Federal Register / Vol. 69, No. 204 / Friday, October 22, 2004 / Notices 62065

Agenda: To review and evaluate grant 

applications. 

Place: Hyatt Regency Bethesda, One 

Bethesda Metro Center, 7400 Wisconsin 

Avenue, Bethesda, MD 20814. 

Contact Person: Christine A. Livingston, 

PhD, Scientific Review Administrator, Center 

for Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 5202, 

MSC 7846, Bethesda, MD 20892, (301) 435–

1172, livingsc@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel; ZRG1 ASG–

01 Q: Aging Systems and Geriatrics: Quorum. 

Date: November 4–5, 2004. 

Time: 8:30 a.m. to 3 p.m. 

Agenda: To review and evaluate grant 

applications. 

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Wisconsin Avenue, Bethesda, MD 20814. 

Contact Person: Charles G. Hollingsworth, 

DRPH, Scientific Review Administrator, 

Center for Scientific Review, National 

Institutes of Health, 6701 Rockledge Drive, 

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301–345–2406, hollinc@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel; Bacterial 

Biodefense Agents. 

Date: November 4–5, 2004. 

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Agenda: To review and evaluate grant 

applications. 

Place: Hyatt Regency Bethesda, One 

Bethesda Metro Center, 7400 Wisconsin 

Avenue, Bethesda, MD 20814. 

Contact Person: Fouad A. El-Zaatari, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 3206, 

MSC 7808, Bethesda, MD 20892, (301) 435–

1149, elzaataf@csr.nih.gov.

Name of Committee: Center for Scientific 

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1143 New Hampshire Avenue, Washington, 

DC 20037. 

Contact Person: Vonda K. Smith, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 4172, 

MSC 7806, Bethesda, MD 20892, (301) 435–

1789, smithvo@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel 

Developmental Disabilities, Communication 

and Science Education. 

Date: November 4–5, 2004. 

Time: 9 a.m. to 5 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: George Washington University Inn, 

824 New Hampshire Ave., NW., Washington, 

DC 20037. 

Contact Person: Thomas A Tatham, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 3178, 

MSC 7848, Bethesda, MD 20892, (301) 594–

6836, tathamt@csr.nih.gov.

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Review Special Emphasis Panel 

Orthopaedics. 

Date: November 4, 2004.

Time: 1 p.m. to 2:30 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: National Institutes of Health, 6701 

Rockledge Drive, Bethesda, MD 20892, 

(Telephone Conference Call). 

Contact Person: Aftab A Ansari, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 4108, 

MSC 7814, Bethesda, MD 20892, (301) 594–

6376, ansaria@csr.nih.gov.

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Imaging and Bioengineering Research. 

Date: November 4, 2004. 

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MSC 7854, Bethesda, MD 20892, (301) 435–

1744, lixiang@csr.nih.gov.

Name of Committee: Center for Scientific 

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Signaling. 

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(Telephone Conference Call). 

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Scientific Review, National Institutes of 

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MSC 7802, Bethesda, MD 20892, (301) 435–

1195, sur@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel; ZRG1 IFCN 

E (11) Pain SBIR–STTR. 

Date: November 4, 2004. 

Time: 2 p.m. to 4:40 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: National Institutes of Health, 6701 

Rockledge Drive, Bethesda, MD 20892, 

(Telephone Conference Call). 

Contact Person: Bernard F. Driscoll, PhD, 

Scientific Review Administrator, Center for 

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MSC 7844, Bethesda, MD 20892, (301) 435–

1242, driscolb@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel Parasitology. 

Date: November 4, 2004. 

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Agenda: To review and evaluate grant 

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Place: National Institutes of Health, 6701 

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(Telephone Conference Call). 

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MSC 7858, Bethesda, MD 20892, (301) 435–

1148, wachtelm@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel; NASAA 

Members Special Emphasis Panel.

Date: November 4, 2004. 

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Agenda: To review and evaluate grant 

applications. 

Place: National Institutes of Health, 6701 

Rockledge Drive, Bethesda, MD 20892, 

(Telephone Conference Call). 

Contact Person: William N. Elwood, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 3162, 

MSC 7770, Bethesda, MD 20892, (301) 435–

1503, elwoodwi@csr.nih.gov.

