Safe and Effective Medicines for Children Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (2012) / Chapter Skim
Currently Skimming:
6 BPCA, PREA, and Drug Studies with Neonates
6 BPCA, PREA, and Drug Studies with Neonates
Pages 141-176
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 141... ...
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)
|
From page 142... ...
, 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.
|
From page 143... ...
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)
|
From page 144... ...
. 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.
|
From page 145... ...
(2011) , based on neonatal intensive care unit data from Clark et al.
|
From page 146... ...
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)
|
From page 147... ...
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.
|
From page 148... ...
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.
|
From page 149... ...
Written Requests, PREA Requirements, and Labeling Changes Written Requests Under BPCA In the table supplied by FDA and presented in the addendum to this chapter, studies of 25 of 28 products were associated with written requests under BPCA. As noted above, this group included five products for which 4 In 2011, FDA approved labeling changes for more products for which sponsors submit ted information from studies with neonates.
|
From page 150... ...
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)
|
From page 151... ...
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.
|
From page 152... ...
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)
|
From page 153... ...
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)
|
From page 154... ...
. The safety and effectiveness of OFIRMEV for the treatment of acute pain and fever in pediatric patients ages 2 years and older is [sic]
|
From page 155... ...
. For the third product listed in Box 6-1, the 2008 labeling change for rocuronium bromide (Zemuron)
|
From page 156... ...
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.
|
From page 157... ...
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)
|
From page 158... ...
. 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)
|
From page 159... ...
. The products for which FDA issued written requests for studies with neonates were omeprazole (Prilosec)
|
From page 160... ...
. 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.
|
From page 161... ...
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)
|
From page 162... ...
. (Note that earlier labeling changes had extended the indication from adults to older children.)
|
From page 163... ...
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 onpatent 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.
|
From page 164... ...
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)
|
From page 165... ...
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.
|
From page 166... ...
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.
|
From page 167... ...
167 BPCA, PREA, AND DRUG STUDIES WITH NEONATES not adequately evaluated in neonates, one option for Congress is to provide additional resources for short- and long-term neonatal drug studies through the BPCA program at NIH. Finally, the committee recognizes that long-term studies with any age group are difficult to design, fund, and execute.
|
From page 168... ...
Studied Neonates (Excluding Other Changes) Origin Date Studied Labeling Change for at Least 1 Pediatric Age Group 1.
|
From page 169... ...
GERD in infants in pediatric patients <1 year of age. PREA Information about neonatal clinical trial, PK, safety.
|
From page 170... ...
7/29/2008 Cancidas Empirical therapy The efficacy and safety of Cancidas have not BPCA, 4/15/2008 18 (caspofungin) for presumed been adequately studied in prospective clinical PREA fungal infections trials involving neonates and infants less than 3 in febrile, months of age.
|
From page 171... ...
12. 12/22/2006 Emtriva HIV-1 infection in Efficacy in preventing or treating HIV infection BPCA 5/24/2006 22 (emtricitabine)
|
From page 172... ...
10/8/2002 Epivir HIV infection Lamivudine clearance was substantially reduced BPCA 9/22/2000 Not (lamivudine) in 1-week-old neonates relative to pediatric specified patients >3 months of age.
|
From page 173... ...
20. 4/1/2002 Videx HIV infection Safety and effectiveness were established down to BPCA 8/13/2001 8 (didanosine)
|
From page 174... ...
reflux receiving ECMO did not demonstrate efficacy but provided information on dose and PK. No Labeling Change for Any Age Group 25.
|
From page 175... ...
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)
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.