[Federal Register Volume 69, Number 204 (Friday, October 22, 2004)]
[Notices]
[Pages 62065-62068]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-23724]


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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 Oral Azithromycin for the 
Treatment or Prevention of Pneumonia or Conjunctivitis Caused by 
Chlamydia Trachomatis in Infants

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

[[Page 62066]]

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 <[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 
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[reg] (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.[lpar]\1\[rpar] 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.[lpar]\2\[rpar] In 1997, the AAP also 
recommended prophylactic antimicrobial treatment with erythromycin 
of infants exposed to CT at 
delivery.[lpar]\3\[rpar] 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.[lpar]\4,\ \5,\ \6\[rpar] 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.[lpar]\7\[rpar] 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.[lpar]\8\[rpar] 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

[[Page 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 non-
inferiority 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 non-inferiority 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 African-American 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-[infin]), 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 co-
primary 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.

[[Page 62068]]

    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