is a continuing concern. One of the tasks for the Institute of Medicine (IOM) committee was to examine the use of neonatal assessment tools in studies conducted under BPCA and PREA or predecessor policies. This chapter begins by highlighting the challenges of conducting studies with this age group and reviewing data on the extensive off-label use of medications for 141

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142 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN treatment of neonates. It then discusses neonatal assessments resulting from requests under BPCA or requirements under PREA. MEDICATION TESTING AND MEDICATION USE WITH NEONATES Challenges of Medication Testing with Neonates Testing the safety and efficacy of medicines in neonates is particularly challenging (see, e.g., Kearns et al., 2003; NICHD/FDA, 2004; Anand et al., 2005; Baer, 2009; Rakhmanina and van den Anker, 2009; PhRMA, 2011a). The short neonatal period (28 days) presents a brief window for study en- rollment and participation. Ethical issues may also complicate enrollment. Especially for parents of a premature or sick newborn, the period after birth is a stressful time. In some cases, very ill newborns may be quickly trans- ferred to hospitals with critical care capacities, resulting in the separation of the newborns from their parents and complications for researchers seeking fully informed parental permission for a child’s participation in research (see, e.g., Nicklin and Spencer, 2004, and Chapter 4). Although some stud- ies with neonates have involved hundreds of neonates, small sample sizes are common, thus limiting the likelihood that less frequent adverse effects of medications or medication interactions will be detected in clinical trials. Moreover, variability within the neonatal population is considerable and can influence the pharmacokinetics, pharmacodynamics, safety, and efficacy of medications. For example, neonates of the same chronological age—as dated from birth—may differ substantially in weight (e.g., from weights of about a barely viable one-half kilogram to more than 6 kilo- grams) and in developmental maturation (e.g., their ability to metabolize and respond to drugs). This variability, which is often a function of gesta- tional age (dated from the first day of the mother’s last menstrual period), can significantly alter how drugs affect and are affected by the body. Chapter 2 emphasized the need to consider gestational as well as chronological age in designing pharmacokinetic and other studies and to be careful about extrapolating from older pediatric populations. For example, in the early 1980s, vitamin E was administered parenterally to premature infants to supplement antioxidant defenses and reduce the risk of throm- bocytosis, hemolytic anemia, and edema. This practice, initiated without systematic prospective evaluation in studies, resulted in 38 deaths (Brion et al., 2003). It remains unclear whether adverse effects resulted from the vitamin E itself, from other components of the product (e.g., polysorbates), or from an unidentified contaminant. Gestational as well as chronological age and other variability among neonates may also affect the feasibility of certain research procedures. For

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143 BPCA, PREA, AND DRUG STUDIES WITH NEONATES example, repeated or relatively large blood draws for research purposes may be safe for larger but not smaller neonates, who could be put at risk of anemia (Proytcheva, 2009). As with any age group, investigators must consider how different disease processes (e.g., systemic infection or cardiac anomalies) may affect the pharmacokinetics, pharmacodynamics, safety, and efficacy of medica- tions used with neonates. Likewise, they must consider how variability in severity, etiology, or other characteristics for the same condition may affect study results. In addition, the exposure of ill neonates to many different medications and therapeutic agents has the potential to create drug-drug and drug-disease interactions that confound study findings. Even more than is the case with other age groups, short- and long-term risks to neonates may not be identified through preclinical testing and rela- tively small, short-term clinical investigations that typically support drug approval for this age group. Possible adverse effects of trial medications on neurological and other aspects of development may not be detectable for months or years. Some have cited this possibility to be a concern in Food and Drug Administration (FDA) assessments of the effects of anesthetics on neonates (Rappaport, 2011c). Questions about the long-term effects of morphine use to relieve pain in neonates (de Graaf et al., 2011) and dexa- methasone, a corticosteroid used to prevent chronic lung disease in preterm newborns, have likewise been raised (see, e.g., Yeh et al., 2004; Lee et al., 2008; and Doyle et al., 2010). Concerns about long-term effects of medication use go beyond neu- rological outcomes. For example, studies are assessing whether certain treatments for premature newborns play a role in the association between prematurity and the development in early childhood of hepatoblastoma, the most common type of liver cancer in children (see, e.g., MCC, 2010; Nishi, 2010). Postmarket reporting and analysis of adverse events can identify some short- and long-term risks that drug trials do not. For example, prompted by postmarket reports of fatalities among neonates, FDA issued alerts and directed revisions in the labeling of the antibacterial agent ceftriaxone (Rocephin and generic versions) to warn that the drug should not be used with neonates who are receiving intravenous medications that contain cal- cium (see Genentech, 2010a). To cite another example, in 2011, after postmarket reports of life- threatening cardiac and other events in premature babies treated with lopinavir-ritonavir (Kaletra) oral solution, FDA revised the product’s label- ing to add a warning against use with infants under 14 days of age (Klein and Struble, 2011). According to the FDA, the risk may be related to the lopinavir, propylene glycol, or ethanol in the drug. The last two substances compete with lopinavir and ritonavir for the same metabolic enzymes, which

