EXHIBIT 10.10
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Memorandum
Shionogi & Co., Ltd. and Peninsula Pharmaceuticals, Inc. hereby agree to attach
the Doripenem Development Plan attached hereto to the License Agreement on
S-4661 dated July 11, 2002 as Appendix IV in accordance with the Subsection
3.3(b)of the License Agreement.
Date: March 17th, 2003
Shionogi & Co., Ltd. Peninsula Pharmaceuticals, Inc.
/s/ Xxxxxx Xxxxxx Sawada /s/ Xxxx Xxxx, M.D.
--------------------------------- ----------------------------------
Xxxxxx Xxxxxx Sawada Xxxx Xxxx, M.D.
General Manager, Senior Vice President
Strategic Development Department Clinical Development
Pharmaceutical Research &
Development Division
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Clinical Development Plan
Doripenem 28 Aug 02
PENINSULA PHARMACEUTICALS INC. (PPI)
DORIPENEM
DEVELOPMENT PLAN
FOR ATTACHMENT TO LICENSE
AGREEMENT - APPENDIX IV
5 SEPTEMBER 2002
CONFIDENTIAL STATEMENT:
THIS DOCUMENT IS A CONFIDENTIAL DOCUMENT OF PENINSULA PHARMACEUTICALS, INC.
ACCEPTANCE OF THIS DOCUMENT CONSTITUTES AN AGREEMENT BY THE RECIPIENT(S) THAT
NO UNPUBLISHED INFORMATION CONTAINED HEREIN WILL BE PUBLISHED OR DISCLOSED
WITHOUT PENINSULA'S PRIOR WRITTEN APPROVAL
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Clinical Development Plan
Doripenem 28 Aug 02
1. EXECUTIVE SUMMARY
1.1 OVERVIEW
Doripenem is a sterile, synthetic, parenteral carbapenem antibiotic. The
carbapenems, modified beta-lactam structures, are highly useful due to their
potent antibacterial activities with broad antibacterial spectrum and stability
against most beta-lactamases. This class of antibiotic has been studied for
several decades, and at least one member of the class (imipenem-cilastatin) has
been commercially available for over 10 years. Subsequent carbapenems, meropenem
and most recently ertapenem, have been introduced into the U.S. marketplace and
are commercially available. Ertapenem is not yet available in the European
commercial market. The product is manufactured by Shionogi & Co., Ltd., Osaka
Japan for Peninsula Pharmaceuticals, Inc. (PPI). It is currently in Phase III
development by Shionogi in Japan.
PPI is developing doripenem for the treatment of serious bacterial infections.
The targeted indications are complicated urinary tract infections and
pyelonephritis, community-acquired pneumonia, intra-abdominal infections, and
gynecologic infections.
Submission of the NDA for these four indications is estimated to be in [*] with
FDA approval within one year of submission, followed by immediate launch of the
product into the US market.
This document is intended to provide a detailed plan for the clinical
development of doripenem. The following information will describe the medical
need for doripenem, prior experience with the drug, PPI's clinical development
strategy, summaries of planned clinical studies, timelines for completion of
development, and costs associated with the program.
1.2 DEVELOPMENT MILESTONES
TABLE 1 MEASURES OF SUCCESS MILESTONES
-------------------------------------------------------------------------------
MILESTONE DATE
-------------------------------------------------------------------------------
Definitive agreement with Shionogi for right to
develop doripenem for the US market June 2002
------------------------------------------------ ---------------------------
Initiation of Phase I multiple dose study July 2002
------------------------------------------------ ---------------------------
Initiation of Phase I renal impairment study August 2002
------------------------------------------------- ---------------------------
Submission of US IND November 2002
------------------------------------------------- ---------------------------
Initiation of Phase II cUTI study January 2003
------------------------------------------------- ---------------------------
Completion of Phase II cUTI study December 2003
------------------------------------------------- ---------------------------
Type B meeting with FDA [*]
------------------------------------------------- ---------------------------
Initiation of first Phase III study [*]
------------------------------------------------- ---------------------------
Completion of Phase III [*]
------------------------------------------------- ---------------------------
Submission of NDA [*]
------------------------------------------------- ---------------------------
Launch [*]
------------------------------------------------- ---------------------------
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Clinical Development Plan
Doripenem 28 Aug 02
2. PRODUCT CHARACTERISTICS
2.1 CHEMICAL NAME
(+)-(4R,5S,6S)-6-[(IR)-l-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-
[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]l-azabicylo
[3.2.0.]hept-2-ene-2-carboxylicacid
[CHEMICAL STRUCTURE]
2.2 GENERIC NAME
Doripenem
2.3 TRADE NAME
To be determined
2.4 NUMERICAL IDENTIFIER(S)
S-4661
2.5 CLASS OF COMPOUND
Carbapenem
2.6 DESCRIPTION
Doripenem, the generic name assigned by (INN), is a broad spectrum
methylcarbapenem antibiotic with the molecular formula C15H24N4O6S2
2.7 PREVIOUS HUMAN EXPERIENCE IN JAPAN
Please refer to newest version of the Investigational Brochure (IB) for more
detailed information.
