[Federal Register Volume 69, Number 95 (Monday, May 17, 2004)]
[Notices]
[Pages 27942-27945]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-11063]


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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 Rifampin for the Treatment 
of Bacterial Endocarditis Caused by Methicillin-Resistant 
Staphylococcus aureus

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 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 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].

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 Rifampin for the 
treatment of bacterial endocarditis caused by methicillin-resistant S. 
aureus in pediatric patients is hereby requested by the NIH.

    Dated: May 11, 2004.
Duane Alexander,
Director, National Institute for Child Health and Human Development, 
National Institutes of Health.

Rifampin Written Request

    Dear Contact: To obtain needed pediatric information on this active 
moiety, 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 (the Act), that you submit information from 
studies in pediatric patients described below. These studies 
investigate the use of rifampin for the management of infectious 
bacterial endocarditis in pediatric patients.

Background and Rationale

    Infective endocarditis (IE) is a serious, life-threatening 
infection that requires hospitalization. The frequency of IE in 
hospitalized pediatric patients reported in the literature varies 
widely. The most widely quoted estimates are 55 to 78 cases of IE per 
100,000 pediatric hospital admissions (PHA) but rates as low as 22/
100,000 PHA and as high as 200/100,000 have been cited in the 
literature. Most of these estimates are individual hospital-based 
retrospective reviews. In a larger survey of 26 major cardiovascular 
medical center hospitals, Kaplan et. al. reported an average 11 cases 
of IE per center per year.

[[Page 27943]]

    There are no published population-based national incidence data of 
IE in the pediatric population in the United States. The U.S. 
Hospitalcare Cost and Utilization Project (HCUP) reported 1012 
pediatric hospitalizations for endocarditis in the year 2000, of which 
657 were coded as acute/sub-acute bacterial endocarditis. Other 
literature suggests that the frequency of IE in the pediatric age 
population seems to be increasing primarily due to the improved 
survival rates of children who are at increased risk for endocarditis, 
such as those with congenital heart disease and hospitalized newborn 
infants. An increased use of indwelling central venous catheters in the 
pediatric population may also be a contributing factor in the possible 
increasing frequency of pediatric IE.
    Although IE occurs relatively infrequently in the pediatric 
population, it is a serious condition associated with considerable 
morbidity and mortality and the incidence of IE may be increasing. 
Mortality estimates for patients with IE reported in the literature 
range from 10 to greater than 40 percent. IE due to S. aureus is 
usually associated with higher mortality rates than IE due to other 
common bacterial etiologies. A recent study reported a mortality rate 
of 42% within 3 months of diagnosis in patients with prosthetic valve 
IE due to S. aureus.
    In children, staphylococci are a frequent cause of IE. 
Staphylococcus aureus is the leading cause of acute bacterial 
endocarditis in children. S. aureus and coagulase negative 
staphylococci are frequent causes of IE associated with prosthetic 
heart valves, prosthetic material, and indwelling vascular catheters.
    Increasing rates of antimicrobial resistance in staphylococci have 
made treatment of serious staphylococcal infections more difficult. In 
2000, 55% of S. aureus isolates in hospitalized patients reported to 
the national nosocomial infection surveillance system were methicillin 
resistant. Coagulase negative staphylococci are usually methicillin 
resistant, especially in the setting of endocarditis occurring within 
one year of cardiac surgery.
    A recent scientific statement from the American Heart Association 
provides treatment guidelines for pediatric patients with 
staphylococcus endocarditis. For native valve endocarditis due to 
methicillin-resistant staphylococci, the guidelines recommend treatment 
with vancomycin with or without gentamicin for the first 3 to 5 days of 
therapy. For staphylococcal endocarditis on prosthetic cardiac valves 
or other cardiac prosthetic material, the guidelines recommend 
treatment with a regimen of vancomycin and rifampin with the addition 
of gentamicin for the first two weeks of therapy. The AHA guidelines 
also discuss the role for a combined medical-surgical approach to the 
management of S. aureus prosthetic valve endocarditis. The AHA 
guidelines represent recommendations from an expert panel based upon 
evidence derived largely from clinical studies in adults.
    There is incomplete information about dosing, pharmacokinetic (PK) 
parameters, effectiveness, and safety of rifampin in the treatment of 
staphylococcal endocarditis in children and no adequate and well 
controlled clinical trials have been performed in children. Rifampin is 
not currently indicated for the treatment of staphylococcal 
endocarditis in the FDA-approved package labeling.