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144 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN are known to be immature at birth. The drug had been labeled for use only by infants ages 14 days or over in 2008, but off-label use to treat younger neonates was common (Boxwell, 2011). In addition to underscoring the importance of postmarket safety surveillance, this example also highlights the importance of testing not only medications but also ingredients in the medications that are regarded as inactive (AAP Committee on Drugs, 1997). Medications Commonly Used with Hospitalized Neonates As documented later in this chapter, studies with neonates have con- tributed to relatively few labeling changes that have resulted from studies conducted under BPCA and PREA. Many drugs are used off-label in this age group. Most studies of such use focus on drugs used in neonatal inten- sive care units. They suggest that many if not most medications used in such units have not been studied with this population or at least not studied to the standard required to label the drug for use with neonates. For example, a study of medication use in neonatal care units in the United Kingdom examined whether the medicines used were licensed for use by term or preterm infants and had dosing information in the British National For- mulary for Children for both categories of neonates (Turner et al., 2009). The researchers found that licensing and dosing information was complete for only a quarter of the uses (3,924 uses of 119 different medications) and that 4 percent of uses involved medications that had no licensing or dosing information for term or preterm infants. The therapeutic area most often identified with incomplete information was chronic lung disease. An earlier study performed in the United Kingdom reported that up to 93 percent of neonates in intensive care units received at least one treatment of a medica- tion off-label (Conroy and McIntyre, 2005). Studies conducted elsewhere show a generally similar picture (Jong et al., 2001 [Netherlands]; Barr et al., 2002 [Israel]; O’Donnell et al., 2002 [Australia]; Cuzzolin et al., 2006 [review]; Neubert et al., 2010 [Germany]; Yang et al., 2010 [United States]). Given the large number of neonates who receive intensive care, the potential for harm from the use of medications not studied or incompletely evaluated in studies with neonates needing intensive care is a significant concern. Of the more than 4 million babies born annually in the United States, an estimated 6 percent are admitted to neonatal intensive care units (Osterman et al., 2009). Using data from a large U.S. data set, Table 6-1 shows therapeutics commonly used with neonates admitted to intensive care. Of the 10 most commonly used medications, 6 have some information on dosing in the labeling and 4 do not. One of the medications in the table, caffeine citrate, was the subject of

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145 BPCA, PREA, AND DRUG STUDIES WITH NEONATES TABLE 6-1 Therapeutics Commonly Used in Neonatal Intensive Care Medication % Exposed FDA Labeling for Use with Neonates Ampicillin 74 None Gentamicin 68 Labeled for use (premature and term) Cefotaxime 36 Labeled for use Caffeine [citrate] 19 Labeled for use (28 up to 33 weeks gestational age) Furosemide 19 Safety warnings (premature and term neonates) Vancomycin 17 Dosing (premature and term neonates) Beractant 14 Labeled for use for premature newborns Metoclopramide 11 Cautions Aminophylline 11 Labeled for use (term neonates) Dopamine 10 None (mention of reports) NOTES: If the information on dosing for neonates appears in the dosing and administration section of labeling, the product is categorized as labeled for use in the age group. Dosing- relevant information may also appear in the pharmacology section or elsewhere in the label. Older products tend to have labeling that is less clear and explicit than labeling for more recently approved products. SOURCES: The information in the left and center columns is from Berezny et al. (2011), based on neonatal intensive care unit data from Clark et al. (2006). Labeling information is based on the results of searches at Daily Med (a website with drug labeling information, including for generic medications, sponsored by the National Institutes of Health). a recent report by investigators who described the results at the 5-year point of long-term follow-up of a randomized, placebo-controlled study to de- termine whether use of the drug to treat apnea of prematurity “has lasting benefits or newly apparent risks at early school age” (Schmidt et al., 2012, p. 275). They reported that the early benefits of the therapy diminished as children developed but also that the absence of adverse effects was reas- suring. Further follow-up of the children at ages 11 to 12 years will focus on differences in motor and visual impairment as predictors of academic success. The study, which was funded by the Canadian Institute for Health Research, illustrates the importance of long-term studies of the benefits and risks of neonatal therapies and the importance of public funding for such studies, particularly for long-marketed drugs. Other (not yet published) data on medications used to treat neonates in children’s hospitals show some differences in the rankings of commonly used drugs compared to Table 6-1 (data supplied by Chris Feudtner, Center for Pediatric Clinical Effectiveness, Children’s Hospital of Philadelphia, January 23, 2012; for information about the data set and information about drugs commonly used with older children, see Feudtner et al., 2012). Excluding products such as intravenous fluids, vitamins, hyperalimentation