Name of Committee: Center for Scientific 

Review Special Emphasis Panel ZRG1 F02A 

(20)L Fellowships: Behavioral Neuroscience 

Date: November 4–5, 2004. 

Time: 7 p.m. to 4 p.m. 

Agenda: To review and evaluate grant 

applications. 

Place: Holiday Inn Select Bethesda, 8120 

Wisconsin Ave., Bethesda, MD 20814. 

Contact Person: Michael Selmanoff, PhD, 

Scientific Review Administrator, Center for 

Scientific Review, National Institutes of 

Health, 6701 Rockledge Drive, Room 3134, 

MSC 7844, Bethesda, MD 20892, 301–435–

1119, mselmanoff@csr.nih.gov.

(Catalogue of Federal Domestic Assistance 

Program Nos. 93.306, Comparative Medicine; 

93.333, Clinical Research, 93.306, 93.333, 

93.337, 93.393–93.396, 93.837–93.844, 

93.846–93.878, 93.892, 93.893, National 

Institutes of Health, HHS)

Dated: October 14, 2004. 

LaVerne Y. Stringfield, 

Director, Office of Federal Advisory 

Committee Policy.

[FR Doc. 04–23651 Filed 10–21–04; 8:45 am] 

BILLING CODE 4140–01–M

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 

Oral Azithromycin for the Treatment or 

Prevention of Pneumonia or 

Conjunctivitis Caused by Chlamydia 

Trachomatis in Infants

ACTION: Notice.

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 

62066 Federal Register / Vol. 69, No. 204 / Friday, October 22, 2004 / Notices 

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 

45 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 

<BestPharmaceuticals@mail.nih.gov>.

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 

<BestPharmaceuticals@mail.nih.gov>.

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 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 

oral azithromycin to treat Chlamydia 

trachomatis pneumonia in infants less 

than four months of age, and to prevent 

Chlamydia trachomatis conjunctivitis 

and pneumonia in at-risk infants less 

than two weeks of age, is hereby 

requested by the NIH.

Duane Alexander, 

Director, National Institute for Child Health 

and Human Development, National Institutes 

of Health.

Azithromycin Written Request 

Dear Contact: Reference is made to your 

New Drug Application 50–710 for 

Zithromax (azithromycin) for Oral 

Suspension. To obtain needed pediatric 

information on the use of oral azithromycin, 

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: Genital infection with 

Chlamydia trachomatis (CT) is the most 

commonly reported sexually transmitted 

disease in the U.S. Because of the high 

prevalence of CT infection in women of 

childbearing age, it is estimated that more 

than 100,000 newborn babies are exposed 

during the birth process annually. An infant 

born to a woman with an untreated or 

inadequately treated genital CT infection is at 

considerable risk for acquiring the organism, 

particularly during vaginal delivery. CT is 

acquired in approximately 50% of infants 

born vaginally to infected mothers and has 

been reported in infants delivered by 

cesarean section with intact membranes. 

Results from existing studies indicate that the 

risk of developing conjunctivitis ranges from 

8 to 44%, and the risk of developing 

pneumonia ranges from 0 to 17% in those 

infants who are exposed to CT at birth. The 

mean rates calculated from those studies are 

15% for conjunctivitis, and 7% for 

pneumonia.(1) Conjunctivitis most often 

occurs during the first two to three weeks 

after birth, and pneumonia most often occurs 

between two weeks and three months of age, 

with a peak incidence of pneumonia between 

six and nine weeks of age. Antecedent 

conjunctivitis is not always present. 

Recommended treatment by the American 

Academy of Pediatrics (AAP) Committee on 

Infectious Diseases in 2003 for CT 

conjunctivitis and pneumonia includes a 14-

day course of orally administered 

erythromycin, given in four divided doses 

daily.(2) In 1997, the AAP also recommended 

prophylactic antimicrobial treatment with 

erythromycin of infants exposed to CT at 

delivery.(3) However, the recommendation 

was changed following the recognition of an 

association between erythromycin use during 

the first two weeks of life and subsequent 

infantile hypertrophic pyloric stenosis 

(IHPS). 

The incidence of IHPS in infants treated 

with erythromycin during the first two weeks 

of life ranges from 27 to 32 cases per 1000 

live births.(4, 5, 6) The baseline IHPS 

incidence rate reported in the general infant 

population ranges from 0.85 to 5 cases per 

1000 live births, with a most recent estimate 

between 1 and 3 cases per 1000.(7) It is not 

clear whether IHPS is associated with the 

macrolide class of antibiotics or limited to 

erythromycin. Azithromycin may have a 

lower potential for IHPS, based on 

physicochemical differences that exist 

between azithromycin and erythromycin in 

the areas of gastrokinesis and acid 

catalysis.(8) From an ethical standpoint, a 

study using azithromycin to prevent CT 

conjunctivitis and pneumonia is justified 

because antibiotic prophylaxis was the 

standard of care until the association of 

erythromycin with IHPS was recognized. 

There is still a need to prevent conjunctivitis 

and pneumonia in infants exposed to CT at 

birth. 

Azithromycin is labeled for use in infants 

six months of age and older. Off-label use of 

azithromycin in infants younger than six 

months of age occurs. However, no published 

controlled studies of azithromycin treatment 

for chlamydial pneumonia during the first six 

months of life were located in the English 

literature (1990–2003). In vitro, minimal 

inhibitory and minimal bactericidal 

concentrations of azithromycin have been 

reported to be similar to those of 

erythromycin against CT in vitro. 

Differences between azithromycin and 

erythromycin metabolism may provide 

dosing regimen advantages of azithromycin 

for the infant. Based on a longer half-life, 

azithromycin would need to be given less 

frequently than erythromycin. 

Drug Indications:

1. Oral azithromycin for the treatment of 

CT pneumonia in infant patients less than 

four months of age. 

2. Oral azithromycin for the prevention of 

CT conjunctivitis and pneumonia in at-risk 

infants less than two weeks of age. 

Types of Studies and Study Objectives:

1. Single Dose Pharmacokinetics (PK) 

Study: Will characterize single dose oral 

azithromycin pharmacokinetics, safety and 

tolerability in patients with CT pneumonia or 

conjunctivitis at one or more potentially 

clinically relevant doses. The initial dose of 

azithromycin in this study will be guided by 

extrapolation from data of azithromycin use 

in older infants, published literature and 

current medical practice. PK information 

from patients with pneumonia will guide the 

starting dose for Study 2. PK information 

from patients with conjunctivitis will help to 

guide the starting dose(s) used in Studies 3 

and 4. 

2. Efficacy, Safety and PK Study: 

a. Will determine oral azithromycin 

efficacy for the treatment of chlamydial 

pneumonia in comparison to oral 

erythromycin. 

b. Will characterize the safety profile of 

oral azithromycin in the treatment of CT 

pneumonia. 

c. To characterize oral azithromycin 

multiple-dose pharmacokinetics in patients 

with CT pneumonia. 

3. Single dose PK Study: Will characterize 

single-dose oral azithromycin PK, safety and 

tolerability in infants less than two weeks of 

age born to mothers with untreated or 

inadequately treated genital tract infection at 

one or more clinically relevant doses. Initial 

dose will be guided by results of Studies 1 

and 2. 

4. Efficacy, Safety and PK Study:

a. Will determine oral azithromycin 

efficacy, in comparison to placebo, for the 

Federal Register / Vol. 69, No. 204 / Friday, October 22, 2004 / Notices 62067

prevention of CT conjunctivitis and 

pneumonia, in infants less than two weeks of 

age. 

b. Observe the incidence of IHPS following 

oral azithromycin use in infants less than two 

weeks of age, compared with placebo. 

c. Determine individual incidence rates of 

CT conjunctivitis and pneumonia following 

azithromycin use or placebo, in infants less 

than two weeks of age, who were born to 

mothers with untreated or inadequately 

treated CT genital tract infection. 

d. Characterize a safety profile for oral 

azithromycin. 

e. Characterize azithromycin multiple-dose 

pharmacokinetics in infants less than two 

weeks of age. 

Study 1 will be submitted to and assessed 

by the FDA in a timely manner, prior to 

proceeding with Study 2. Study 2 will be 

submitted to and assessed by the FDA prior 

to proceeding with Studies 3 and 4. In 

particular, the adverse event profile observed 

in Studies 1 and 2 will play a primary role 

in deciding whether to proceed. The 

pharmacokinetic data from Studies 1 and 2 

will guide dosing in Studies 3 and 4. Results 

from the single dose pharmacokinetic studies 

of azithromycin (Studies 1 and 3) will be 

used in planning Studies 2 and 4, 

respectively. 

Age group in which all studies will be 

performed:

Studies 1 and 2: Patients will be less than 

four months of age at study entry. 

Studies 3 and 4: Patients will be less than 

two weeks of age at study entry. 

Entry Criteria: Studies 1 and 2 will include 

male and female patients with physical, 

radiologic and bacteriologic and other 

laboratory findings consistent with a 

diagnosis of CT pneumonia with or without 

conjunctivitis. Study 1 will also include 

patients with physical and bacteriologic 

findings consistent with a diagnosis of CT 

conjunctivitis alone. Studies 3 and 4 will 

include male and female patients who were 

born to mothers with untreated or 

inadequately treated CT genital tract 

infection, and lack evidence of CT infection 

at the time of study entry. The protocol will 

specify additional criteria for study 

inclusion/exclusion, and should specifically 

address prior antibiotic use. 

Study Design: Criteria for withdrawal of 

individual patients from any study will be 

defined in the protocols for Studies 2 and 4. 

An independent Data Monitoring Committee 

(DMC) will be established for Studies 2 and 

4. The study stopping rules used by the DMC 

will be specified in all protocols. 

Studies 1, 2, 3, and 4: Studies that assess 

pharmacokinetics will utilize sparse 

sampling and a population PK approach to 

minimize blood loss to individual patients. 

Sparse blood samples should be obtained at 

defined intervals to avoid collection of 

samples at fixed times. Bioanalytical 

methods to determine azithromycin 

concentrations must be capable of using 

small blood volumes to minimize blood loss. 

Study 2: This study will be multicenter, 

prospective, randomized, double-blind, 

parallel-arm, and active-controlled, to assess 

oral azithromycin non-inferiority to oral 

erythromycin for the treatment of CT 

pneumonia with or without conjunctivitis. 

The protocol will specify the criteria for the 

diagnosis of CT pneumonia as well as criteria 

for pneumonia cure. Multiple-dose 

pharmacokinetics will be assessed in a subset 

of patients. Rationale for study duration will 

be provided in the protocol, taking into 

account that CT pneumonia may occur in 

patients through three months of age, with or 

without prior history of CT conjunctivitis. 

Study 4: This study will be a multicenter, 

prospective, randomized, double-blind, 

parallel-arm and placebo-controlled. The 

study will evaluate oral azithromycin 

effectiveness in the prevention of CT 

conjunctivitis and pneumonia in comparison 

to placebo. The protocol will specify criteria 

for the diagnoses of CT conjunctivitis and 

pneumonia. Criteria for the definition of 

IHPS will be specified in the protocol. 

Multiple-dose pharmacokinetics will be 

assessed in a subset of patients in Study 4. 

Number of Patients: Studies (1, 2, 3, and 

4): A sufficient number of patients to 

characterize single-dose and multiple-dose 

pharmacokinetics. 

Study 2: A sufficient number of patients 

should be enrolled to have at least 80% 

power to demonstrate non-inferiority of 

azithromycin to erythromycin for the 

treatment CT pneumonia using a two-sided 

95% confidence interval and a pre-specified 

non-inferiority margin that has been justified 

and agreed upon by the FDA. The size of the 

margin should take into account historical 

evidence of the treatment effect of 

erythromycin relative to placebo for the 

treatment of CT pneumonia. Natural history 

studies show a spontaneous cure rate of 

27.2% (three of 11 patients) with a 

corresponding 95% confidence interval 

(6.0%, 61%).(9) Assuming an 80% cure rate 

for erythromycin, the lower bound of the 

two-sided 95% confidence interval of the 

treatment effect of erythromycin relative to 

placebo is approximately 20%. A noninferiority margin of 10% should be used in 

order to preserve a fraction of the treatment 

effect. 

Study 4: There are two co-primary 

endpoints and the number of patients 

enrolled should fulfill both of the following: 

(a) A sufficient number of patients should be 

enrolled to have at least 80% power to 

demonstrate superiority of azithromycin to 

placebo for prevention of CT conjunctivitis 

and pneumonia, using an alpha level=0.05. 

(b) A sufficient number of patients should be 

enrolled to have at least 80% power to 

demonstrate the non-inferiority of 

azithromycin to placebo in the incidence of 

IHPS using a two-sided 95% confidence 

interval and a pre-specified non-inferiority 

margin that has been justified and agreed 

upon by the FDA. Based on these 

requirements for the IHPS endpoint, a sample 

size of approximately 290 evaluable patients 

per arm would provide at least 80% power 

to demonstrate the non-inferiority of 

azithromycin to placebo in the incidence of 

IHPS for up to a four-fold increase in the 

IHPS rate for the azithromycin group relative 

to placebo. The estimated placebo IHPS 

incidence rate is 0.19%, and the noninferiority margin is 3%.(10) In addition, all 

parameter estimates used in the sample size 

calculation should be pre-specified and 

justified in the protocol.

Consideration should be given to the fact 

that IHPS occurs predominantly in males, 

and is more frequent in Caucasian and 

Hispanic/Latino infants than AfricanAmerican and Asian infants. Investigators are 

strongly encouraged to enrich the study 

population with respect to the risk of IHPS, 

while at the same time assuring adequate 

gender, ethnic and racial distribution to 

allow for labeling of azithromycin for all 

population groups. 

The protocols for these studies will be 

discussed with the FDA and agreed upon 

prior to study initiation. All measurement 

estimates used in sample size calculation 

will be specified and justified in the protocol. 

Statistical Information: These studies must 

have a pre-specified detailed statistical 

analysis plan appropriate for the study 

design and outcome measures. It will be 

discussed with the FDA and agreed upon 

prior to initiating studies. Demographic and 

safety data other than incidence of IHPS will 

be tabulated, and descriptive analysis of 

safety data will be provided. Descriptive 

statistics of the pharmacokinetic data must 

also be provided and dose-response 

relationships and relationships between PK 

parameters and patient characteristics will 

also be explored. 

Assessment Parameters:

Pharmacokinetics: (All studies): The 

plasma clearance and volume of distribution 

of oral azithromycin will be calculated and 

to the extent possible 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 (AUC0–t), 

the elimination rate constant (Ke), terminal 

elimination half-life (t1/2), and AUC 

extrapolated to infinity (AUC0–∞), should be 

determined. Adequate rationale for excluding 

any of the aforementioned PK parameters 

will be provided. If possible, the protein 

binding of azithromycin should be 

determined over the range of clinically 

relevant concentrations. 

Efficacy: Study 2: The protocol will specify 

a primary endpoint to comparatively evaluate 

the use of oral azithromycin and oral 

erythromycin in treatment of chlamydial 

pneumonia. This must include measures of 

bacteriologic and clinical cure. Secondary 

endpoints may include duration of time 

required for resolution of clinical and 

laboratory findings, need for hospitalization, 

and recurrence of chlamydial infection after 

initial resolution, and bacteriologic and 

clinical cure of conjunctivitis. 

Study 4: The protocol will specify oral 

azithromycin effectiveness, compared with 

placebo, for the prevention of CT 

conjunctivitis and pneumonia as one of the 

co-primary endpoints. Criteria for diagnoses 

of CT conjunctivitis and pneumonia will be 

provided in the protocol, including clinical 

and bacteriologic measures. Incidence of 

IHPS will be evaluated as the second coprimary endpoint element. Criteria for the 

diagnosis of IHPS will be provided in the 

protocol. Secondary endpoints will include 

comparison of individual rates of CT 

conjunctivitis and pneumonia in relation to 

oral azithromycin or placebo administration.

62068 Federal Register / Vol. 69, No. 204 / Friday, October 22, 2004 / Notices 

Drug—Specific Safety Concerns (all 

studies):

1. It is unknown whether azithromycin has 

an adverse events profile similar to or 

different than that reported for erythromycin, 

with respect to infantile hypertrophic pyloric 

stenosis. 

2. Colonization and infection with other 

bacterial (including macrolide-resistant 

organisms) and non-bacterial organisms (e.g.

fungus) may occur with azithromycin 

treatment. 

3. Macrolides have been associated with 

hearing loss at high doses. The potential for 

hearing loss with azithromycin treatment in 

this population will be assessed. 

Safety (all studies): Safety assessments will 

include occurrence of any adverse events 

(AEs), incidence of superinfections 

(particularly fungal infections), vital signs 

that include heart rate , blood pressure, 

respiratory rate , pulse oximetry, 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. 