Types of Studies

    A single trial to evaluate the safety and efficacy of rifampin in 
the pediatric population when used in the treatment of infective 
endocarditis due to methicillin-resistant S. aureus (MRSA) or coagulase 
negative staphylococci. Patients who are enrolled are to be stratified 
by:
    (a) Patients with native valve endocarditis due to MRSA.
    (b) Patients with a prosthetic heart valve or other prosthetic 
cardiac material and endocarditis due to either MRSA or coagulase 
negative staphylococci.
    Different protocol-specified antimicrobial therapy may be used in 
the study for the native valve endocarditis (stratum ``a'' above) and 
prosthetic material endocarditis (stratum ``b'' above). Within each 
stratum, the group receiving rifampin plus other protocol-specified 
antimicrobial therapy will be compared to the control group of the same 
stratum not receiving rifampin (i.e., receiving only the ``other 
protocol-specified antimicrobial therapy'').
    This study must also include a sub-study describing the 
pharmacokinetics of oral and intravenous rifampin in children with 
endocarditis who are ages:
    (1) 1 month to <2 years.
    (2) 2 years to <6 years.
    (3) 6 years to <12 years.
    (4) 12 years to 16 years.
    Full rifampin plasma concentration versus time profiles, using 
sparse sampling, will be determined for each group to characterize the 
pharmacokinetics of rifampin. [Relevant FDA guidance documents 
regarding pharmacokinetic evaluation are available at the FDA Web site 
(http://www.fda.gov/cder/guidance/index.htm).
    It is recognized that although a single study is specified above, 
it may be administratively preferable to submit a separate study 
protocol for each of the strata mentioned above (i.e. native valve 
endocarditis or prosthetic material endocarditis). This is also 
acceptable as fulfillment of this request.

Objectives

     To evaluate in the pediatric population the safety and 
efficacy of intravenous rifampin, followed by oral rifampin, when used 
in combination with other protocol-specified antimicrobial therapy in 
the treatment of staphylococcal endocarditis in children. The two 
groups of children to be studied are (a) children with native valve 
endocarditis due to methicillin resistant S. aureus, and (b) children 
with prosthetic material endocarditis due to methicillin resistant S. 
aureus or coagulase negative staphylococci.
     To describe the pharmacokinetics of intravenous and oral 
rifampin in pediatric patients with staphylococcal endocarditis.

Study Design

    The proposed study will be a randomized, multicenter, active-
controlled trial, designed to test superiority of rifampin plus other 
protocol-specified antimicrobial therapy compared to the ``other 
protocol specified antimicrobial therapy'' in the absence of rifampin 
(i.e., the ``control'' antibiotic regimen). Patients to be enrolled 
will be pediatric patients (ages 1 month to 16 years of age) with 
native valve endocarditis due to MRSA or prosthetic material 
endocarditis due to MRSA or coagulase negative staphylococci. The study 
will evaluate the efficacy of rifampin in combination with other 
protocol-specified antimicrobial therapy (the experimental group) 
compared to an identical regimen without rifampin (the control group). 
The design of the study could specify a different antibiotic regimen to 
be used in the control group for each stratum, [i.e., the strata of 
pediatric patients with native valve endocarditis could receive a 
different protocol-specified treatment regimen than patients with 
prosthetic material endocarditis (e.g. the use of different 
antimicrobial agents and/or a different treatment duration)]. However, 
within each stratum, the treatment regimen for the rifampin-containing 
(experimental) group would be identical to the control regimen except 
for the addition of rifampin. Rifampin will initially be

