National Academies Press: OpenBook
« Previous: 5 Safety and Efficacy Assessments in Studies Conducted Under BPCA and PREA
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 enrollment 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 transferred 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 studies 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 kilograms) and in developmental maturation (e.g., their ability to metabolize and respond to drugs). This variability, which is often a function of gestational 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 thrombocytosis, 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 medications 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 relatively 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 dexamethasone, 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 neurological 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 calcium (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 labeling 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 contributed 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 intensive 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 Formulary 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 medication 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 determine 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 reassuring. 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

products, heparin flush products, and dextrose water, the most commonly used products included ampicillin, gentamicin, heparin, potassium chloride, 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 nonsteroidal 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 dosing 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 assessment 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 addendum 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 pediatric 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)

images

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 biologics 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 postmarket 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.

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 involving 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 labeling 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 factor, 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

images

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 Therapeutics, FDA, June 17, 2011).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 approval 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 concentration 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, almost 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

images

4 In 2011, FDA approved labeling changes for more products for which sponsors submitted information from studies with neonates. These products included clopidogrel (Plavix) and esomeprazole intravenous (Nexium).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 letters (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 committee 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 studies 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 reported 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 examined 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 subject 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 neonates were approved many years ago and have no remaining patent life or exclusivity. Thus, the primary incentive under BPCA has no relevance.

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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) applies to original or supplemental New Drug Applications (NDAs) and Biologics 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 juvenile 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 because 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

images

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 legislation (CDER, 2010).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

data for neonates (and other pediatric subgroups) may not, in fact, be available in many cases. In the view of the committee, the conditions cited in the preceding paragraph are rare or are not diagnosed in children less than 1 month of age. In discussions with GAO staff, FDA officials explained that the conditions subject to PREA requirements were often conditions “typically applicable to adults and older pediatric populations that would not apply to neonates” (GAO, 2011, p. 40).

By consulting the FDA tracking database for postmarket study requirements and commitments, the committee found recent examples of deferred studies for neonates. For example, in approving rilpivirine (Edurant) for treatment of HIV infection in treatment-naïve adults, FDA deferred required pediatric studies of safety and antiviral activity in children from birth up to 12 years and from 12 up to 18 years (Cox, 2011). In deferring pharmacokinetic, safety, and efficacy studies of ondansetron (Zuplenz) for treatment of postoperative nausea and vomiting in children 0 to 17 years of age, FDA noted that an age-appropriate formulation must be developed for younger patients (Griebel, 2010).

Explanations for deferred studies may note special issues involving neonates. In one recent approval of the continued marketing of an old, previously unapproved oxycodone product, FDA deferred studies with the pediatric population. The summary review for the action stated that knowledge about “the site of action of oxycodone and … the developmental maturity of the mu opioid receptor” would allow extrapolation of efficacy for children more than 2 years of age, but efficacy studies for ages 0 to 2 years were necessary (Hertz, 2010b, pp. 6–7).

At least one recent approval letter—for the drug ceftaroline fosamil (Teflaro) for the treatment of bacterial skin infections and community-acquired pneumonia—reflected the consideration of gestational as well as chronological age. It specified PREA requirements for a pharmacokinetic study with five pediatric-age cohorts within the overall age group from birth up to 12 years (Cox, 2010). One of these cohorts was term neonates (stratified by ages 0 to 14 days and 15 up to 28 days), and another was preterm neonates (with the same stratification).6

The committee also found several recent examples of waivers of required studies for the neonatal age group. For a combination hydrocodone and pseudoephedrine product (Rezira) for the treatment of colds and coughs, FDA explained the waiver for neonates on the grounds that hydrocodone poses a risk of fatal respiratory depression in this age group (Chowdhury, 2011). In waiving studies for children less than 6 years of age

images

6 Requirements also included a cerebrospinal fluid concentration trial with at least 12 infants less than 2 months of age as well as separate randomized trials for two infectious conditions with children less than 17 years of age (with no age subgroups specified).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

for a sublingual formulation of fentanyl (Abstral) for breakthrough pain for cancer patients, FDA explained that studies would not be feasible because too few children in this age group could use the product appropriately (Rappaport, 2011a). Although data cited earlier show that the drug is frequently used to treat pain in neonates, no fentanyl products are approved for use with neonates (personal communication, Division of Anesthesia, Analgesia, and Addiction Products, FDA, January 23, 2012). Other recent waivers of studies with neonates involved conditions such as schizophrenia, anal fissures, plaque psoriasis, type 2 diabetes, depression, restless leg syndrome, breakthrough cancer pain, insomnia, eradication of Helicobacter pylori infection, hepatitis C, and partial onset seizures.

On the basis of its selective review of recent deferral and waiver decisions, the committee has the impression that the agency is more carefully considering the rationale for requiring studies with neonates than was the case in earlier periods, a development that may reflect the involvement of the Pediatric Review Committee (PeRC) as described in Chapter 3. This consideration may include more careful assessment of claims that studies are impractical or impossible because the condition is rare in neonates.

Labeling Changes Resulting from Studies with Neonates

Overall, most of the requested or required studies with neonates did not lead to labeling of the product as safe and effective for use with neonates. For the majority of products, the labeling changed to include some information (e.g., pharmacokinetic data) from the studies, but for five products, as noted earlier, no substantive information from the studies with neonates was included in the labeling. Four of these studies were for bacterial conjunctivitis. For two of these three products with approvals prior to the reauthorization of BPCA in 2007, neither the written requests nor the FDA clinical reviews are public, although as required in 2002, FDA posted brief summaries (less than two pages) of the reviews. Consistent with requirements in the reauthorization of BPCA in 2007, FDA now must make public certain information for products approved after 2007 with exclusivity and no labeling change (see Chapter 3).

Box 6-1 provides examples of the kinds of labeling changes that provided information about the studies conducted with neonates. Some of the examples of labeling changes also illustrate ambiguous or unusual situations. The first example listed involves a study that the FDA clinical reviewer criticized and believed did not fairly meet the terms of the written request, although FDA subsequently decided to grant exclusivity. The second example involves a product for which FDA accepted extrapolation of efficacy in the treatment of acute pain in children ages 2 years and older but required, under PREA, a “randomized, double-blind, adequately controlled

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

BOX 6-1
Examples of Labeling Changes with Information Based
on BPCA-or PREA-Related Neonatal Studies

Clopidogrel bisulfate (Plavix) (NDA 020839/051) (BPCA)

Excerpt from labeling for a change approved in 2011: “Safety and effectiveness in pediatric populations have not been established. A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.” (Sanofi-Aventis, 2011, p. 3)

Acetaminophen (Ofirmev injection) (NDA 022450) (PREA)

Excerpts from labeling for a change approved in 2010: “A total of 355 pediatric patients (47 neonates, 64 infants, 171 children, and 73 adolescents) have received OFIRMEV in active-controlled (n = 250) and open-label clinical trials (n = 225).… The maximum exposure was 7.7, 6.4, 6.8, and 7.1 days in neonates, infants, children, and adolescents, respectively.… The safety and effectiveness of OFIRMEV for the treatment of acute pain and fever in pediatric patients ages 2 years and older is [sic] supported by evidence from adequate and well-controlled studies of OFIRMEV in adults. Additional safety and pharmacokinetic data were collected in 355 patients across the full pediatric age strata, from premature neonates (≥32 weeks post menstrual age) to adolescents. The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients <2 years of age.… Dosing simulations from pharmacokinetic data in infants and neo-nates suggest that dose reductions of 33% in infants 1 month to <2 years of age, and 50% in neonates up to 28 days, with a minimum dosing interval of 6 hours, will produce a pharmacokinetic exposure similar to that observed in children age 2 years and older.” (Cadence Pharmaceuticals, 2010, unpaged)

Rocuronium bromide (Zemuron) (NDA 20214/030) (BPCA)

Excerpts from labeling for a change approved in 2008: “The recommended initial intubation dose of ZEMURON is 0.6 mg/kg, however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient….

study of efficacy, pharmacokinetics and pharmacodynamics” for children less than 2 years of age (Hertz, 2010a, p. 3). Although the dosing and indications section of the label associated with that approval does not include information on dosing for that age group, the pharmacokinetic section of the label does include such information (Cadence Pharmaceuticals, 2010). The review memoranda show considerable amounts of redacted text; it is possible that this text discusses the 47 neonates studied (out of 355 children

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.… The infusion of ZEMURON must be individualized for each patient.… ZEMURON was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG [electrocardiographic] data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents can prolong the QTc interval. The data also suggest that ZEMURON may increase heart rate. However, it was not possible to conclusively identify an effect of ZEMURON independent of that of anesthesia and other factors.” (Teva Pharmaceuticals, 2008, unpaged)

6% Hydroxyethyl starch (Voluven) (NDA 70012/000) (PREA)

Excerpt from labeling for a change approved in 2007: “Limited clinical data on the use of Voluven® in children are available. In 41 children including newborns to infants (<2 years), a mean dose of 16 ± 9 mL/kg was administered. The dosage in children should be adapted to the individual patient colloid needs, taking into account the disease state, as well as the hemodynamic and hydration status. The safety and efficacy of Voluven® have not been established in the age group of 2 to 12 years. Use of Voluven® in children >12 years is supported by evidence from adequate and well-controlled studies of Voluven® in adults and by data from children <2 years old.” (Hospira, 2007, p. 4)

Emtricitabine (Emtriva) (NDA 21896/001) (BPCA)

Excerpts from labeling for a change approved in 2006: “The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg QD × 4 days) during the first 3 months of life. Emtricitabine exposures in neonates were similar to the exposures achieved in patients >3 months to 17 years.… During the two short dosing periods on emtricitabine there were no safety issues identified in the treated neonates. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV could not be determined.” (Gilead Sciences, 2008, p. 11)

overall) and provides the rationale for the labeling (Fang, 2009; Spaulding, 2009).

For the third product listed in Box 6-1, the 2008 labeling change for rocuronium bromide (Zemuron) came almost 10 years after the sponsor’s initial proposal for a written request but shortly after the final amendment to the written request. That amendment reduced the number of neonates to be included in the pharmacodynamic study based on the conclusion that

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

study of an additional two neonates would not affect the judgment that each patient would require individual monitoring for the product to be used safely (Schultheis and Roca, 2008).

Examples of Successful and Unsuccessful Studies

Given the several trials with neonates that failed to provide evidence of efficacy or even information for labeling, the committee attempted to identify factors that might be associated with such failures. It examined the trials of drugs for the prevention or treatment of HIV infection in neonates that led to labeling changes (including several with labeling for neonatal use) and compared their characteristics with those of the trials of drugs to treat bacterial conjunctivitis and GERD. All the studies were requested under BPCA.

