[Federal Register Volume 70, Number 13 (Friday, January 21, 2005)]
[Notices]
[Pages 3209-3212]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-1093]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Request for Public Comment on a Written Request Issued by the 
Food and Drug Administration on the Use of Meropenem for the Treatment 
of Complicated Intra-Abdominal Infections in Preterm and Term Newborn 
and Infant Patients Younger Than 91 Days of Age

ACTION: Notice.

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SUMMARY: The National Institutes of Health (NIH) is requesting public 
comment on the following Written Request issued by the Food and Drug 
Administration (FDA) for off-patent drugs as defined in the Best 
Pharmaceuticals for Children Act (BPCA). The Written Request was 
referred to the NIH by the FDA as required by the BPCA. The Written 
Request was developed following formulation of an NIH-generated 
priority list, which prioritizes certain drugs most in need of study 
for use by children. The priority list was produced in consultation 
with the FDA, other NIH Institutes and Centers, and pediatric experts, 
as mandated by the BPCA. The studies that are described in the Written 
Request are intended to characterize the safety, efficacy, and 
pharmacokinetics of the drug for optimum use in pediatric patients.

DATES: Comments are requested within 30 days of publication of this 
notice.

ADDRESSES: Submit comments to: Anne Zajicek, M.D., Pharm.D., National 
Institute of Child Health and Human Development (NICHD), 6100 Executive 
Boulevard, Suite 4B--09, Bethesda, MD 20892-7510, telephone 301-435-
6865 (not a toll-free number), e-mail [email protected].

FOR FURTHER INFORMATION CONTACT: Anne Zajicek, M.D., Pharm.D., National 
Institute of Child Health and Human Development (NICHD), 6100 Executive 
Boulevard, Suite 4B--09, Bethesda, MD 20892-7510, telephone 301--435-
6865 (not a toll-free number), e-mail [email protected].

SUPPLEMENTARY INFORMATION: The NIH is providing notice of Written 
Requests issued by the FDA, and is requesting public comment. On 
January 4, 2002, President Bush signed into law the Best 
Pharmaceuticals for Children Act (BPCA). The BPCA mandates that NIH, in 
consultation with the FDA and experts in pediatric research, shall 
develop, prioritize, and publish an annual list of certain approved 
drugs for which pediatric studies are needed. In response to this list, 
the FDA then issues a Written Request to holders of the New Drug 
Application (NDA) or abbreviated New Drug Application (aNDA) to request 
that pediatric studies be performed to provide needed safety and 
efficacy information for pediatric labeling. If the Written Request is 
declined by the NDA/aNDA holder (s), the Written Request is referred to 
the NIH, specifically the NICHD. A Request for Proposal (RFP) is then 
issued based on the Written Request and proposals are reviewed by a 
peer-review process for contract award.
    To assure that the most appropriate pediatric studies are 
delineated in the RFP, public comment on the Written Request for the 
use of Meropenem for the treatment of complicated intra-abdominal 
infections in preterm and term newborn and infant patients younger than 
91 days of age is hereby requested by the NIH.

Duane Alexander,
Director, National Institute for Child Health and Human Development, 
National Institutes of Health.

Meropenem Written Request

    Dear Contact:
    To obtain needed pediatric information on the use of meropenem, the 
Food and Drug Administration (FDA) is hereby making a formal Written 
Request, pursuant to section 505A of the Federal Food, Drug, and 
Cosmetic Act that you submit information from studies in pediatric 
patients described below.
    Rationale:
    The last 30 years have seen a dramatic rise in antibiotic 
resistance by common bacterial pathogens. This increasing microbial 
drug resistance requires the use of antibiotics with broad spectrum 
activity that can be relied upon when first line antimicrobials fail.
    Imipenem-cilastatin and meropenem are carbapenems with widespread 
pediatric use. Imipenem-cilastatin has been labeled for use in 
pediatric patients (including newborns) for many serious infections 
such as pneumonia, skin and skin structure infections, osteomyelitis 
and complicated intra-abdominal infections. Meropenem is labeled for 
pediatric patients from three months of age through adolescence as 
single agent antimicrobial therapy for meningitis and complicated 
intra-abdominal infections, and is a recommended option for monotherapy 
of high severity complicated intra-abdominal infections in adults.\9\
    There is significant off-label use of meropenem in newborn and 
infant patients younger than three months of age. For example, in 2003, 
the Child Health Corporation of America Pediatric Health Information 
System dataset (inpatient data from 31 free-standing children's 
hospitals) mentions 589 uses in this population for serious infections 
such as necrotizing enterocolitis and peritonitis. This off-label use 
occurs despite the lack of adequate pharmacokinetic, dosing, 
tolerability and safety data for this vulnerable age group. Collecting 
this data through the study of newborns and young infants with 
complicated intra-abdominal infections will fill this knowledge gap.

