[Federal Register: May 17, 2004 (Volume 69, Number 95)]
[Notices]
[Page 27942-27945]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17my04-111]
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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 BestPharmaceuticals@mail.nih.gov.
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 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 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