Studies with Neonates Leading to Important Labeling Changes: HIV Infection

By December 31, 2010, seven requested studies of products to treat HIV infection in neonates had led to the addition of information to product labeling. Four drugs were labeled for use with neonates (one starting at birth and three starting at about 2 weeks of age) (Table 6-2). For the other three drugs, the labeling changes included pharmacokinetic and other information. As noted earlier, FDA recently warned explicitly against the (off-label) use of lopinavir-ritonavir (Kaletra) with neonates less than 14 days of age. In addition, the committee understands that although didanosine (Videx) is labeled for neonatal use, concerns about toxicity limit its use with that age group.

At the time that the requests were issued (as early as 1999), pediatric studies of HIV infection had several advantages compared with the studies for bacterial conjunctivitis and GERD. These included reasonably straightforward diagnostic criteria and procedures and validated surrogate endpoints, notably, measures based on the HIV-1 RNA viral load. Most neonatal studies included such measures, although a working group had advised that the course of the disease was similar in adults and children and, thus, that efficacy could be extrapolated with requirements for additional information on pharmacokinetics and safety (Working Group, 2003). Some clinical reviews reported data on activity.

In 2003, the Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee discussed the evaluation of antiretroviral drugs in studies with neonates and concluded that FDA should continue to request pharmacokinetic and safety studies for every such drug approved, assuming that the studies were ethical and promised a public health benefit (PAS/AIDAC, 2003). It also advised that decisions about written requests should take into account bioavailability, tolerable toxicity, and the availability of an appropriate formulation.

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

TABLE 6-2 Labeling Changes for Drugs for Treatment of HIV Infection from Studies That Included Neonates


Agent     Ages
Studied
    Labeling Information (year)

Nevirapine (Viramune)     ≥15 days–3 months     Indicated for ages >15 days (2008)
Lopinavir-ritonavir (Kaletra)     ≥14 days–6 months     Indicated for ages ≥14 days (2008)
Emtricitabine (Emtriva)     0–3 months     Safety, PK,a dosing, but not efficacy (2006)
Nelfinavir (Viracept)     Birth–13 years     PK from birth to 13 years; no reliable data for dosing for ages <2 years (2004)
Lamivudine (Epivir)     ≤1 week     Reduced clearance in 1-week-old neonates; insufficient information for dosing; limited safety information (2002)
Didanosine (Videx)     2 weeks–8 months     Indicated for ages ≥2 weeks (2002)
Stavudine (Zerit)     Birth–13 days     Indicated for all ages (2002)

   a PK = pharmacokinetics.

   SOURCES: Product labels and FDA clinical reviews.

Studies with Neonates Resulting in No Labeling Change: Bacterial Conjunctivitis

In contrast to the studies of HIV infection, none of the requested neonatal studies of four products for the treatment of bacterial conjunctivitis resulted in the addition of information to product labeling. Clinical reviews and written requests are available for two of these products, moxifloxacin (Vigamox) and gatifloxacin (Zymar), although some information in the reviews is redacted. The written requests were nearly identical. Neither the requests nor the reviews discussed dacryostenosis as a confounding diagnosis or differences in microbiology between conjunctivitis in neonates and older children.

For moxifloxacin (Vigamox), although FDA’s clinical review describes a study with neonates (Hubbard and Chambers, 2003), the 2003 labeling change merely noted that safety and efficacy had not been established for

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

children less than 1 year of age; it did not include any information from the neonatal study. For gatifloxacin (Zymar), the study of neonates as conducted used moxifloxacin as an active comparator. The reviewer stated that evidence of superiority was expected, but the study showed lower efficacy (i.e., the percentage of subjects whose study eye achieved a score of zero for conjunctival erythema and conjunctival discharge at day 7 of the study was lower) (Nevitt, 2009). The reviewer’s summary and risk-benefit assessment were redacted. Again, no information from the study, for which pediatric exclusivity was granted in 2009, was added to the label.

For the other two products studied with neonates, ciprofloxacin (Ciloxan) and ofloxacin (Ocuflox), FDA has made available only brief summaries of the studies submitted. Both products were granted pediatric exclusivity in 2003 before Congress required that clinical and other reviews and written requests be made public following a grant of exclusivity.7 For studies that did not lead to a labeling change and for which clinical and other reviews are not available, knowledge is advanced only to the extent that study results are reported—accurately and fully—in the scientific literature. Given concerns about publication bias in industry-sponsored trials, access to the full FDA reviews and redacted text would assist with the evaluation of any published studies.

Although they are not entirely consistent, recent FDA approvals of other products for bacterial conjunctivitis suggest that FDA has changed its views about the nature of this infection in neonates. In each recent case, FDA waived required studies for this age group. For example, in 2010, when FDA approved moxifloxacin hydrochloride (Moxeza) for the treatment of bacterial conjunctivitis in patients 4 months of age and older, it waived pediatric study requirements for ages 0 to 1 month “because the disease does not exist in that age group” (Chambers, 2010, p. 2). (The product is a different formulation of Vigamox, one of the four products discussed above.)

In 2009, in approving besifloxacin ophthalmic suspension (Besivance), a new chemical entity, FDA waived studies with neonates because “ophthalmia neonatorum, a related but different condition, affects children under 1 month of age” (Cox, 2009). Nonetheless, FDA lists a written request as having been issued for besifloxacin (the date and other details are not publically available). In addition, ClinicalTrials.gov (a clinical trials registration

images

7 The sponsors refused FDA’s request that they allow the clinical and other reviews to be made available to the IOM (personal communication, Catherine Lee, Office of Pediatric Therapeutics, FDA, May 19, 2011, and July 23, 2011). FDA has concluded that the law precludes public disclosure of written requests and FDA reviews when a product had no labeling change and the pediatric studies were conducted and exclusivity was granted before the 2007 reauthorization of BPCA (personal communication, Robert Nelson, Office of Pediatric Therapeutics, FDA, March 31, 2011).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

database that is described further in Chapter 8) lists a trial registered by the product’s sponsor in April 2011 that was recruiting neonates for a randomized, double-blind study to evaluate the safety and efficacy of the product compared to gatifloxacin for treatment of bacterial conjunctivitis (ClinicalTrials.gov identifier: NCT01330355). FDA does not comment on trials under way, but this trial—if related to a written request—would seem to be inconsistent with FDA’s recent statements and waivers.

The recent waivers of studies of bacterial conjunctivitis in neonates may reflect recognition of the microbiological and other differences between bacterial conjunctivitis in neonates and older children. Alternatively or in addition, the decisions may reflect the availability of additional pediatric expertise in the review of potential requests or requirements for studies with neonates. Although the details are not available to the committee, this condition was the subject of a consultation with FDA’s pediatric ethicists (personal communication, Robert Nelson, Office of Pediatric Therapeutics, FDA, August 10, 2011).

Studies of GERD in Neonates and Changes in Agency Thinking

Like the studies of bacterial conjunctivitis, the requested studies of four proton pump inhibitor (PPI) products for the treatment of GERD in neonates have yielded little labeling information specific to neonates, and studies of PPIs have also not shown the products to be effective for infants ages 1 month up to 1 year. For older pediatric age groups, requested trials have supported labeling for pediatric use, with the exception of one product (pantoprazole) that was not labeled for use by children up to 5 years of age because of concerns about the formulation used for that age group (Griebel, 2009).

The products for which FDA issued written requests for studies with neonates were omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium), and pantoprazole (Protonix). (The requests also sought studies with older age groups.) The efficacy study for the first of these products included only one neonate (Korvick, 2008); it was excluded by FDA from its table of studies with neonates and was likewise excluded from this analysis. A written request for a fifth product, rabeprazole (Aciphex), is not public, but a pharmacokinetic, pharmacodynamic, and safety trial of this product with newborns is registered at ClinicalTrials.gov and is described as recruiting participants (ClinicalTrials.gov identifier: NCT00855361).

The studies of PPIs in neonates and infants less than 12 months of age illustrate a dilemma for FDA when clinicians disagree both about the occurrence of GERD in these children and about how to evaluate whether treatment with PPIs is effective (if the condition exists). In 2002, experts in neonatology and pediatric gastroenterology met at a meeting sponsored by

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

the Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee but could not agree on how to measure GERD or how to study PPIs in newborns and infants (PAS/AIDAC, 2002). Despite an early lack of agreement among neonatologists and pediatricians about the condition and its treatment, prescriptions for PPIs for infants less than 12 months of age increased fourfold from 1999 to 2004 (Barron et al., 2007).

As early as 1999, FDA concluded that study of the pharmacokinetics and pharmacodynamics of PPIs in all pediatric age groups was appropriate and began to issue written requests for pediatric studies. Pediatric gastroenterologists and FDA staff agreed that GERD in infants was different from the condition in older age groups, so the efficacy of PPIs determined from studies with adults could not be extrapolated to infants (see the discussion of the 2000 symposium on pediatric GERD in Gallo-Torres, 2002). Compared with older infants and children, biopsies of inflamed areas of the esophagus and esophagogastroduodenoscopy are seldom, if ever, used for diagnosis of the condition in newborns. Acid reflux is frequently measured by pH probes in the esophagus, but all babies reflux and spit up to some degree. Moreover, acid reflux is not the same as GERD, although it can lead to GERD. When acid reflux leads to GERD with inflammation and pain, babies cannot report their symptoms. Instead, clinicians or researchers rely on reports from parents (or on investigator observation) of crying, irritability, emesis, arching of the back, and refusal to feed both to diagnose presumed GERD and to measure response to acid suppression.

The committee reviewed written requests for studies of three PPIs to treat GERD in newborns and infants less than 12 months of age. They are nearly identical (for a description of the template, see Gallo-Torres, 2002). The requests were for one study of pharmacokinetics and pharmacodynamics in neonates and a second study of efficacy.8 Both types of studies were also to assess safety. The pharmacodynamic and safety component of the first study was specifically to include measures of apnea and bradycardia. Later amendments dropped the requested studies of efficacy in neonates.

The studies with neonates were first requested from 1999 to 2001, and information from the studies was added to the labels in 2008 or 2009, after completion of the studies. The submitted studies did not show a difference in the signs of GERD between neonates who were continued on the drug and neonates who were not. The pharmacodynamic studies showed that the doses used decreased gastric acid production and raised gastric pH.

images

8 In addition to symptom assessments, the initial written requests required measurement of gastric secretion with aspiration of gastric acid every 30 minutes for 6 hours. They also required measurement of the frequency of obstructive apnea; several studies of apnea and reflux show a very low correlation between this measure and other measures of GERD (Peter et al., 2002; Molloy et al., 2005; Mousa et al., 2005; Di Fiore et al., 2010).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

The clinical reviews did not identify unexpected adverse events in neonates, although the reviews did not always specifically describe safety findings for this age group.

