80 FR 30467 - Pediatric Studies of Meropenem Conducted in Accordance With the Public Health Service Act; Availability of Summary Report and Requested Labeling Changes

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 102 (May 28, 2015)

Page Range		30467-30468
FR Document		2015-12848

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.

Federal Register, Volume 80 Issue 102 (Thursday, May 28, 2015)

[Federal Register Volume 80, Number 102 (Thursday, May 28, 2015)]
[Notices]
[Pages 30467-30468]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-12848]


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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.

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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

30468 Federal Register / Vol. 80, No. 102 / Thursday, May 28, 2015 / Notices

The meropenem docket remained percent confidence interval, 78.5 to 89.2 http://www.fda.gov/Drugs/
opened for public comment from percent). DevelopmentApprovalProcess/
February 27, 2012, until March 28, Analysis of safety was a primary DevelopmentResources/ucm379088.htm
2012. There were no comments objective of the study. The following and in the docket (Ref. 1).
submitted to the docket during that assessments were included in the study: Dated: May 21, 2015.
time. The key findings of this final Monitoring for adverse events, serious
Leslie Kux,
clinical study report are: adverse events, and death;
documentation of seizures; acute Associate Commissioner for Policy.
The submitted study was an open-
abdominal complications; development [FR Doc. 2015–12848 Filed 5–27–15; 8:45 am]
label, non-comparative, multicenter,
prospective, multiple pharmacokinetic of resistant bacterial infection or BILLING CODE 4164–01–P

(PK) and safety study in infants less candidiasis; treatment failure; physical
than 91 days of age. The study enrolled examination; clinical laboratory values;
cultures from sterile sites, and DEPARTMENT OF HEALTH AND
200 infants with a median postnatal age HUMAN SERVICES
of 21 days (range 1 to 92 days) and a concomitant medications. There were
median gestation age (GA) of 27.8 weeks 11 deaths in the study; all occurred in
patients less than 32 weeks GA. The Food and Drug Administration
(range 22.5 to 40 weeks). Infants with
complicated intra-abdominal infections most common cause of death was multi- [Docket No. FDA–2015–N–0012]
who were receiving meropenem based organ failure. None of the deaths were
on local standard of care were eligible related to meropenem administration. Molecular Characterization of Multiple
for enrollment. Complicated intra- The following adverse events occurred Myeloma Black/African Ancestry
abdominal infections were defined per with a frequency in the study that Disparity
the protocol as physical, radiologic, or differed from that seen in previous
pediatric and adult studies: Convulsion AGENCY: Food and Drug Administration,
bacteriologic findings of complicated HHS.
intra-abdominal infection to include (seizures), 5 percent,
hyperbilirubinemia, 4.5 percent and ACTION: Notice.
peritonitis, necrotizing enterocolitis
(NEC) grade II or higher by Bell’s vomiting, 2.5 percent. Study oversight
SUMMARY: The Food and Drug
criteria, Hirschsprung’s disease with included a safety committee and an
Administration (FDA) is announcing the
perforation, spontaneous perforation, independent data safety monitoring
board. availability of grant funds for the
meconium ileus with perforation, bowel support of the efforts of the Center for
The Division of Anti-Infective
obstruction with perforation, as Drug Evaluation and Research (CDER).
Products agreed that meropenem was
evidenced by free peritoneal air on well-tolerated in the pediatric FDA is announcing its intent to accept
abdominal radiograph, intestinal population enrolled in the study. Of the and consider a single-source application
pneumatosis, or portal venous gas on 10 patients with seizures, 8 patients for the award of a grant to the Multiple
abdominal radiographic examination, or were adjudicated to have developed Myeloma Service of Memorial Sloan
possible NEC. seizures possibly due to the study Kettering Cancer Institute. The goal of
The study was not statistically medication. Because cerebrospinal fluid the cooperative agreement between
powered to establish efficacy because was only evaluated in a limited number CDER and the Multiple Myeloma
the Division of Anti-Infective Products of patients with seizures, it is not Service of Memorial Sloan Kettering
agreed that extrapolation of efficacy to possible to determine if the seizure Cancer Institute is to support the
pediatric populations from adult threshold may have changed due to development of appropriate
populations was acceptable. However, possible underlying meningitis and the methodologies to conduct clinical trial
clinical efficacy endpoints were also administration of meropenem. design evaluation and determine
evaluated. The efficacy assessment extrapolation of findings from the
included a comparison of the clinical II. Recommendation general population to the U.S. Black
status at study baseline and at day 28 or This study supports the use of population.
after a minimum of 7 days of treatment, meropenem in neonates and infants less DATES: Important dates are as follows:
using a combination of an assessment than 91 days of age for complicated 1. The application due date is July 20,
using the Score for Neonatal Acute intra-abdominal infections. However, 2015.
Physiology II tool and other protocol infants with complicated intra- 2. The anticipated start date is August
specified outcome criteria. The clinical abdominal infections are anticipated to 2015.
endpoint was defined as the patient have different physiological 3. The opening date is May 18, 2015.
being alive, with negative bacterial characteristics than patients with 4. The expiration date is July 21,
cultures from a sterile body fluid, and meningitis that may impact the PK of 2015.
a presumptive clinical cure. Clinical meropenem; as such, it may not be
failure was defined as death, change in appropriate to apply the PK findings ADDRESSES: Submit electronic
antibiotic therapy while on study drug, from this population to a patient applications to: http://www.Grants.gov.
or lack of presumptive clinical cure. The population with meningitis. The For more information, see section III of
addition of treatment directed against Division recommended that the the SUPPLEMENTARY INFORMATION section
Gram-positive pathogens from a non- evaluation of meropenem in infants less of this notice.
abdominal source was not considered to than 91 days of age be limited to the FOR FURTHER INFORMATION CONTACT:
asabaliauskas on DSK5VPTVN1PROD with NOTICES

represent treatment failure. Using these treatment of complicated intra- Dickran Kazandjian, Center for Drug
criteria, 195/200 patients or 97.5 percent abdominal infections at this time. Evaluation and Research, Food and
were considered to have achieved the FDA’s requested labeling changes, Drug Administration, 10903 New
clinical endpoint. Of the 195 patients including dosing recommendations for Hampshire Ave., Bldg. 22, Rm. 2320,
included in the efficacy population, 192 the use of meropenem in neonates and Silver Spring, MD 20993–0002, 240–
(98.5 percent) were evaluated for infants less than 91 days of age for 402–5272; or Vieda Hubbard, Division
efficacy. The overall efficacy success complicated intra-abdominal infections, of Acquisition Support and Grants
rate for the study was 84.4 percent (95 are available on the FDA Web site at (HFA–500), Food and Drug

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Document Created: 2018-02-21 10:32:48
Document Modified: 2018-02-21 10:32:48

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice.
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]
FR Citation		80 FR 30467

80 FR 30467 - Pediatric Studies of Meropenem Conducted in Accordance With the Public Health Service Act; Availability of Summary Report and Requested Labeling Changes

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 80, Issue 102 (May 28, 2015)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration