[Federal Register Volume 80, Number 102 (Thursday, May 28, 2015)]
[Notices]
[Pages 30467-30468]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-12848]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0918]


Pediatric Studies of Meropenem Conducted in Accordance With the 
Public Health Service Act; Availability of Summary Report and Requested 
Labeling Changes

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a summary 
report of the pediatric studies of meropenem conducted in accordance 
with the Public Health Service Act (the PHS Act) and is making 
available requested labeling changes for meropenem. The Agency is 
making this information available consistent with the PHS Act.

FOR FURTHER INFORMATION CONTACT: Lori Gorski, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6415, Silver Spring, MD 20993-0002, 301-
796-2200, FAX: 301-796-9855, email: [email protected].

SUPPLEMENTARY INFORMATION: 

I. Meropenem Summary Review

    In the Federal Register of August 13, 2003 (68 FR 48402), meropenem 
was identified as a drug that needed further study in pediatrics. The 
approved labeling lacked adequate information on dosing, 
pharmacokinetic, tolerability, and safety data in newborns and young 
infants with complicated intra-abdominal infections.
    A written request for pediatric studies of meropenem was issued on 
September 10, 2004, to AstraZeneca Pharmaceuticals, the holder of the 
new drug application (NDA) for meropenem. FDA did not receive a 
response to the written request. Accordingly, the National Institutes 
of Health (NIH) issued a request for proposals to conduct the pediatric 
studies described in the written request on August 15, 2005, and 
awarded funds to Duke University and Stanford University on September 
28, 2007, to complete the studies described in the written request.
    On completion of the studies, the Eunice Kennedy Shriver National 
Institute of Child Health and Human Development (NICHD) submitted a 
final clinical study report for meropenem to FDA for review under 
investigational new drug application (IND) 101043: (NICHD-2005-18) ``A 
Multiple Dose PK Study of Meropenem In Young Infants (less than 91 days 
of age) With Suspected or Complicated Intra-abdominal Infections.''
    In the Federal Register of February 27, 2012 (77 FR 11556), FDA 
announced the opening on February 17, 2012, of docket FDA-2011-N-0918 
for submission of data from pediatric studies of meropenem. The data 
submitted to the docket by NIH were submitted in accordance with 
section 409I of the PHS Act (42 U.S.C. 284m) and were the same data 
submitted to IND 101043, with the exception that personal privacy 
information had been redacted from the data submitted to the docket.

[[Page 30468]]

    The meropenem docket remained opened for public comment from 
February 27, 2012, until March 28, 2012. There were no comments 
submitted to the docket during that time. The key findings of this 
final clinical study report are:
    The submitted study was an open-label, non-comparative, 
multicenter, prospective, multiple pharmacokinetic (PK) and safety 
study in infants less than 91 days of age. The study enrolled 200 
infants with a median postnatal age of 21 days (range 1 to 92 days) and 
a median gestation age (GA) of 27.8 weeks (range 22.5 to 40 weeks). 
Infants with complicated intra-abdominal infections who were receiving 
meropenem based on local standard of care were eligible for enrollment. 
Complicated intra-abdominal infections were defined per the protocol as 
physical, radiologic, or bacteriologic findings of complicated intra-
abdominal infection to include peritonitis, necrotizing enterocolitis 
(NEC) grade II or higher by Bell's criteria, Hirschsprung's disease 
with perforation, spontaneous perforation, meconium ileus with 
perforation, bowel obstruction with perforation, as evidenced by free 
peritoneal air on abdominal radiograph, intestinal pneumatosis, or 
portal venous gas on abdominal radiographic examination, or possible 
NEC.
    The study was not statistically powered to establish efficacy 
because the Division of Anti-Infective Products agreed that 
extrapolation of efficacy to pediatric populations from adult 
populations was acceptable. However, clinical efficacy endpoints were 
also evaluated. The efficacy assessment included a comparison of the 
clinical status at study baseline and at day 28 or after a minimum of 7 
days of treatment, using a combination of an assessment using the Score 
for Neonatal Acute Physiology II tool and other protocol specified 
outcome criteria. The clinical endpoint was defined as the patient 
being alive, with negative bacterial cultures from a sterile body 
fluid, and a presumptive clinical cure. Clinical failure was defined as 
death, change in antibiotic therapy while on study drug, or lack of 
presumptive clinical cure. The addition of treatment directed against 
Gram-positive pathogens from a non-abdominal source was not considered 
to represent treatment failure. Using these criteria, 195/200 patients 
or 97.5 percent were considered to have achieved the clinical endpoint. 
Of the 195 patients included in the efficacy population, 192 (98.5 
percent) were evaluated for efficacy. The overall efficacy success rate 
for the study was 84.4 percent (95 percent confidence interval, 78.5 to 
89.2 percent).
    Analysis of safety was a primary objective of the study. The 
following assessments were included in the study: Monitoring for 
adverse events, serious adverse events, and death; documentation of 
seizures; acute abdominal complications; development of resistant 
bacterial infection or candidiasis; treatment failure; physical 
examination; clinical laboratory values; cultures from sterile sites, 
and concomitant medications. There were 11 deaths in the study; all 
occurred in patients less than 32 weeks GA. The most common cause of 
death was multi-organ failure. None of the deaths were related to 
meropenem administration. The following adverse events occurred with a 
frequency in the study that differed from that seen in previous 
pediatric and adult studies: Convulsion (seizures), 5 percent, 
hyperbilirubinemia, 4.5 percent and vomiting, 2.5 percent. Study 
oversight included a safety committee and an independent data safety 
monitoring board.
    The Division of Anti-Infective Products agreed that meropenem was 
well-tolerated in the pediatric population enrolled in the study. Of 
the 10 patients with seizures, 8 patients were adjudicated to have 
developed seizures possibly due to the study medication. Because 
cerebrospinal fluid was only evaluated in a limited number of patients 
with seizures, it is not possible to determine if the seizure threshold 
may have changed due to possible underlying meningitis and the 
administration of meropenem.

II. Recommendation

    This study supports the use of meropenem in neonates and infants 
less than 91 days of age for complicated intra-abdominal infections. 
However, infants with complicated intra-abdominal infections are 
anticipated to have different physiological characteristics than 
patients with meningitis that may impact the PK of meropenem; as such, 
it may not be appropriate to apply the PK findings from this population 
to a patient population with meningitis. The Division recommended that 
the evaluation of meropenem in infants less than 91 days of age be 
limited to the treatment of complicated intra-abdominal infections at 
this time.
    FDA's requested labeling changes, including dosing recommendations 
for the use of meropenem in neonates and infants less than 91 days of 
age for complicated intra-abdominal infections, are available on the 
FDA Web site at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm379088.htm and in the docket (Ref. 1).

    Dated: May 21, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-12848 Filed 5-27-15; 8:45 am]
 BILLING CODE 4164-01-P