Currently, no PPI is labeled as being effective for treatment of neonates or infants less than 12 months of age. Labels do include brief information from the studies with neonates but do not refer specifically to safety findings for this age group. Two labels state that use by children less than 1 year of age is not indicated. One says that the product is not indicated for use by children 1 month to 1 year of age but does not explicitly mention the younger age group (Box 6-2).

A recent review concluded that although these drugs were frequently used, none “has strong evidence for efficacy in decreasing the complications of reflux in preterm infants or term neonates” and, further, that “a few well-conducted, masked, randomized studies that have accounted for maturational changes in their design have raised concerns about the safety of these medications in infants” (Hibbs, 2011, p. e159).

FDA reported that the numbers of new patient prescriptions for all PPIs in the 0-to 1-year-old age group increased from 38,000 in 2002 to 404,000 in 2009 (Green and Moeny, 2010). At a 2010 meeting of the FDA Gastrointestinal Drugs Committee, the focus was mostly on studies of GERD in infants 1 month of age and older. However, the meeting summary states that with respect to neonates, the “committee members remarked that this population is unique and the existing PK [pharmacokinetic] and PD [pharmacodynamic] data are not applicable to this subset” (GIDAC, 2010, p. 6). Some of the comments about older infants are relevant to neonates, for example, comments noting the varied etiology of symptoms and diversity of subpopulations (e.g., infants with cystic fibrosis, erosive esophagitis, or underlying neurological disorders). Continued scientific investigation may help resolve or inform continuing debate about this condition in neonates.

Comment

The studies of drugs for the treatment of HIV infection, bacterial conjunctivitis, and GERD in neonates illustrate situations and factors that appear to promote productive clinical studies, including studies of efficacy, in this age group. Such factors, which were present for the HIV infection studies and absent for the others, include (1) clarity and agreement about the nature of the condition to be studied; (2) valid, reliable, and practical methods to diagnose the condition in neonates and account for the heterogeneity of the population; and (3) valid and reliable endpoints for studies of response or efficacy.

The studies also illustrate how long it can take for requested or required studies to be completed and result in labeling changes that can

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

BOX 6-2
Current Labeling of PPIs: References to Neonates and Infants

Lansoprazole (Prevacid) (2008 labeling change): “The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and 1 to 11 months. Compared to healthy adults receiving 30 mg, neonates had higher exposure (mean weight-based normalized AUC [area under the concentration-time curve] values 2.04-and 1.88-fold higher at doses of 0.5 mg/kg/day and 1 mg/kg/day, respectively. Infants aged10 weeks had clearance and exposure values that were similar to neonates.… PREVACID was not effective in patients with symptomatic GERD 1 month to less than 1 year of age in a multicenter, double-blind, placebo controlled study” (emphasis added). (Note that earlier labeling changes had extended the indication from adults to older children.)

Pantoprazole (Protonix) (2009 labeling change): “In a population pharmacokinetic analysis, the systemic exposure was higher in patients less than 1 year of age with GERD compared to adults who received a single 40 mg dose (geometric mean AUC was 103% higher in preterm infants and neonates receiving single dose of 2.5 mg of PROTONIX, and 23% higher in infants 1 through 11 months of age receiving a single dose of approximately 1.2 mg/kg). In these patients, the apparent clearance (CL/F) increased with age (median clearance: 0.6 L/hr, range: 0.03 to 3.2 L/hr). These doses resulted in pharmacodynamic effects on gastric but not esophageal pH. Following once daily dosing of 2.5 mg of PROTONIX in preterm infants and neonates, there was an increase in the mean gastric pH (from 4.3 at baseline to 5.2 at steady-state) and in the mean % time that gastric

inform clinical decision making. In the interim, off-label use can become substantial, as has been reported for the PPIs.

Without additional historical analysis, it is difficult to appreciate the extent of relevant knowledge of bacterial conjunctivitis and GERD in neonates at the time that the studies of these conditions were requested and initiated. Nonetheless, greater internal or consulting expertise in neonatal pharmacology and neonatal medicine at FDA might have averted the initiation of some studies of limited value by pointing out issues of toxicity, population heterogeneity, uncertainties about diagnostic criteria, and disagreement about appropriate study endpoints and asking whether a health benefit could be expected from continuing to request such studies.

The 2011 report from GAO noted criticism that FDA lacked sufficient expertise in the assessment of studies with neonates, particularly neonates who are seriously ill (GAO, 2011). It reported that the PeRC included one neonatologist among its 40 members and that FDA had three other neonatologists in the review divisions at the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, but it did not

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

pH was >4 (from 60% at baseline to 80% at steady-state). Following once daily dosing of approximately 1.2 mg/kg of PROTONIX in infants 1 through 11 months of age, there was an increase in the mean gastric pH (from 3.1 at baseline to 4.2 at steady-state) and in the mean % time that gastric pH was >4 (from 32% at baseline to 60% at steady-state). However, no significant changes were observed in mean intraesophageal pH or % time that esophageal pH was <4 in either age group.… Because PROTONIX was not shown to be effective in the randomized, placebo-controlled study in this age group, the use of PROTONIX for treatment of symptomatic GERD in infants less than 1 year of age is not indicated” (emphasis added). (Note that this labeling change extended the indication from adults to individuals aged 5 years and also explained that safety and efficacy were supported for ages 1 up to 5 years but that no suitable formulation was available for patients less than 5 years of age.)