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146 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN products, heparin flush products, and dextrose water, the most commonly used products included ampicillin, gentamicin, heparin, potassium chlo- ride, acetaminophen, fentanyl, cefotaxime, erythromycin, lidocaine, and morphine. In this listing, the prominence of medications for pain is notable. A recent FDA workshop on clinical trials for pediatric analgesia noted the lack of clear evidence for the efficacy for acetaminophen or nonsteroi- dal anti-inflammatory drugs in neonates (Berde et al., 2012). No fentanyl product is labeled for neonatal use. Labeling for lidocaine hydrochloride injection products is generally vague (recommending merely reduced dos- ing commensurate with age, weight, and physical condition). As described later in this chapter, the National Institutes of Health (NIH) is supporting a study of morphine in the treatment of neonates. DRUG STUDIES WITH NEONATES CONDUCTED UNDER BPCA AND PREA One question for the IOM committee was how to define neonatal as- sessment tools, a term specified but not defined in the statement of task. Were they simply any endpoints used in studies with neonates, or were they composite endpoints involving more than one such measure? Or was something more comprehensive intended? A presentation by FDA at the committee’s first meeting in December 2010 suggested that the term might be defined more broadly than simply alternative endpoints or outcome measures used with neonates (Nelson, 2010). The committee decided to take a broader approach and examined neonatal assessments or studies that were conducted in response to requests under BPCA or requirements under PREA. The committee also considered in more detail three clinical areas that have been the focus of numerous written requests for drug studies that included neonates: HIV infection, bacterial conjunctivitis, and gastroesophageal reflux disease (GERD). Numbers and Origins of Studies with Neonates To assist the IOM, FDA supplied a table of information about products with labeling changes related to neonatal studies that were conducted under BPCA and PREA from July 1, 1998, through December 31, 2010. The ad- dendum to this chapter summarizes this information. FDA created the table from a master list of labeling changes. As explained in Appendix A, that list excluded biologics that are regulated under the Public Health Service Act and that had labeling changes before September 27, 2007. For the period after September 2007, FDA lists no biologics as having labeling changes

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147 BPCA, PREA, AND DRUG STUDIES WITH NEONATES made on the basis of studies with neonates.1 The master list also excludes labeling changes attributable to other policies, for example, the Orphan Drug Act. An example of an orphan drug evaluated in studies with neonates is antihemophilic factor (recombinant) (ReFacto), a biologic. Of the approximately 365 labeling changes that FDA identified for the period from 1998 to 2010 that involved the submission of new pe- diatric studies, only 23 (6 percent) involved the addition of information from studies that included neonates.2 One other product (moxifloxacin [Vigamox]) that was studied with neonates and also older children had a labeling change that did not mention specific results from the studies of neonates. The list provided by FDA also includes four additional products for which labeling changes were not made but for which FDA had granted exclusivity for studies conducted in response to written requests. Three of these requests were for studies of bacterial conjunctivitis in neonates only and involved products that were previously approved for treatment of the condition in children 1 year of age or older. Of the products included in the addendum table (including those for which no labeling change occurred), the requested or required studies of neonates are concentrated in a few therapeutic areas: • Infectious conditions (14 products studied, including 7 for treatment of HIV infection and 4 for treatment of bacterial conjunctivitis) • Gastroenterology (4 products studied, all for treatment of GERD) • Cardiology (3 products studied) • Anesthesia (3 products studied) 1 One product in the FDA list, hydroxyethyl starch (Voluven; a plasma volume expander), is under the regulatory oversight of the Center for Biologics Evaluation and Research, but it was approved in 2007 through a New Drug Application under the Food, Drug, and Cosmetic Act and does not meet the definition of a biologic. Appendix Table D-2, which shows biolog- ics for which pediatric studies have been registered at ClinicalTrials.gov, lists some trials of biologics that are described as including neonates, e.g., bevacizumab (Avastin) for retinopathy of prematurity. These studies may result in future labeling changes. 2 Additional studies with neonates may be under way as a result of written requests under BPCA, but FDA does not make such information public. In FDA’s database for tracking post- market study requirements and commitments, the committee identified examples of required studies that have been deferred for the neonatal age group. (The database can be accessed at http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm. Some of the 339 entries do not note the age groups for deferred studies.) For example, the database lists as “ongoing” a study of difluprednate ophthalmic emulsion (Durezol) 0.05% to treat postoperative inflammation in children 0 to 3 years of age who undergo cataract surgery. To cite another example, a study of the use of tenofovir disoproxil fumarate (Viread) in combination with other antiretroviral agents to treat HIV infection in children from birth to 2 years of age is described as “delayed” pending the completion of safety assessments from studies with children 2 to 18 years of age.