[[Page 3210]]

    Complicated intra-abdominal infections are heterogeneous in 
etiology. By definition, these infections are characterized by systemic 
inflammation and an intra-abdominal process extending into the 
peritoneal space that necessitates a surgical or percutaneous drainage 
procedure. The post-procedure findings of purulent exudates with 
inflamed or necrotic tissue confirms the diagnosis.\8\ Examples of 
intra-abdominal processes in the youngest patients that can result in 
peritonitis include: Necrotizing enterocolitis, bowel obstruction with 
perforation, Hirschsprung's disease with perforation, meconium ileus 
with perforation, and others.
    Though complicated intra-abdominal infections in the youngest 
pediatric patients are more severe than in older infants and children, 
the bacterial pathogens that contribute to this disease process are 
similar. Thus, the efficacy of antimicrobial agents such as meropenem 
for the treatment of complicated intra-abdominal infections can be 
extrapolated from older children to the youngest.
    Administration of antimicrobials prior to enrollment is a common 
problem in clinical trials of antibiotics and a concern for the studies 
requested below. The onset of complicated intra-abdominal infections in 
the youngest patients may range from an acute and fulminant 
presentation to a more indolent process that progresses over hours to 
days. The indolent presentation often begins with a non-specific 
pattern of signs and symptoms suggestive of an infectious process; only 
later does the intra-abdominal nature of the infection become apparent. 
During this period of sub-acute infection, infants with a possible 
intra-abdominal infection may receive antibiotic treatment. Such early 
antibiotic treatment complicates the design of clinical trials to 
evaluate efficacy and safety of specific antimicrobials. As a result, 
clinical trials of complicated infections routinely require a design 
strategy that minimizes the influence of early therapy on the later 
interpretation of safety and efficacy data.
    We request the following studies of meropenem for use in 
complicated intra-abdominal infection in preterm and term newborn and 
infant patients younger than three months of age.
    Indication to be studied:
    Meropenem for the treatment of complicated intra-abdominal 
infections in preterm and term newborn and infant patients younger than 
91 days of age.
    Types of Studies and Study Objectives:
    1. Single Dose Pharmacokinetic (PK), Safety, and Tolerability Study 
(Study 1): To characterize single dose meropenem PK, safety, and 
tolerability in preterm and term newborn and infant patients with 
complicated intra-abdominal infections.
    2. Safety and Multi-dose PK Study (Study 2):
    a. To characterize the safety profile of meropenem in the treatment 
of complicated intra-abdominal infections in comparison to an 
alternative standard antibiotic regimen.
    b. To characterize meropenem multiple-dose PK in patients with 
complicated intra-abdominal infections.
    c. To assess collected efficacy data for meropenem for the 
treatment of complicated intra-abdominal infections.
    Age group in which studies will be performed:
    Study 1:
    Premature to term gestation male and female newborn and infant 
patients who are younger than 91 days of age and have a suspected or 
early complicated intra-abdominal infection. These patients must be 
subdivided into the following four groups:
    Group 1: Gestational age at birth below 32 weeks and post-natal age 
younger than 8 days;
    Group 2: Gestational age at birth below 32 weeks and post-natal age 
of 8 days through 90 days;
    Group 3: Gestational age at birth 32 weeks or older and post-natal 
age younger than 8 days; and
    Group 4: Gestational age at birth 32 weeks or older and post-natal 
age of 8 days through 90 days.
    Study 2:
    Premature and term gestation newborn and infant patients younger 
than 91 days of age with complicated intra-abdominal infections, 
including patients from all four groups described above. For the PK 
substudy, patients in study 2 should be enrolled based on the age 
groups described above under study 1.
    Inclusion Criteria:
    Study 1 will include male and female patients with physical, 
radiological, and/or bacteriological findings of a suspected or early 
complicated intra-abdominal infection who require antimicrobial therapy 
and who have no physiological changes that would significantly alter 
the elimination of meropenem.
    Study 2 will include male and female patients with physical, 
radiological, and/or bacteriological findings of a complicated intra-
abdominal infection as defined in the ``Rationale'' section. The 
protocol will specify additional criteria for study inclusion/
exclusion, and will specifically address the presence of viral or 
fungal infections and the method for addressing antibiotic 
administration prior to enrollment or randomization.
    Study Design:
    PK studies within Study 1 and Study 2 will utilize sparse sampling 
and a population PK approach to minimize blood loss for individual 
patients. Sparse blood samples should be obtained at defined time 
intervals rather than at fixed times. Bio-analytical methods to 
determine meropenem concentrations must be capable of evaluating the 
smallest possible sample volumes (preferably less than 100 
microliters). Measurements of renal function are to be done in 
conjunction with PK determinations. Multiple-dose PK will be assessed 
in a subset of patients in Study 2. Confirmation of adequate steady-
state levels is a primary endpoint of Study 2.
    Study 1 will evaluate at least three clinically relevant doses of 
meropenem in the four subgroups described in the ``Age group in which 
studies will be performed'' section above. The doses to be studied will 
be guided by extrapolation from the data of meropenem use in older 
infants and will be justified in the protocol. For example, one 
possible range of single doses is 10 mg/kg, 20 mg/kg, and 40 mg/
kg.1 3 These studies are most commonly conducted as an add-
on dose of study drug among patients who are already receiving 
antimicrobial therapy.
    Study 2 will be a multi-center, prospective, randomized, parallel-
arm, preferably blinded, and active controlled safety study of 
meropenem for the treatment of complicated intra-abdominal infections 
in comparison to an alternative standard antibiotic regimen. The 
definition of complicated intra-abdominal infections for this study is 
provided in the ``Rationale'' section above and has been derived from 
the current Infectious Diseases Society of America (IDSA) guidelines 
\8\ with modifications to adjust the definition for the newborn and 
infant population in this study. Investigators are strongly encouraged 
to identify and incorporate methods for blinding to treatment 
assignment into the design and analysis. Efficacy data will also be 
collected.
    Currently meropenem is approved for single-agent antimicrobial 
therapy for complicated intra-abdominal infections in pediatric 
patients older than three months. The protocol will specify a standard 
antibiotic regimen for both study arms, a rationale for each antibiotic 
to be used, and whether meropenem will be used alone or in combination 
with a second antibiotic. If

[[Page 3211]]

a second antibiotic is used with meropenem, a microbiological 
justification for its use must be provided and this additional 
antibiotic must also be included in the comparator regimen. The 
protocol will also justify the selection of antibiotics for the 
comparator arm which may consist of two or more antimicrobial agents.
    As mentioned in the ``Rationale'', antibiotic administration prior 
to enrollment or randomization may occur and will complicate the 
interpretation of safety and efficacy data collected for meropenem. 
Therefore, the protocol must be designed to minimize the influence of 
prior antibiotic exposure on the evaluation of meropenem safety and 
efficacy.
    The empiric use of vancomycin within 72 hours prior to enrollment 
is strongly discouraged. Any change in antibiotic therapy while on 
study drug will be considered a treatment failure except the addition 
of vancomycin to treat organisms that require it and have been isolated 
from a non-abdominal source (including coagulase-negative 
staphylococcus and methicillin resistant Staphylococcus aureus). The 
protocol must specify how all use of vancomycin will be addressed in 
the design, conduct and analysis of this study.
    The protocol must specify and justify the duration of antibiotic 
therapy. At four to six weeks following the initial dose, all patients 
must be followed for safety and those patients who completed the full 
treatment course of study drug must have an efficacy determination.\8\ 
The protocol will specify and justify other criteria for determining 
treatment success or failure and their related efficacy endpoints.
    Preferably patients will be enrolled and randomized either at the 
time of surgery or peritoneal drain placement or immediately 
afterwards. For these patients, fungal, aerobic and anaerobic bacterial 
cultures of peritoneal fluid and/or intraoperative specimens must be 
obtained prior to administration of study drug. Patients may be 
enrolled and randomized pre-operatively if the complicated intra-
abdominal infection is confirmed by surgical intervention within 24 
hours of study entry and intraoperative specimens are obtained for 
culture as described above. Investigators must specify criteria for 
microbiological cure or resolution and are strongly encouraged to 
obtain repeat peritoneal fluid and other cultures.
    The protocol will address how patients with prior seizures will be 
followed.
    The protocols for Study 1 and Study 2 will be submitted to and 
assessed by the FDA and agreed upon prior to study initiation. Results 
from the single dose PK studies of meropenem (Study 1) will be used to 
guide dosing in Study 2 and must be reviewed by the FDA prior to 
initiating Study 2.
    Criteria for withdrawal of individual patients from Study 1 and 2 
must be defined in the protocol. An independent Data Monitoring 
Committee (DMC) must be established for these studies. The study 
stopping rules used by the DMC must be specified in the protocol.
    Number of Patients:
    Study 1: A sufficient number of patients to conduct a dose-ranging 
study and to adequately characterize single-dose PK of meropenem in the 
four gestational and post-natal age groups described in the section 
entitled, ``Age group in which studies will be performed'' must be 
studied. A minimum of 12 patients per group per dose must be studied. 
Investigators are strongly encouraged to assure an even distribution of 
gestational and post-natal age within each PK study group.
    Study 2: This study is powered to assess safety as the primary 
endpoint and will enroll a sufficient number of patients with 
complicated intra-abdominal infections to detect serious adverse events 
in the meropenem arm occurring at the frequency of one percent. 