Esomeprazole (Nexium) (2009 labeling change): “The following pharmacokinetic and pharmacodynamic information was obtained in pediatric patients with GERD aged birth to less than one year of age. In neonates (<1 month old) given NEXIUM 0.5 mg/kg once daily, the percent time with intragastric pH >4 over the 24 hour dosing period increased from 44% at baseline to 83% on Day 7.… Apparent clearance (CL/F) increases with age in pediatric patients from birth to 2 years of age.… Because NEXIUM was not shown to be effective in the randomized, placebo-controlled study for this age group, the use of NEXIUM in patients less than 1 year of age is not indicated” (emphasis added). (Note that earlier labeling changes had extended the indication from adult to age 12 years and then to age 1 year.)

identify the divisions. Whether additional neonatal expertise would have altered any written requests is unknown.

BPCA, NIH, AND STUDIES WITH NEONATES

Chapters 1 and 3 explained that BPCA created a role for NIH and the Foundation for the NIH in supporting pediatric drug studies for both on-patent and off-patent drugs. If a sponsor declines a written request for a drug that is still on-patent, FDA may refer the request to the Foundation for the NIH. For drugs that are off-patent and that are included in its list of priorities for studies of pediatric therapeutics, NIH may submit a proposal to FDA for a study under BPCA. FDA may issue a written request to all companies that manufacture the product. If all decline, FDA may refer the request to NIH for study.

Table 6-3 lists the written requests issued to NIH that involve studies with neonates. Taken as a whole, the list reflects the importance of antibi-

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

TABLE 6-3 Written Requests for Neonatal Drug Studies Referred by FDA to NIH, by Patent Status and Study Status


Drug Patent Status and Generic Name
(Indication)
    Study Performed or
Under Way
    Request for
Neonatal Study Only

Off-patent                
   Ampicillin (neonatal sepsis)     None to date     Yes
   Azithromycin oral (chlamydia)     No study done     Yes
   Azithromycin intravenous (ureaplasma)     Yes     Yes
   Lorazepam (sedation)     Yes     No
   Meropenem (intra-abdominal infections)     Yes     Yes
   Sodium nitroprusside (blood pressure)     Yes     No
   Vincristine (cancer)     Yes     No
On-patent                
   Morphine intravenous (pain)     Yes     No

SOURCE: Personal communication, Anne Zajicek, Chief, Obstetric and Pediatric Pharmacology Branch, National Institute of Child Health and Human Development, June 29, 2011; see also http://bpca.nichd.nih.gov/clinical/requests/index.cfm.

otics to treat a range of infections in neonates and, to a lesser extent, the prevalent use of pain medications in this and other pediatric populations.

As part of a BPCA-related Newborn Drug Development Initiative that focused on drugs with no remaining patent term, the National Institute of Child Health and Human Development (NICHD) asked a panel to identify criteria to assist with the setting of priorities for studies with neonates (Giacoia and Mattison, 2005; Ward et al., 2006). In addition to the lack of adequately controlled studies with neonates, the group identified four broad categories of criteria for priority setting, as shown in Box 6-3.

In 2011, NICHD published a list of pediatric therapeutic priorities, the latest in a series of such priority lists (NICHD, 2011). For the neonatal group, the list included eight items, all involving studies of medications:

• Betamethasone, azithromycin (intravenous), and hydrochlorothiazide for bronchopulmonary dysplasia. NICHD grants are supporting dosing and efficacy studies of the first two products; the third is the subject of data collection collaboration with the National Heart, Lung, and Blood Institute.

• Morphine for treatment of pain. NICHD is supporting studies of dosing and possible biomarkers.

• Methadone for treatment of opioid-exposed neonates. NICHD is funding multisite pharmacokinetic and safety studies.

• Metronidazole, ampicillin, and meropenem for treatment of neonatal infections. Funding is under consideration for the first two

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

BOX 6-3
Criteria for Selecting Drugs for Priority
Investigation in Newborns

Category 1: criteria related to the disease and indication, including the potential for adverse outcomes, frequency in newborns, and level of evidence for treatment of newborns.

Category 2: criteria related to drug characteristics, including elements such as duration of dosing, lack of age-appropriate formulation, clinically relevant drug-drug and drug-disease interactions, and drug disposition in newborns.

Category 3: criteria related to feasibility and methodology for newborn studies, including both analytical considerations and clinical endpoints.

Category 4: criteria related to the ethical basis for study, including the potential benefit or harm due to exposure to the study drug, study methodology, and benefit of the new treatment relative to established standard therapy.

images

SOURCE: Ward et al. (2006).

   products; the study of the third product is completed and to be submitted to FDA.

As shown above in Table 6-3, FDA has made written requests for studies of three of the priority medications: ampicillin, azithromycin (intravenous), and meropenem. Among other projects supported by NICHD and other units of NIH are studies involving the use of fentanyl, dopamine, and antistaphylococcal antibiotics with neonates (personal communication, Anne Zajicek, Chief, Obstetric and Pediatric Pharmacology Branch, NICHD, June 29, 2011).