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148 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN For the total of 28 products studied with neonates and listed in the addendum to this chapter, the agency attributed studies for 16 to BPCA alone, 3 to PREA alone, and 9 to BPCA and PREA. For the five products for which neonatal studies had been conducted but no labeling changes based on neonatal studies had been made, all are attributed to BPCA. For the recent period after the reauthorization of BPCA and PREA in September 2007, the Government Accountability Office (GAO) reported that at least 130 products had labeling changes that were linked to the two policies (GAO, 2011) and that 9 (7 percent) of these products were investigated in studies with neonates. For these nine products, seven labeling changes were related to BPCA and two were related to PREA. Overall, BPCA accounts for a larger share of labeling changes involv- ing studies with neonates (48 percent) than is the case for labeling changes across all pediatric age groups (35 percent), and PREA accounts for a much lower percentage (13 percent for the neonatal age group versus 54 percent for all pediatric age groups). For studies attributed by FDA to both BPCA and PREA, the figures are 39 versus 11 percent, respectively. Chapter 7 reports that FDA characterized approximately 66 percent of studies for all the BPCA- and PREA-related labeling changes approved since September 2007 as efficacy studies. Of the 23 products with label- ing changes related to studies with neonates (since July 1, 1998), 14 (61 percent) of the requested or required studies were characterized by FDA as efficacy studies (9 studies) or studies of drug response (5 studies), which reviewers may cite as an indicator of efficacy. All clinical studies, even those that FDA characterizes as pharmacokinetic and pharmacodynamic studies, yield data that FDA evaluates for safety. One complication in identifying studies with neonates conducted under BPCA or PREA involves studies that included neonates in a group that also included older children. Study descriptions do not always make clear how many neonates—if any—were actually included in the study group. In compiling the list of products with labeling changes based on studies with neonates, FDA excluded some products for which a specified study age range included neonates but no neonates were actually enrolled according to the FDA reviews. (For an example, see the review of antihemophilic fac- tor, recombinant [Kogenate FS], a biologic product [Jain, 2008]).3 For other products for which information was not explicit, the inclusion of neonates in studies was inferred from the wording of the reviews or labeling, for 3 FDA also excluded studies for two products in which only one neonate was identified in the relevant study group (albuterol sulfate HFA inhalation aerosol [Ventolin HFA] and omeprazole magnesium [Prilosec]) (personal communication, Catherine Lee, Office of Pediatric Therapeu- tics, FDA, June 17, 2011).

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149 BPCA, PREA, AND DRUG STUDIES WITH NEONATES example, when the indication for use of a product was extended from a lower age of 12 years to a lower age of 14 days. Some of the studies with neonates listed in the addendum involved very small numbers. For example, according to the labeling for the 2004 ap- proval of fenoldopam (Corlopam) for in-hospital, short-term reduction in blood pressure, two neonates were among the 77 children from birth to 12 years of age enrolled for study of the relationship between drug concentra- tion and vital signs (Hospira, 2006). For the study of sotalol hydrochloride (Betapace) for treatment of arrhythmias, a single-dose pharmacokinetic study included two neonates and a multiple-dose pharmacokinetic and pharmacodynamics study included seven (Karkowsky, 2000). In contrast, more than 2,100 preterm neonates were enrolled in the safety and efficacy studies of inhaled nitric oxide (INOmax) for prevention of chronic lung disease (bronchopulmonary dysplasia) (Witzmann, 2010). (Both drugs were studied in response to written requests.) Of the 23 changes in labeling noted in the table in the addendum, al- most half (n = 11) occurred between January 1, 2007, and December 31, 2010.4 For safety and efficacy studies in particular, it frequently takes many years from the time of a request or requirement for a study to be initiated, completed, and analyzed before the results are submitted to and assessed by FDA. For example, for one of the products (clopidogrel [Plavix]) for which neonatal and infant studies were requested and for which a labeling change was approved in May 2011, FDA issued the original written request in 2001 and amended it in 2007 (Behrman, 2001b; Rose, 2010). In some cases, the time span from request to labeling is much shorter because the requested studies were completed prior to the request. For example, FDA issued a written request in April 2010 for a study of nitric oxide (INOmax) and granted exclusivity in November of the same year, with a labeling change following in December 2010 (Witzmann, 2010). Two of the studies for which information was submitted were completed in 2005, and a third study was completed in 2008. Written Requests, PREA Requirements, and Labeling Changes Written Requests Under BPCA In the table supplied by FDA and presented in the addendum to this chapter, studies of 25 of 28 products were associated with written requests under BPCA. As noted above, this group included five products for which 4 In 2011, FDA approved labeling changes for more products for which sponsors submit- ted information from studies with neonates. These products included clopidogrel (Plavix) and esomeprazole intravenous (Nexium).

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150 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN no information from the neonatal studies was added to the product label. Some of the requests specified only a study with neonates (e.g., inhaled nitric oxide [INOmax] for bronchopulmonary dysplasia), whereas others sought studies for children in more than one age group. Although FDA let- ters (particularly recent letters) describe the reasons for waivers of studies required under PREA, written requests typically do not explain the basis for excluding an age group. FDA publishes a list of products (active moieties) for which written requests for study have been issued since 1998, but the list does not identify the age groups or indications included in the request, nor does it identify the requests that have been declined by sponsors. As a result, the commit- tee could not determine how many written requests issued since 1998 had specified studies with neonates, how many such requests had been declined by sponsors, how many initially requested studies with neonates had been eliminated through amendments to requests, or how many requested stud- ies with this age group might be under way or might have been submitted to FDA with no announcement so far of the results of the FDA evaluation. For the period after the reauthorization of BCPA in 2007, GAO re- ported that 3 of the 37 written requests issued by FDA mentioned a study with neonates as an option but not a requirement (GAO, 2011). A fourth request specifically required a study with neonates to meet the terms of the request. The GAO report did not discuss whether the sponsor had accepted or declined the request. In the requests and requirements for studies exam- ined by the committee, the age groups omitted typically were not limited to neonates but covered a broader age range, for example, children less than 6 years of age. One instance of a neonatal study originally requested but then removed involves darunavir (Prezista) for the treatment of HIV, which was the sub- ject of both a BPCA request and a requirement under the Pediatric Rule. The original request issued in 2006 included neonates (Murray, 2006), but the amended request issued in 2007 changed the age range—without comment—to children 3 years of age to adolescence (Murray, 2007). In 2008, a letter approving an expanded indication and new dosing regimen for the product waived required studies for the same age group (Murray, 2008). This letter cited “evidence [from studies with juvenile rats] strongly suggesting that the drug product would be unsafe in this pediatric group” (Murray, 2008, p. 1). In explaining the small number of requests for studies with neonates, FDA officials told GAO that the “neonate population has diseases that are very different from other pediatric populations” (GAO, 2011, p. 41). Another constraint is that many of the drugs frequently used to treat neo- nates were approved many years ago and have no remaining patent life or exclusivity. Thus, the primary incentive under BPCA has no relevance.

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151 BPCA, PREA, AND DRUG STUDIES WITH NEONATES As discussed below, a number of off-patent drugs have been identified as priorities for study under the BPCA program at NIH. Pediatric Rule and PREA Requirements As described in Chapter 3, PREA (and the earlier Pediatric Rule) ap- plies to original or supplemental New Drug Applications (NDAs) and Bio- logics License Applications (BLAs) for approval of a new active ingredient, a new indication, a new dosage form, a new dosing regimen, or a new route of administration, unless FDA has waived or deferred the requirement. The agency can require pediatric studies only for the indication that is the subject of an NDA or BLA submission. Of the 28 products listed in the table in the addendum to this chapter, 12 had studies that were associated with requirements under PREA, although just 3 of these involved a PREA requirement only. The committee found no comprehensive information on the extent to which required pediatric studies have been waived, deferred, or fulfilled for neonates. Of the overall sample of 45 labeling changes that the committee assessed (see Chapter 5), 5 were for products for which FDA had initially deferred studies for age groups that included neonates. Subsequently, FDA released two of the sponsors from the requirements for those studies. One had been for the study of adalimumab (Humira) in the 0- to 4-year-old age group, and the other was for a study of omalizumab (Xolair) in the 0- to 5-year-old age group (Roca, 2008; Gilbert-McClain, 2010). For the products in the overall sample, none of the age groups waived from the requirement for study was limited to neonates. In addition to ju- venile rheumatoid arthritis, conditions for which FDA has waived studies with neonates (among other young children) include autism, neutropenia associated with myelosuppressive anticancer drugs, osteogenesis imperfecta, asthma, migraine, atopic dermatitis, and tonsillitis. In the committee’s sample and in general, FDA’s usual explanation for a waiver (if provided) is that the studies are impractical or impossible be- cause the condition is rare or is not diagnosed in the age group in question (CDER, 2010).5 Supporting data are rarely if ever cited, and prevalence 5 The age groups covered by waivers and the rationales for waivers may vary from decision to decision involving the same indication and similar products. An example can be cited for products to treat autism. In a 2006 letter for one product, FDA waived study requirements for children less than 2 years of age on the grounds that the condition is difficult to diagnose and treat in that age group (Laughren, 2006); in a 2009 letter involving another product, it waived studies with children less than 5 years old on grounds of impossibility or impracticality (Laughren, 2009a). During the period covered by the two actions, FDA began an analysis of the extent to which reasons for waivers of PREA requirements matched the criteria in legisla- tion (CDER, 2010).