Efficacy data will be collected, however the study is not powered to be 
an efficacy trial. Each study arm must enroll a minimum of 300 treated 
patients who receive 48 hours or more of study drug. Patients who drop 
out of the trial prior to 48 hours of study treatment should be 
replaced until the minimum of 300 patients per study arm is achieved. 
Patients who receive at least one dose of study drug should be followed 
for safety until the trial is completed. The multi-dose PK study must 
include at least 12 patients from each of the four age groups described 
for Study 1. If enrollment of patients within any of these four age 
groups is unfeasible, then the sponsor/investigator must formally 
discuss this enrollment problem with the FDA.
    Statistical information:
    These studies must have a pre-specified detailed statistical 
analysis plan appropriate for the study design and outcome measures. 
The plan will be discussed with the FDA and agreed upon prior to 
initiating studies. Descriptive statistics of the PK data must also be 
provided and dose-response relationships and relationships between PK 
parameters and patient characteristics including renal function will 
also be explored.
    Assessment Parameters:
    Pharmacokinetics (All studies): The plasma clearance and volume of 
distribution of meropenem will be calculated and other PK parameters 
such as the maximum plasma concentration (Cmax), time of 
Cmax (Tmax), area under the plasma concentration-
time curve from zero to the last quantifiable concentration 
(AUCo-t), the elimination rate constant (Ke), terminal 
elimination half-life (t1/2), and AUC extrapolated to 
infinity (AUCo-oo), will be determined to the extent 
possible. The sponsor/investigator is strongly encouraged to study the 
correlation between pharmacokinetic parameters and pharmacodynamic 
parameters such as MIC for various doses of meropenem.
    Efficacy:
    The protocol will specify and justify the method for identifying 
severity of acute illness to assist in measuring improvement or 
resolution of infection, clearly delineate criteria and endpoints for 
treatment success and failure, and provide definitions of evaluable 
patients and microbial clearance.
    Safety (all studies):
    Safety assessments will track the occurrence of any adverse events 
(AEs) including: Seizures; the incidence of superinfections 
(particularly fungal infections); vital signs including heart rate, 
blood pressure, and respiratory rate; pulse oximetry; apnea monitoring; 
standard laboratory assessments of hematologic, liver, and renal 
function; assessments of hearing and growth (weight, length, and head 
circumference). Criteria for identification and clinical evaluation of 
suspected seizures will be described in the protocol. AEs will be 
followed to their resolution or stabilization. Nosocomial infections 
will be tracked by pathogen.
    Drug-Specific Safety Concerns (all studies):
    1. In older susceptible patients, treatment with carbapenems 
(including meropenem) may decrease the seizure threshold.4 5 
In meningitis treatment studies of patients without CNS abnormalities, 
the rate of seizures among those patients receiving meropenem was 
similar to that of patients treated with cefotaxime or 
ceftriaxone.2 6 7 The clinical manifestation of seizures in 
newborn and young infants can be subtle. The protocol must specify the 
definition of seizures and the criteria for identification and 
documentation of possible seizures and must address the role of 
electroencephalograms and other diagnostic methods in seizure 
diagnosis. Collection of a serum meropenem level at time of suspected 
seizure is strongly encouraged.
    2. The use of carbapenems and other similar broad spectrum 
antimicrobials

[[Page 3212]]

poses a risk of fungal superinfection. The protocol will specify the 
method of tracking the incidence of superinfections, both bacterial and 
fungal.
    3. In children, the most common adverse events occurring with 
meropenem treatment are diarrhea, rash, nausea, and emesis. Hemolytic 
anemia in pediatric patients on meropenem has been reported.
    Drug information:
     Dosage form: Powder for injection. Reconstitute with a 
compatible diluent.
     Route of administration: intravenous.
     Regimen: The pharmacokinetic data from Study 1 will guide 
dosing in Study 2.
    Labeling that may result from these studies:
    Appropriate sections of the label may be changed to incorporate the 
findings of the studies performed in response to this written request.
    Format of reports to be submitted:
    Full study reports with analysis, assessment, and interpretation, 
not previously submitted to the Agency addressing the issues outlined 
in this request, will be submitted. Pharmacokinetic study reports 
should include analytical method and assay validation, individual drug 
and/or metabolite concentration-time data and individual 
pharmacokinetic parameters. In addition, the reports are to include 
information on the representation of pediatric patients of ethnic and 
racial minorities. All pediatric patients enrolled in the study 
(studies) should be categorized using one of the following designations 
for race: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander or White. For 
ethnicity one of the following designations should be used: Hispanic/
Latino or Not Hispanic Latino.
    Response to Written Request:
    As per the Best Pharmaceuticals for Children Act, section 3, if we 
do not hear from you within 30 days of the date of this Written 
Request, we will refer this Written Request to the Director of the NIH. 
If you agree to the request, then you must indicate when the pediatric 
studies will be initiated.
    Please submit protocols for the above studies to an investigational 
new drug application (IND) and clearly mark your submission ``PEDIATRIC 
PROTOCOL SUBMITTED IN RESPONSE TO WRITTEN REQUEST'' in large, bold type 
at the beginning of the cover letter of the submission. Please notify 
us as soon as possible if you wish to enter into a written agreement by 
submitting a proposed written agreement. Clearly mark your submission 
``PROPOSED WRITTEN AGREEMENT FOR PEDIATRIC STUDIES'' in large, bold 
type at the beginning of the cover letter of the submission.
    Reports of the studies should be submitted as a new drug 
application (NDA) or as a supplement to an approved NDA with the 
proposed labeling changes you believe would be warranted based on the 
data derived from these studies. When submitting the reports, please 
clearly mark your submission ``SUBMISSION OF PEDIATRIC STUDY REPORTS--
COMPLETE RESPONSE TO WRITTEN REQUEST'' in large font, bolded type at 
the beginning of the cover letter of the submission and include a copy 
of this letter.
    In accordance with section 9 of the Best Pharmaceuticals for 
Children Act, Dissemination of Pediatric Information, if a pediatric 
supplement is submitted in response to a Written Request and filed by 
FDA, FDA will make public a summary of the medical and clinical 
pharmacology reviews of pediatric studies conducted. This disclosure, 
which will occur within 180 days of supplement submission, will apply 
to all supplements submitted in response to a Written Request and filed 
by FDA, regardless of the following circumstances:
    1. The type of response to the Written Request (complete or 
partial);
    2. The status of the supplement (withdrawn after the supplement has 
been filed or pending);
    3. The action taken (i.e. approval, approvable, not approvable); or
    4. The exclusivity determination (i.e. granted or denied).
    FDA will post the medical and clinical pharmacology review 
summaries on the FDA website at http://www.fda.gov/cder/pediatric/Summaryreview.htm and publish in the Federal Register a notification of 
availability.
    If you wish to discuss any amendments to this Written Request, 
please submit proposed changes and the reasons for the proposed changes 
to your application. Submissions of proposed changes to this request 
should be clearly marked ``PROPOSED CHANGES IN WRITTEN REQUEST FOR 
PEDIATRIC STUDIES'' in large font, bolded type at the beginning of the 
cover letter of the submission. You will be notified in writing if any 
changes to this Written Request are agreed upon by the Agency.
    We hope you will fulfill this pediatric study request. We look 
forward to working with you on this matter in order to develop 
additional pediatric information that may produce health benefits in 
the pediatric population.