CONCLUSIONS

Overall, this report concludes that BPCA and PREA have increased the clinical investigation of drugs in the pediatric population. The committee did not find summary data on studies with neonates before the adoption of these policies but believes, on the basis of experience, that the policies have also led to more studies with neonates than would have occurred without requests under BPCA or requirements under PREA. Nonetheless, by 2010, only 23 labeling changes (not taking into account changes for biologics approved before September 2007) had included information from studies with neonates. Another five products with awards of exclusivity had been

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 execution or had been the subject of NDAs or BLAs for which final determinations 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 pediatric 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 preservatives 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 generally 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 appropriate safety and efficacy endpoints, inclusion criteria, trial design, and other study elements.

To the extent that many drugs used to treat neonates are old products 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

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 concern 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 adverse 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.

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

ADDENDUM

Labeling Changes Based on Neonate Studies Requested Under BPCA or Required Under PREA, July 1998 Through December 2010

Pediatric Labeling Date Trade Name (Generic or Proper Name) Indication(s) Studied Summary of Labeling Change from Studies with Neonates (Excluding Other Changes) Study Origin Pediatric Exclusivity Date Number of Neonates Studied
1. 12/21/2010 INOmax for inhalation (nitric oxide) Prevention of bronchopulmonary dysplasia (BPD) INOmax is not indicated for prevention of BPD in preterm neonates ≤34 weeks of gestational age.
Efficacy for the prevention of BPD in preterm infants was not established in three double-blind, placebo-controlled clinical trials with a total of 2,149 preterm infants.
Information on clinical trials, adverse reactions.
BPCA 11/2/2010 Three trials with 800, 587, and 793 neonates
2. 11/2/2010 Ofirmev injection (acetaminophen) Management of mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and reduction of fever The effectiveness of Ofirmev for the treatment of acute pain and fever has not been studied in pediatric patients <2 years of age.
The PK of exposure to Ofirmev observed in children and adolescents is similar to that observed in adults but is higher in neonates and infants. Dosing simulations from PK data 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.
PREA NA 47
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
3. 11/12/2009 Protonix (pantoprazole) GERD Effectiveness was not demonstrated in a clinical trial of patients 1 month to 11 months of age with symptomatic GERD.
Information on PK, PD in neonates.
BPCA, PREA 2/17/2009 68 neonates enrolled; 59 randomized
4. 8/28/2009 Valcyte (valganciclovir) Prevention of cytomegalovirus (CMV) disease in pediatric kidney and heart transplant patients Efficacy and safety for prevention of CMV disease after solid organ transplant have not been established in patients <4 months of age.
Information on PK, PD in neonates.
BPCA, PREA 7/24/2008 24
5. 6/18/2009 Nexium (esomeprazole) Short-term treatment of GERD Effectiveness was not demonstrated in a randomized, placebo-controlled study with neonates to <1 year.
Information on clinical study and PK/PD parameters in neonates is included in the label.
BPCA, PREA 5/1/2009 26
6. 10/28/2008 Prevacid (lansoprazole) Symptomatic GERD in infants Safety and effectiveness have not been established in pediatric patients <1 year of age.
Information about neonatal clinical trial, PK, safety.
BPCA, PREA 7/15/2008 24
7. 8/28/2008 Zemuron (rocuronium) Adjunct to general anesthesia Expanded pediatric indication to include children ages 0 to 17 years. Previously approved for use by children ages 3 months to 14 years.
The time to maximum block for an intubating 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 parameters, and other details.
BPCA, PREA 4/3/2008 18 ITT for study 1; 10 ITT for study 2
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Pediatric Labeling Date Trade Name (Generic or Proper Name) Indication(s) Studied Summary of Labeling Change from Studies with Neonates (Excluding Other Changes) Study Origin Pediatric Exclusivity Date Number of Neonates Studied
8. 7/29/2008 Cancidas (caspofungin) Empirical therapy for presumed fungal infections in febrile, neutropenic patients; candidemia and certain Candida infections; esophageal candidiasis; and invasive aspergillosis in patients who are refractory to or intolerant of other therapies The efficacy and safety of Cancidas have not been adequately studied in prospective clinical trials involving neonates and infants less than 3 months of age. Although limited PK data were collected from neonates and infants less than 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin for the treatment of neonatal candidiasis. Invasive candidiasis has a higher rate of CNS and multiorgan involvement in neonates than in older patients. BPCA, PREA 4/15/2008 18
9. 6/24/2008 Viramune tablets, 200 mg Viramune oral suspension, 10 mg/mL (nevirapine) Use in combination with other antiretroviral agents for the treatment of HIV-1 infection Dosing information provided for children ages >15 days to <16 years.
Safety was evaluated in children ages 2 weeks and older in five clinical trials. Important adverse events (all causality) include rash (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.
PREA NA Not specified
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
10. 6/20/2008 Kaletra (lopinavir/ritonavir) Use in combination with other antiretroviral agents for HIV-1 infection The safety, efficacy, and PK profiles have not been established in pediatric patients <14 days.
Dose should be calculated on the basis of body weight or BSA so that it does not exceed the 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.
BPCA, PREA 3/7/2008 Not specified
11. 12/27/2007 Voluven (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) Plasma volume substitute for treatment and prophylaxis of hypovolemia Limited clinical data on the use of Voluven in children are available. In 41 children, including newborns to infants (<2 years), a mean dose of 16 ± 9 mL/kg of body weight was administered. The dosage in children should be adapted to the individual patient’s colloid needs, taking into account the disease state, as well as the hemodynamic and hydration status. PREA NA Not specified
12. 12/22/2006 Emtriva (emtricitabine) HIV-1 infection in combination with other antiretroviral agents Efficacy in preventing or treating HIV infection in neonates to age 3 months could not be determined after a PK study with 20 neonates born to HIV-positive mothers.
Information on dose in neonates 0 to 3 months of age, additional safety and PK parameters.
BPCA 5/24/2006 22