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166 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN studied in neonates, but no information from these studies was added to the labeling. The committee could not determine how many additional BPCA- or PREA-related studies with neonates were in some stage of planning or ex- ecution or had been the subject of NDAs or BLAs for which final determi- nations had yet to be made. In its report on BPCA and PREA, GAO noted that FDA lacked a formal mechanism for tracking applications through the submission and review process. It recommended the creation of such a system that would, among other features, include information on pediat- ric studies. If FDA implements such a system, it would be helpful for the system to track pediatric studies by age group, including term and preterm neonates specifically. Although it is difficult to assess the relevant knowledge base at the time that some of the written requests were issued, the committee had some concerns about whether sufficient expertise in neonatology and neonatal pharmacology was brought to bear on some requests, for example, those for bacterial conjunctivitis and GERD. In requesting or requiring studies with neonates, it is important that FDA consider the extent of use of the drug in this population, the state of current knowledge about the diagnosis in neonates, and the availability of valid and reliable endpoints. In addition, it is important for requests and requirements to be informed by current knowledge of the known and unknown safety profiles of a drug’s preserva- tives and other additives (if any) in neonates. Resource constraints at FDA are and will be an issue in many areas, including the provision of appropriate, current expertise in pediatrics gener- ally and in neonatology specifically. If, however, the agency is to request or require studies with neonates, it is important that it have sufficient expertise provided by multidisciplinary staff or consultants to determine the likely health benefit of such studies and to work with sponsors to specify the ap- propriate safety and efficacy endpoints, inclusion criteria, trial design, and other study elements. To the extent that many drugs used to treat neonates are old prod- ucts that have no remaining patent life or exclusivity and that are not the subject of supplemental NDAs or BLAs covered by PREA, the incentives of BPCA and the requirements of BPCA have limited effect. The BPCA program at NIH offers a route for studies of such products with neonates, but proposals for such studies must compete for funding with proposals for studies with other age groups and with proposals considered outside the BPCA program. To date, one study conducted under the auspices of this program has resulted in submission of an NDA, although other studies that may lead to future submissions are under way. Most appear to focus on relatively short-term use, but as noted above, long-term safety studies are also important. To promote more studies of drugs commonly used but

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167 BPCA, PREA, AND DRUG STUDIES WITH NEONATES not adequately evaluated in neonates, one option for Congress is to provide additional resources for short- and long-term neonatal drug studies through the BPCA program at NIH. Finally, the committee recognizes that long-term studies with any age group are difficult to design, fund, and execute. They are a particular con- cern with immature and rapidly developing neonates. Although FDA may in some instances request or require that sponsors conduct such studies of neonates, long-term investigations more likely will depend on collaborative efforts that include NIH, FDA, and academic centers. For short-term ad- verse effects, FDA’s postmarket surveillance system may identify problems, as it did with lopinavir-ritonavir (Kaletra), although it cannot be relied upon to do so in a systematic way. If implemented, recommendations to strengthen the system for long-term safety monitoring and assessment could be expected to improve the identification of safety concerns for neonates.

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ADDENDUM 168 Labeling Changes Based on Neonate Studies Requested Under BPCA or Required Under PREA, July 1998 Through December 2010 Pediatric Trade Name Pediatric Number of Labeling (Generic or Indication(s) Summary of Labeling Change from Studies with Study Exclusivity Neonates Date Proper Name) Studied Neonates (Excluding Other Changes) Origin Date Studied Labeling Change for at Least 1 Pediatric Age Group 1. 12/21/2010 INOmax for Prevention of INOmax is not indicated for prevention of BPD BPCA 11/2/2010 Three inhalation bronchopulmonary trials with in preterm neonates ≤34 weeks of gestational (nitric oxide) dysplasia (BPD) age. 800, 587, Efficacy for the prevention of BPD in preterm and 793 infants was not established in three double- neonates blind, placebo-controlled clinical trials with a total of 2,149 preterm infants. Information on clinical trials, adverse reactions. 2. 11/2/2010 Ofirmev Management of The effectiveness of Ofirmev for the treatment of PREA NA 47 injection mild to moderate acute pain and fever has not been studied in (acetaminophen) pain, management pediatric patients <2 years of age. of moderate to The PK of exposure to Ofirmev observed in severe pain with children and adolescents is similar to that adjunctive opioid observed in adults but is higher in neonates analgesics, and and infants. Dosing simulations from PK data reduction of fever for infants and neonates suggest that dose reductions of 33% in infants 1 month to <2 years of age and 50% in neonates up to 28 days of age, with a minimum dosing interval of 6 hours, will produce a PK exposure similar to that observed in children age 2 years and older. Safety and PK data, dosing, and AE information.

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3. 11/12/2009 Protonix GERD Effectiveness was not demonstrated in a clinical BPCA, 2/17/2009 68 (pantoprazole) trial of patients 1 month to 11 months of age PREA neonates with symptomatic GERD. enrolled; Information on PK, PD in neonates. 59 randomized 4. 8/28/2009 Valcyte Prevention of Efficacy and safety for prevention of CMV BPCA, 7/24/2008 24 (valganciclovir) cytomegalovirus disease after solid organ transplant have not PREA (CMV) disease been established in patients <4 months of age. in pediatric Information on PK, PD in neonates. kidney and heart transplant patients 5. 6/18/2009 Nexium Short-term Effectiveness was not demonstrated in a BPCA, 5/1/2009 26 (esomeprazole) treatment of randomized, placebo-controlled study with PREA GERD neonates to <1 year. Information on clinical study and PK/PD parameters in neonates is included in the label. 6. 10/28/2008 Prevacid Symptomatic Safety and effectiveness have not been established BPCA, 7/15/2008 24 (lansoprazole) GERD in infants in pediatric patients <1 year of age. PREA Information about neonatal clinical trial, PK, safety. 7. 8/28/2008 Zemuron Adjunct to general Expanded pediatric indication to include children BPCA, 4/3/2008 18 ITT for (rocuronium) anesthesia ages 0 to 17 years. Previously approved for use PREA study 1; by children ages 3 months to 14 years. 10 ITT for The time to maximum block for an intubating study 2 dose was shortest in infants and longest in neonates. The duration of clinical relaxation following an intubating dose is shortest in children ages >2 years to 11 years and longest in infants. Additional information on safety, dose, PK/PD 169 parameters, and other details. continued

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ADDENDUM Continued 170 Pediatric Trade Name Pediatric Number of Labeling (Generic or Indication(s) Summary of Labeling Change from Studies with Study Exclusivity Neonates Date Proper Name) Studied Neonates (Excluding Other Changes) Origin Date Studied 8. 7/29/2008 Cancidas Empirical therapy The efficacy and safety of Cancidas have not BPCA, 4/15/2008 18 (caspofungin) for presumed been adequately studied in prospective clinical PREA fungal infections trials involving neonates and infants less than 3 in febrile, months of age. Although limited PK data were neutropenic collected from neonates and infants less than patients; 3 months of age, these data are insufficient candidemia and to establish a safe and effective dose of certain Candida caspofungin for the treatment of neonatal infections; candidiasis. Invasive candidiasis has a higher esophageal rate of CNS and multiorgan involvement in candidiasis; neonates than in older patients. and invasive aspergillosis in patients who are refractory to or intolerant of other therapies 9. 6/24/2008 Viramune Use in Dosing information provided for children ages PREA NA Not tablets, 200 mg combination with >15 days to <16 years. specified Viramune oral other antiretroviral Safety was evaluated in children ages 2 weeks suspension, 10 agents for the and older in five clinical trials. Important mg/mL treatment of HIV-1 adverse events (all causality) include rash (nevirapine) infection (21%), neutropenia (8.9%), anemia (7.3%), and hepatotoxicity (2.4%). Safety and pharmacokinetics were evaluated in HIV-infected pediatric patients ages 15 days to <3 months.

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10. 6/20/2008 Kaletra Use in The safety, efficacy, and PK profiles have not BPCA, 3/7/2008 Not (lopinavir/ combination with been established in pediatric patients <14 days. PREA specified ritonavir) other antiretroviral Dose should be calculated on the basis of body agents for HIV-1 weight or BSA so that it does not exceed the infection adult dose. Infants <6 months of age generally had lower lopinavir AUC12 values than children 6 months to 12 years of age. Other information on clinical studies and AEs. 11. 12/27/2007 Voluven Plasma volume Limited clinical data on the use of Voluven in PREA NA Not (6% substitute for children are available. In 41 children, including specified hydroxyethyl treatment and newborns to infants (<2 years), a mean starch 130/0.4 prophylaxis of dose of 16 ± 9 mL/kg of body weight was in 0.9% hypovolemia administered. The dosage in children should sodium chloride be adapted to the individual patient’s colloid injection) needs, taking into account the disease state, as well as the hemodynamic and hydration status. 12. 12/22/2006 Emtriva HIV-1 infection in Efficacy in preventing or treating HIV infection BPCA 5/24/2006 22 (emtricitabine) combination with in neonates to age 3 months could not be other antiretroviral determined after a PK study with 20 neonates agents born to HIV-positive mothers. Information on dose in neonates 0 to 3 months of age, additional safety and PK parameters. 13. 5/12/2005 Zyvox CNS infections Use of linezolid for the empirical treatment of BPCA 2/11/2005 42 (linezolid) pediatric patients with CNS infections is not completed recommended. Additional information on efficacy in pediatric patients with infectious vancomycin-resistant Enterococcus faecium is provided. PK studies, dosage, AE. 171 continued

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ADDENDUM Continued 172 Pediatric Trade Name Pediatric Number of Labeling (Generic or Indication(s) Summary of Labeling Change from Studies with Study Exclusivity Neonates Date Proper Name) Studied Neonates (Excluding Other Changes) Origin Date Studied 14. 4/1/2004 Corlopam Indicated for Indicated for in-hospital, short-term (up to 4 BPCA NA At least 2 (fenoldopam) in-hospital, short- hours) reduction in blood pressure in pediatric term reduction in patients ages <1 month (weight at least 2 kg) blood pressure to 12 years. 15. 3/19/2004 Viracept HIV-1 infection A reliably effective dose was not established for BPCA, 9/4/2003 31 (nelfinavir) patients <2 years of age. PREA Two studies with infants less than 12 weeks old looking at PK and safety. 16. 3/8/2004 Ultiva Maintenance of Safety and efficacy for the maintenance of BPCA, 3/15/2000 8 in PK (remifentanil) anesthesia anesthesia were established for patients from PREA study; birth to 1 year of age. other not Recommended dosing guidelines for maintenance specified of anesthesia were established for patients from birth to age 2 months. The clearance rate observed in neonates was highly variable: approximately two times higher than that in young healthy adults. 17. 4/15/2003 Vigamox Bacterial None specifically from studies with neonates. BPCA 1/10/2003 209 (moxifloxacin) conjunctivitis 18. 10/8/2002 Epivir HIV infection Lamivudine clearance was substantially reduced BPCA 9/22/2000 Not (lamivudine) in 1-week-old neonates relative to pediatric specified patients >3 months of age. Two safety and PK trials with neonates and some information on AE.

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19. 6/6/2002 Pepcid Gastroesophageal Labeling for patients less than 1 year of age was BPCA 11/21/2000 10 (famotidine) reflux disease provided, including information on dose, PK/ PD parameters, and AE profile. Lower dose recommended in patients <3 months of age. Some data on PK and dosing studies with neonates. 20. 4/1/2002 Videx HIV infection Safety and effectiveness were established down to BPCA 8/13/2001 8 (didanosine) 2 weeks of age. Dosing information for children between 2 weeks and 8 months of age. 21. 3/29/2002 Zerit HIV infection Safety and effectiveness were established down BPCA 8/13/2001 8 (stavudine) to birth. A dose for newborns from birth to 13 days was established. Description of clinical trial with newborns. 22. 10/1/2001 Betapace Arrhythmia Analysis of two trials provided information on BPCA 1/6/2000 2 (study 1) (sotalol) PK and PD in children ages 3 days to 12 years; 7 (study 2) safety and efficacy not established. Information on dose. Pharmacokinetics: BSA was the most important covariate and more relevant than age. Smaller children (BSA <0.33 m2) showed a tendency for larger change in QTc interval and increased frequency of prolongation of the QTc interval as well as greater beta-blocking effects. Individualized dosing on a mg/m2 basis. continued 173

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ADDENDUM Continued 174 Pediatric Trade Name Pediatric Number of Labeling (Generic or Indication(s) Summary of Labeling Change from Studies with Study Exclusivity Neonates Date Proper Name) Studied Neonates (Excluding Other Changes) Origin Date Studied 23. 3/30/2001 Ultane Induction and New study with pediatric patients ages 9 days to BPCA 8/2/2000 At least 3 (sevoflurane) maintenance of 12 years compared sevoflurane and halothane. general anesthesia No specific data for neonates in the clinical trial information. 24. 10/22/1999 Zantac Gastroesophageal Small studies with newborns ages 0 to 1 month BPCA 1/19/1999 12 (ranitidine) reflux receiving ECMO did not demonstrate efficacy but provided information on dose and PK. No Labeling Change for Any Age Group 25. NA Angiomax Anticoagulant None BPCA 6/17/2009 10 (bivalirudin) in pediatric patients during percutaneous intravascular procedures for management of congenital heart disease 26. NA Zymar Bacterial None BPCA 5/19/2009 171 (gatifloxacin) conjunctivitis 27. NA Ciloxan Bacterial None BPCA 1/10/2003 209 (ciprofloxacin) conjunctivitis

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28. NA Ocuflox Bacterial None BPCA 3/12/2003 173 (ofloxacin) conjunctivitis NOTES: Twenty-eight products were evaluated: 23 with labeling change and 5 with no labeling change related to studies with neonates. Abbreviations: AE = adverse events; AUC12 = area under the concentration-time curve from time zero to 12 h; B = BPCA; BSA = body surface area; CNS = central nervous system; ECMO = extracorporeal membrane oxygenation; ITT = intent to treat; NA = not applicable; P = PREA; PK = pharmacokinetics; PD = pharmacodynamics; R = Pediatric Rule. SOURCE: Summarized from a compilation supplied by FDA. Except for the last four products listed, most of the information is taken from a table accessible online at http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/UCM163159.pdf. Data on number of neonates studied is from the product’s label or from posted FDA summary reviews (2003 to 2008) or FDA clinical or clinical pharmacology reviews (from September 27, 2007). 175

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