[[Page 27944]]

administered intravenously, with a switch to oral rifampin at a time 
specified and justified in the protocol.
    Pediatric patients will be stratified at enrollment as having (a) 
native valve endocarditis due to MRSA or (b) endocarditis in the 
setting of a prosthetic valve or other prosthetic cardiac material. 
Each stratum will be analyzed separately, with the study being 
statistically powered to evaluate the effect of rifampin on outcome for 
each stratum separately. (As noted earlier, each stratum may be 
considered as a separate study and two separate protocols may be 
submitted in fulfillment of this Written Request.)
    Treatment regimens selected for the active control arm of each 
stratum must be justified by the sponsor.
    Based on published pharmacokinetic studies, it is expected that 
rifampin dosing in pediatric patients will be approximately 5 mg/kg 
intravenous every 12 hours and 10 mg/kg orally every 12 hours. If the 
study enrolls pediatric patients who may be expected to have different 
pharmacokinetic characteristics from the patients who were enrolled in 
earlier published studies (e.g., children of certain other ethnicities 
outside the United States), then additional pharmacokinetic data may be 
necessary prior to enrollment of these patients. This additional 
pharmacokinetic data would be necessary to ascertain the appropriate 
dose for these subjects that would approximate the same exposure as 5 
mg/kg IV every 12 hours and 10 mg/kg PO every 12 hours used in previous 
studies.

Indications To Be Studied

    Rifampin in combination with other protocol-specified antimicrobial 
therapy will be studied in pediatric patients aged 1 month to 16 years 
for the treatment of (a) native valve endocarditis due to methicillin 
resistant S. aureus (MRSA) or (b) endocarditis in the setting of 
prosthetic cardiac material due to either methicillin-resistant S. 
aureus (MRSA) or coagulase negative staphylococci.

Pediatric Age Groups in Which Study Will Be Performed

    The study will include the following age groups.
    (a) 1 month to <2 years.
    (b) 2 years to <6 years.
    (c) 6 years to <12 years.
    (d) 12 to 16 years.

Number of Patients

    The study will enroll a sufficient number of patients such that it 
is powered to detect a statistically significant effect attributable to 
the addition of rifampin to the active control arm regimen. The study 
must be powered to test significance for each enrollment stratum 
independently, i.e., there should be separate statistical testing for 
subjects with native valve endocarditis and subjects with prosthetic 
material endocarditis. Efficacy results for the two strata should not 
be pooled.

Pharmacokinetics Sub-Study

    A subgroup of patients across both strata should be studied to 
characterize the pharmacokinetics of single dose or multiple dose 
rifampin administration for both the oral and intravenous forms for 
each age grouping described above. A minimum of 8 pediatric patients 
should be studied for each age range (approximately 32-40 overall). 
Patients should be reasonably distributed between the sexes.

Inclusion Criteria

     The protocols must include and justify a reliable 
diagnostic method (e.g. Duke clinical criteria) for enrolling pediatric 
patients with (a) native valve endocarditis due to MRSA or (b) 
prosthetic material endocarditis due to either MRSA or coagulase 
negative staphylococci.
     Microorganisms: Positive blood culture(s) to document 
infection with methicillin-resistant S. aureus (for native valve 
endocarditis or prosthetic material endocarditis) or coagulase negative 
staphylococci (for prosthetic material endocarditis).

Exclusion Criteria

     Alternative etiology for endocarditis (protocol defined)
     Hepatic or renal dysfunction of moderate or greater 
severity (protocol defined)
     Pediatric patients with a known hypersensitivity to 
rifampin or any of the protocol-specified antibiotic regimens
     Patients who are pregnant or who are sexually active using 
oral contraceptives as birth control will be excluded from enrollment
     Anyone with glucose-6-phosphate dehydrogenase (G6PD) 
deficiency shall be excluded from the study
     Anyone who is taking a drug which adversely interacts with 
rifampin (protocol defined)