13. 5/12/2005 Zyvox (linezolid) CNS infections Use of linezolid for the empirical treatment of pediatric patients with CNS infections is not recommended.
Additional information on efficacy in pediatric patients with infectious vancomycin-resistant Enterococcus faecium is provided.
PK studies, dosage, AE.
BPCA 2/11/2005 42 completed
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Pediatric Labeling Date Trade Name (Generic or Proper Name) Indication(s) Studied Summary of Labeling Change from Studies with Neonates (Excluding Other Changes) Study Origin Pediatric Exclusivity Date Number of Neonates Studied
14. 4/1/2004 Corlopam (fenoldopam) Indicated for in-hospital, short-term reduction in blood pressure Indicated for in-hospital, short-term (up to 4 hours) reduction in blood pressure in pediatric patients ages <1 month (weight at least 2 kg) to 12 years. BPCA NA At least 2
15. 3/19/2004 Viracept (nelfinavir) HIV-1 infection A reliably effective dose was not established for patients <2 years of age.
Two studies with infants less than 12 weeks old looking at PK and safety.
BPCA, PREA 9/4/2003 31
16. 3/8/2004 Ultiva (remifentanil) Maintenance of anesthesia Safety and efficacy for the maintenance of anesthesia were established for patients from birth to 1 year of age.
Recommended dosing guidelines for maintenance 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.
BPCA, PREA 3/15/2000 8 in PK study; other not specified
17. 4/15/2003 Vigamox (moxifloxacin) Bacterial conjunctivitis None specifically from studies with neonates. BPCA 1/10/2003 209
18. 10/8/2002 Epivir (lamivudine) HIV infection Lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients >3 months of age.
Two safety and PK trials with neonates and some information on AE.
BPCA 9/22/2000 Not specified
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
19. 6/6/2002 Pepcid (famotidine) Gastroesophageal reflux disease Labeling for patients less than 1 year of age was 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.
BPCA 11/21/2000 10
20. 4/1/2002 Videx (didanosine) HIV infection Safety and effectiveness were established down to 2 weeks of age.
Dosing information for children between 2 weeks and 8 months of age.
BPCA 8/13/2001 8
21. 3/29/2002 Zerit (stavudine) HIV infection Safety and effectiveness were established down to birth.
A dose for newborns from birth to 13 days was established.
Description of clinical trial with newborns.
BPCA 8/13/2001 8
22. 10/1/2001 Betapace (sotalol) Arrhythmia Analysis of two trials provided information on PK and PD in children ages 3 days to 12 years; 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.
BPCA 1/6/2000 2 (study 1) 7 (study 2)
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Pediatric Labeling Date Trade Name (Generic or Proper Name) Indication(s) Studied Summary of Labeling Change from Studies with Neonates (Excluding Other Changes) Study Origin Pediatric Exclusivity Date Number of Neonates Studied
23. 3/30/2001 Ultane (sevoflurane) Induction and maintenance of general anesthesia New study with pediatric patients ages 9 days to 12 years compared sevoflurane and halothane.
No specific data for neonates in the clinical trial information.
BPCA 8/2/2000 At least 3
24. 10/22/1999 Zantac (ranitidine) Gastroesophageal reflux Small studies with newborns ages 0 to 1 month receiving ECMO did not demonstrate efficacy but provided information on dose and PK. BPCA 1/19/1999 12
No Labeling Change for Any Age Group
25. NA Angiomax (bivalirudin) Anticoagulant in pediatric patients during percutaneous intravascular procedures for management of congenital heart disease None BPCA 6/17/2009 10
26. NA Zymar (gatifloxacin) Bacterial conjunctivitis None BPCA 5/19/2009 171
27. NA Ciloxan (ciprofloxacin) Bacterial conjunctivitis None BPCA 1/10/2003 209
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
28. NA Ocuflox (ofloxacin) Bacterial conjunctivitis None BPCA 3/12/2003 173

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).

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

This page intentionally left blank.

Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 141
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 142
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 143
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 144
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 145
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 146
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 147
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 148
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 149
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 150
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 151
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 152
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 153
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 154
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 155
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 156
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 157
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 158
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 159
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 160
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 161
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 162
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 163
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 164
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 165
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 166
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 167
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 168
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 169
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 170
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 171
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 172
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 173
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 174
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 175
Suggested Citation:"6 BPCA, PREA, and Drug Studies with Neonates." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 176
Next: 7 Outcomes of Written Requests, Requirements, Studies, and Labeling Changes »
Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act Get This Book
×
Buy Paperback | $65.00 Buy Ebook | $54.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) were designed to encourage more pediatric studies of drugs used for children. The FDA asked the IOM to review aspects of pediatric studies and changes in product labeling that resulted from BPCA and PREA and their predecessor policies, as well as assess the incentives for pediatric studies of biologics and the extent to which biologics have been studied in children. The IOM committee concludes that these policies have helped provide clinicians who care for children with better information about the efficacy, safety, and appropriate prescribing of drugs. The IOM suggests that more can be done to increase knowledge about drugs used by children and thereby improve the clinical care, health, and well-being of the nation's children.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!