Reference List

1. Blumer, J.L., M. D. Reed, G.L. Kearns, R.F. Jacobs, W.M. Gooch, 
III, R.Yogev, K. Williams, and B.J. Ewing. 1995. Sequential, single-
dosepharmacokinetic evaluation of meropenem in hospitalized infants 
and childrenAntimicrob Agents Chemother 39:1721-1725.
2. Klugman, K.P. and R. Dagan. 1995. Carbapenem treatment of 
meningitis. Scand.J Infect.Dis.Suppl. 96:45-8.:45-48.
3. Martinkova, J., R. de Groot, J. Chladek, et al. 1995. Meropenem 
pharmacokinetics in pre-term and full-term neonates [Abstract 686]. 
Program andabstracts of the 7th European Conference of Clinical 
Microbiology and Infectious Diseases, Vienna.
4. Norrby, S.R. and K.M. Gildon. 1999. Safety profile of meropenem: 
a review of nearly 5,000 patients treated with meropenem. Scand.J 
Infect.Dis. 31:3-10.
5. Norrby, S.R. 2000. Neurotoxicity of carbapenem antibiotics: 
consequences fortheir use in bacterial meningitis. Journal of 
Antimicrobial Chemotherapy 45:5-7.
6. Odio, C.M., J.R. Puig, J.M. Feris, W.N. Khan, W.J. Rodriguez, 
G.H.McCracken, Jr., and J.S. Bradley. 1999. Prospective, randomized, 
investigator-blindedstudy of the efficacy and safety of meropenem 
vs. cefotaxime therapy inbacterial meningitis in children. Meropenem 
Meningitis Study Group. Pediatr InfectDis J 18:581-590.
7. Schmutzhard, E., K.J. Williams, G. Vukmirovits, V. Chmelik, B. 
Pfausler, andA. Featherstone. 1995. A randomised comparison of 
meropenem with cefotaximeor ceftriaxone for the treatment of 
bacterial meningitis in adults. MeropenemMeningitis Study Group. J 
Antimicrob. Chemother 36 Suppl A:85-97.:85-97.
8. Solomkin, J.S., D.L. Hemsell, R. Sweet, F. Tally, and J. 
Bartlett. 1992.Evaluation of new anti-infective drugs for the 
treatment of intraabdominalinfections. Infectious Diseases Society 
of America and the Food and DrugAdministration. Clin.Infect.Dis 15 
Suppl 1:S33-42.:S33-S42.
9. Solomkin, J.S., J.E. Mazuski, E.J. Baron, R.G. Swayer, A.B. 
Nathens, J.T.DiPiro, T. Buchman, E.P. Dellinger, J. Jernigan, S. 
Gorbach, A.W. Chow,and J. Bartlett. 2003. Guidelines for the 
selection of anti-infective agents forcomplicated intra-abdominal 
infections. Clin Infect Dis 37:997-1005.

[FR Doc. 05-1093 Filed 1-19-05; 8:45 am]
BILLING CODE 4167-01-P