Drug Information:

• Dosage Form: approved age appropriate 

oral formulations of azithromycin and 

erythromycin Route of Administration: oral 

• Regimen: To be determined 

Selection of doses for azithromycin in 

Study 1 will be guided by extrapolation of 

data from azithromycin use in older infants, 

published literature and/or current medical 

practice. Azithromycin doses chosen for 

Study 2 will be guided by the results of 

Study 1. For Studies 1 and 2, erythromycin 

dose will be based on current medical 

practice. Selection of azithromycin doses for 

Study 3 will be guided by the results of 

Studies 1 and 2. Azithromycin doses for 

Study 4 will be guided by the results of the 

first three studies. 

Labeling that may result from the studies:

Appropriate sections of the label may be 

changed to incorporate the findings of the 

studies. 

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, assessment, and 

interpretation are required. Pharmacokinetic 

study reports will include analytical method 

and assay validation, individual drug 

concentration-time data and individual 

pharmacokinetic parameters (and 

pharmacodynamic data when available). 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 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 

must 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 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 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.

[FR Doc. 04–23724 Filed 10–21–04; 8:45 am] 

BILLING CODE 4167–01–P

DEPARTMENT OF HOMELAND 

SECURITY 

Federal Emergency Management 

Agency 

[FEMA–1545–DR] 

Florida; Amendment No. 11 to Notice 

of a Major Disaster Declaration

AGENCY: Federal Emergency 

Management Agency, Emergency 

Preparedness and Response Directorate, 

Department of Homeland Security.

ACTION: Notice.

SUMMARY: This notice amends the notice 

of a major disaster for the State of 

Florida (FEMA–1545–DR), dated 

September 4, 2004, and related 

determinations.

EFFECTIVE DATE: October 8, 2004.

FOR FURTHER INFORMATION CONTACT:

Magda Ruiz, Recovery Division, Federal 

Emergency Management Agency, 

Washington, DC 20472, (202) 646–2705.

SUPPLEMENTARY INFORMATION: Notice is 

hereby given that the incident period for 

this disaster is closed effective October 

8, 2004.

(The following Catalog of Federal Domestic 

Assistance Numbers (CFDA) are to be used 

for reporting and drawing funds: 97.030, 

Community Disaster Loans; 97.031, Cora 

Brown Fund Program; 97.032, Crisis 

Counseling; 97.033, Disaster Legal Services 

Program; 97.034, Disaster Unemployment 

Assistance (DUA); 97.046, Fire Management 

Assistance; 97.048, Individuals and 

Households Housing; 97.049, Individuals and 

Households Disaster Housing Operations; 

97.050 Individuals and Households 

Program—Other Needs; 97.036, Public 

Assistance Grants; 97.039, Hazard Mitigation 

Grant Program)

Michael D. Brown, 

Under Secretary, Emergency Preparedness 

and Response, Department of Homeland 

Security.

[FR Doc. 04–23733 Filed 10–21–04; 8:45 am] 

BILLING CODE 9110–10–P

DEPARTMENT OF HOMELAND 

SECURITY 

Federal Emergency Management 

Agency 

[FEMA–1561–DR] 

Florida; Amendment No. 5 to Notice of 

a Major Disaster Declaration

AGENCY: Federal Emergency 

Management Agency, Emergency 

Preparedness and Response Directorate, 

Department of Homeland Security.

ACTION: Notice.

SUMMARY: This notice amends the notice 

of a major disaster declaration for the 

State of Florida (FEMA–1561–DR), 

dated September 26, 2004, and related 

determinations.

EFFECTIVE DATE: October 14, 2004.

FOR FURTHER INFORMATION CONTACT:

Magda Ruiz, Recovery Division, Federal 

Emergency Management Agency, 

Washington, DC 20472, (202) 646–2705.

SUPPLEMENTARY INFORMATION: The notice 

of a major disaster declaration for the 

State of Florida is hereby amended to 

include the following areas among those 

areas determined to have been adversely 

affected by the catastrophe declared a 

major disaster by the President in his 

declaration of September 26, 2004:

Collier, Lee, and Miami-Dade Counties for 

emergency protective measures (Category 

B) under the Public Assistance program.