Study Endpoints

     The primary efficacy endpoint must be specified and 
justified in the protocol(s). The primary efficacy endpoint will 
include both a clinical and a microbiological component. The following 
definitions of clinical cure and microbiological eradication are 
adapted from the 1992 IDSA/FDA guidelines for evaluation of anti-
infective drugs for the treatment of IE.
     Clinical cure--``the resolution of all signs and symptoms 
of disease is observed after a course of therapy.''
     Bacteriological eradication-defined by at least two or 
more negative blood cultures at one month after completion of therapy. 
The primary efficacy endpoint will require both clinical cure and 
bacteriologic eradication in order for the patient to be considered a 
cure. Deaths should be included as treatment failures within the 
primary endpoint. Any patient who relapses (defined in the guidelines 
as ``blood cultures that become negative during treatment and remain so 
for a specified period post-treatment but subsequently become positive 
for the original pathogen'') should have their bacteriologic outcome 
tabulated under bacterial persistence. The study protocol must address 
disposition and plans for the analysis of subjects who receive surgery 
during the study.
     Mandatory secondary endpoints will include all-cause 
mortality, time to last positive blood culture, and relapse-free 
survival after completion of therapy. Secondary endpoints may also 
include time to negative blood cultures (e.g., time until blood 
cultures are negative for at least 3 consecutive days), time to 
resolution of fever (e.g., being afebrile for at least 48 hours), 
normalization of laboratory values such as C-reactive protein, 
erythrocyte sedimentation rate (ESR), and white blood cell count. The 
study must monitor and report the antimicrobial susceptibilities of all 
bacterial isolates obtained in this study.
     Pediatric patients with native valve endocarditis will be 
followed for at least 3 months after completion of therapy for safety 
and efficacy endpoints. Pediatric patients with prosthetic material 
endocarditis will be followed for at least 6 months after the 
completion of therapy for safety and efficacy endpoints.
     Pharmacokinetics substudy: A rifampin plasma concentration 
versus time profile, using sparse sampling, will be determined for each 
patient. Characterization of concentration-time profiles, and 
determination of relevant rifampin PK parameters (to the extent 
possible), for example, clearance (CL), volume of distribution (Vd), 
elimination half-life (T 1/2), maximum concentration (Cmax), time to 
maximum concentration (Tmax), and area under the plasma concentration-
time curve (AUC).

[[Page 27945]]

Drug Information

Rifampin Dosage Forms
     Intravenous: 600 mg Rifampin, sodium formaldehyde 
sulfoxylate 10mg, and sodium hydroxide to adjust pH.
     Oral: 150 mg or 300 mg capsules can be compounded as per 
FDA-approved package labeling to a concentration of 10mg/ml oral 
suspension.
    Route of Administration. Initially, intravenous in all studies with 
protocol-specified switch to oral formulation of rifampin based on 
protocol-specified criteria (e.g., after the patient has stabilized and 
can tolerate oral administration).

Drug Specific Safety Concerns

    Routine safety assessments, such as vitals signs, weight, serum 
chemistry, and monitoring for adverse events must be collected at 
baseline and at intervals throughout the study. Monitoring should be 
appropriate for detecting adverse events, including but not limited to 
hepatotoxicity, renal toxicity, hemolytic anemia, gastrointestinal 
effects, and seizures. Subjects should be maintained on protocol-
specified monitoring even if the experimental or control regimen is 
discontinued, i.e., consenting subjects should remain on study 
regardless of therapeutic course after enrollment. Compliance and drug 
status (i.e., whether the subject is on or off protocol-specified 
therapy) must be monitored throughout the study. All efforts should be 
made to minimize loss to follow-up of study patients.

Statistical Information, Including Power of Study and Statistical 
Assessment

    The study must have a detailed pre-specified statistical analysis 
plan appropriate to the study design and outcome measures. The study 
must be adequately powered (at least 80% power) to detect a 
statistically significant treatment effect on the primary endpoint at a 
significance level of p < 0.05 (two sided test) for each stratum, i.e., 
(a) native valve endocarditis due to methicillin-resistant S. aureus, 
and (b) prosthetic material endocarditis due to methicillin resistant 
S. aureus or coagulase-negative staphylococci. If two separate studies 
are submitted, each will be properly powered for the primary endpoint. 
The assumptions for the sample sizes proposed in the protocol should be 
clearly stated with appropriate references. Interim analyses should 
also be included, as should the role of a Data Safety and Monitoring 
Board.
    Descriptions of the PK parameters to be obtained must be provided. 
Demographic and safety data will be tabulated, and a descriptive 
analysis of safety data will be provided.

Labeling Changes That May Result From These Studies

    Appropriate sections of the rifampin product labeling may be 
altered to incorporate the findings of these studies, including 
recommended pediatric dosing, treatment of endocarditis, pediatric 
pharmacokinetics, and safety information in children.

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(s) must 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.

Time Frame for Submitting Reports of the Studies

    Reports of the above studies must be submitted to the Agency on or 
before September 30, 2007. Please keep in mind that pediatric 
exclusivity attaches only to existing patent protection or exclusivity 
that has not expired at the time you submit your reports of the studies 
in response to this Written Request.

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, Project Manager, at PHONE 
NUMBER.

[FR Doc. 04-11063 Filed 5-14-04; 8:45 am]
BILLING CODE 4140-01-P