[Federal Register Volume 69, Number 95 (Monday, May 17, 2004)]
[Notices]
[Pages 27939-27942]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-11062]


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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 in the Use of Azithromycin for the 
Treatment of Ureaplasma urealyticum Pneumonia in the Preterm Neonate 
and Prevention of Bronchopulmonary Dysplasia

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 NIH by 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 90 days of publication of this 
notice.

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

[[Page 27940]]


FOR FURTHER INFORMATION CONTACT: Anne Zajicek, M.D., Pharm. D., 
National Institute of Child Health and Human Development, 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 in order 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 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.
    In order to assure that the most appropriate pediatric studies are 
delineated in the RFP, public comment of the Written Requests for the 
use of azithromycin in treatment of Ureaplasma urealyticum pneumonia in 
the preterm neonate and prevention of bronchopulmonary dysplasia is 
hereby requested by NIH.

    Dated: May 10, 2004.
Duane Alexander,
Director, National Institute for Child Health and Human Development, 
National Institutes of Health.

Azithromycin Written Request

    Dear Contact: To obtain pediatric information on the use of 
intravenous azithromycin, the 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

    Respiratory tract colonization with Ureaplasma urealyticum may be a 
factor in the development of neonatal bronchopulmonary dysplasia (BPD). 
Although this has not been proven, macrolide antibiotics have been used 
to eradicate U. urealyticum colonization from the respiratory tract in 
this subpopulation. Literature suggests that macrolide antibiotics may 
also have an anti-inflammatory effect. The objective of these studies 
will be to investigate the safety and effectiveness of intravenous 
azithromycin for the prevention of BPD in preterm neonates colonized 
with U. urealyticum.
    Azithromycin offers several potential advantages for treatment of 
U. urealyticum-colonized premature neonates. In vitro data indicate 
that U. urealyticum is susceptible to azithromycin. The intracellular 
accumulation of azithromycin and its tissue penetration are potential 
advantages for the treatment of intracellular pathogens. Azithromycin 
is likely to have fewer drug interactions than the other macrolides, 
since it is minimally metabolized and has a low potential to inhibit 
hepatic CYP 450 isozymes. However, there is minimal information about 
azithromycin dosing, efficacy, and safety in the neonatal period. 
Further, some macrolide antibiotics have been associated with adverse 
effects, such as pyloric stenosis and cardiac arrhythmias, and it is 
unknown whether azithromycin carries similar risk.

Types of Studies

    (1) Single Dose Pharmacokinetic (PK) Study:
     To characterize single dose intravenous (I.V.) 
azithromycin pharmacokinetics, safety and tolerability in mechanically 
ventilated preterm neonatal patients with U. urealyticum endotracheal 
colonization at one or more clinically relevant doses.
    (2) Multiple-dose, Exposure Response Study(-ies):
     To assess the effect of two or more dose regimens of I.V. 
azithromycin on U. urealyticum colonization of the respiratory tract of 
preterm neonatal patients.
     To characterize multiple-dose PK and safety of I.V. 
azithromycin.
     To determine appropriate testing methods for documentation 
of U. urealyticum colonization and eradication.
     To explore potential for azithromycin clinical 
effectiveness.
    (3) Efficacy and Safety Studies:
     Two studies that each assesses I.V azithromycin efficacy 
and safety for the prevention of BPD in mechanically ventilated preterm 
neonatal patients with U. urealyticum endotracheal colonization.
    These studies will be performed in the above sequence and results 
of each study submitted to and assessed by FDA prior to proceeding with 
the next study(ies). Results from the single dose PK study would be 
used in planning the exposure-response study(ies). Similarly, results 
from the exposure response study(ies) will be used, to the extent 
possible, for planning safety and efficacy studies.

Age Group in Which Studies Will Be Performed

    Studies will be performed in preterm neonatal patients <72 hours of 
age.

Entry Criteria

    Preterm male and female patients <72 hours of age who are at least 
23 weeks gestational age and 500 grams weight at time of birth will be 
eligible for enrollment in the studies. These patients will be 
endotracheally intubated, mechanically ventilated and have vascular 
access at the time of randomization. Patients must have documented U. 
urealyticum endotracheal colonization at the time of randomization.
    Patients for whom a decision has been made to withdraw medical 
support, or in whom potentially lethal congenital defect(s) has been 
diagnosed by the medical team, are not eligible for study. Patients 
with central nervous system infections suspected to be due to U. 
urealyticum will be excluded. The protocol will specify additional 
criteria for study inclusion/exclusion, including when there has been 
antenatal maternal treatment with a macrolide or sulfa containing 
antibiotic.

Study Design

    Criteria for withdrawal of individual patients from any study will 
be defined in the protocol.
    An independent Data Monitoring Committee (DMC) will be established 
for all exposure-response and safety and efficacy studies. The study 
stopping rules used by the DMC will be specified in all protocols.
    Study Types 1 and 2: Studies that assess pharmacokinetics may use 
sparse sampling and population PK approach to minimize blood loss to 
individual patients. Bioanalytical methods to determine azithromycin 
concentrations must be capable of evaluating microliter sample volumes. 
Patients will be grouped by gestational age. A rationale will be 
provided for the grouping of patients by gestational age.
    Appropriate testing methods for documentation of U. urealyticum 
colonization in the safety and efficacy trials will in part be 
determined from the exposure-response study(ies). Study(ies) Type 2 
will use both endotracheal culture and polymerase chain reaction (PCR) 
as methods for

[[Page 27941]]

establishing respiratory tract colonization and the microbiological 
effect of azithromycin treatment. Additionally, Study(ies) Type 2 will 
evaluate the relationship between azithromycin dose and/or plasma 
exposure and microbiological eradication, and will explore potential 
for azithromycin clinical effectiveness.
    Study Type 3: Two studies that assess efficacy and safety will be 
multicenter, randomized, double blind, and placebo controlled. There 
are numerous potential factors related to clinical management of sick 
preterm infants that may impact on the development of BPD (e.g. 
prenatal corticosteroids, postnatal corticosteroids, surfactant, type 
and mode of ventilation, inspired oxygen concentration (FiO2), fluid 
and electrolyte management and infant nutrition, vitamin A, congenital 
and nosocomial infections/pneumonia). The study will track and evaluate 
factors that may contribute to the development of BPD.
    Patients will be stratified by gestational age in efficacy and 
safety studies. Other factors such as maternal chorioamnionitis and 
disease severity may be additionally considered. The rationale for 
patient stratification will be provided in protocols.

Number of Patients

    Study Types 1 and 2: A sufficient number of patients to 
characterize single-dose and multiple dose pharmacokinetics will 
complete these studies. The protocol for these studies will be 
discussed with the FDA and agreed upon prior to initiation of the 
studies. Preterm neonates will be reasonably distributed by gender. The 
gestational age of these patients will reflect gestational age range of 
the efficacy and safety studies.
    Study Type 3: Efficacy and safety studies will enroll a sufficient 
number of patients to ensure at least 80% statistical power to 
determine a treatment effect, at a 0.05 statistical significance level 
(two-tailed). All parameter estimates used in the sample size 
calculation will be specified and justified in the protocol.

Assessment Parameters

    Pharmacokinetics (Studies Type 1 and 2): The plasma clearance and 
volume of distribution of I.V. azithromycin 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 (AUC 0-t), the elimination rate 
constant (Ke), terminal elimination half-life (t1/2), and 
AUC extrapolated to infinity (AUC 0-[vprop]) will be 
determined to the extent possible. Adequate rationale for excluding any 
of the aforementioned PK parameters will be provided. The protein 
binding of azithromycin should be determined over the range of 
clinically relevant concentrations.
    Pharmacodynamics (Study(ies) Type 2): Microbiologic persistence of 
U. urealyticum will be assessed by culture and PCR.
    Efficacy (Studies Type 2 and 3): For Study(ies) Type 2, endpoints 
for efficacy will be explored. For powered efficacy and safety studies 
(Study Type 3), the protocol will specify a clinically meaningful 
primary endpoint to assess the treatment effect of azithromycin. 
Examples of such endpoints may include survival without severe BPD, 
survival without BPD, incidence of BPD, or incidence of severe BPD. A 
definition of BPD will be specified in the protocol. This protocol 
definition must include BPD diagnostic criteria and address how a 
patient's requirement for supplemental oxygen will be determined.
    Secondary endpoints will include overall mortality, incidence of 
co-morbidities of prematurity, number of days on the ventilator, number 
of days receiving oxygen supplementation, use of non-study antibiotics, 
and adverse events. Endpoints may also include the microbiological 
persistence of Ureaplasma.
    Safety (Studies Types 1-3): Laboratory tests for safety must be 
performed on microliter serum samples. In addition, safety assessments 
will include occurrence of any adverse events (AEs), comorbidities of 
prematurity {e.g., necrotizing enterocolitis (NEC), sepsis, retinopathy 
of prematurity (ROP), intraventricular hemorrhage (IVH), 
periventricular leukomalacia (PVL), patent ductus arteriosus 
(PDA){time} , incidence of superinfections (particularly fungal 
infections), vital signs that include heart rate (HR), blood pressure 
(BP), respiratory rate (RR), pulse oximetry, electrocardiogram (EKG), 
standard laboratory assessments of hematologic, liver and renal 
function, assessments of hearing, and growth (weight, length and head 
circumference). AEs will be followed to their resolution or 
stabilization. Nosocomial infection will be tracked by pathogen.
    Long-term outcomes (Study Type 3): Assessments of growth, 
neurodevelopmental and pulmonary outcomes will be performed. These 
assessments may include, but are not limited to, weight, length, head 
circumference, physical examination with neurologic assessment, 
neurodevelopmental evaluation using a validated instrument, adverse 
events, hospitalization with emphasis on reactive airway disease and 
infection, medication history and use of oxygen. Provisions for these 
assessments may be included in the safety and efficacy protocols, or 
these assessments may be included in additional study protocols. At a 
minimum, long-term assessments will be performed through 24 months of 
the patient's chronological age.

Drug Information

    Dosage form: Approved intravenous formulation.
    Route: Intravenous.
    Regimen: To be determined.
    Selection of doses in the single-dose studies will be guided by 
literature or current medical practice. Doses chosen for the subsequent 
trials will be guided by the results of preceding studies.

Drug Specific Safety Concerns

    1. It is unknown whether azithromycin has an adverse events profile 
similar to that reported for other macrolide antibiotics. These include 
hypertrophic pyloric stenosis, and cardiac arrhythmias.
    2. It is unknown whether there will be any adverse effects in this 
patient population related to the occurrence of phospholipidosis with 
azithromycin.
    3. Colonization and infection with other bacterial (including 
macrolide-resistant organisms) and nonbacterial organisms (e.g., 
fungus) may occur with azithromycin treatment.
    4. Macrolides have been associated with hearing loss at high doses. 
The potential for hearing loss with azithromycin treatment in this 
population will be assessed.

Statistical Information

    These studies must have a pre-specified and detailed statistical 
analysis plan appropriate to the study design and outcome measures. It 
will be discussed with the FDA and agreed upon prior to initiating 
studies.
    Demographic and safety data will be tabulated and descriptive 
analysis of safety data will be provided. Descriptive statistics of 
pharmacokinetic data must also be provided and dose-response 
relationships and relationships between PK parameters and patient 
characteristics will also be explored.

Labeling that May Result From the Study(ies)

    Appropriate sections of the label may be changed to incorporate the 
findings of the studies.

[[Page 27942]]

Format of Reports To Be Submitted

    Full study reports not previously submitted to the Agency, 
addressing the issues outlined in this request with full analysis 
(including assay method validation information), assessment, and 
interpretation. In addition, the reports are to include information on 
the representation of pediatric patients of ethnic and racial 
minorities.

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 font, 
bolded 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 font, bolded 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. 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 to 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.
    If you have any questions, call NAME at PHONE NUMBER.

[FR Doc. 04-11062 Filed 5-14-04; 8:45 am]
BILLING CODE 4140-01-P