Phase 1 and 2 studies have been completed in Japan. There are ongoing Phase 3
studies in a number of indications, including [*]. In the completed Phase 1
studies, doripenem was administered as [*] in studies involving healthy
subjects.
The following conclusions are based on the Phase I data generated in Japan:
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Clinical Development Plan
Doripenem 28 Aug 02
- All dose levels were well tolerated
- Elimination half-lives and urinary recoveries of doripenem. were [*]
the dose administered in the single-dose studies
- [*] as evidenced by [*]
- [*]
- [*]
Data from [*] in which patients with [*] clinical and bacteriological results.
In the [*] study, [*] patients were enrolled, [*] patients into the [*] and [*]
patients into the [*] Of these, [*] patients were evaluated for [*] patients in
group [*] patients in group [*] In the [*] study, [*] patients were enrolled,
[*] patients into the [*] patients into the [*] Of these, [*] patients were
evaluated for [*]
[*]
[*]
[*]
3. RATIONALE FOR PRODUCT DEVELOPMENT
3.1 MEDICAL NEED
Pathogens, particularly those in hospitalized patients, are becoming more
resistant, creating a need for new, more powerful, broader-spectrum antibiotics.
Doripenem may help to fill that need for the following reasons.
It has broad-spectrum activity against Gram-positive, Gram-negative and
anaerobic pathogens, thereby providing potential for effective empiric and
targeted therapy for frequent and severe hospital and community-acquired
infections.
It has a lower MIC than other carbapenems against P. aeruginosa. Doripenem also
exhibits greater in vitro activity than meropenem against S. pneumoniae and is
highly active against H. influenzae and other important gram-negative bacteria.
In addition, preclinical data indicate a reduced risk for seizures associated
with doripenem compared with other carbapenems.
The results of the Japanese Phase 3 clinical studies will provide increased
assurance that doripenem, will be safe and effective in US clinical studies.
Although Japanese clinical study results are generally not accepted as
sufficient evidence of efficacy and safety for a US NDA, an appropriate
evaluation of objective endpoints such as [*] offers strong supportive evidence
for [*]. In addition, efficacy data from Japan will be supportive of a US NDA,
[*].
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Doripenem 28 Aug 02
In summary, doripenem has demonstrated a broad spectrum of activity against
Gram-positive, Gram-negative, and anaerobic organisms. It is active against
penicillin-resistant S. pneumoniae and comparatively more active against P.
aeruginosa than other betalactam antibiotics. Preclinical pharmacokinetic
studies have shown good tissue distribution and low protein binding, which
suggest no impediments to human dosing. Further, toxicology studies found no
issues of concern. Thus, all preclinical and clinical information to date
suggest that doripenem may be an excellent candidate for further development in
the treatment of serious infections caused by organisms resistant to other
currently marketed antibiotics.
3.2 COMPLICATED UTI (cUTI)
Urinary tract infections (UTI) are among the most commonly seen bacterial
infections in adults. In the US, there are about 8,000,000 visits to physicians
per year, mostly for cystitis and >100,000 admissions to hospitals for acute
pyelonephritis.
Complicated UTIs, frequently due to S. aureus or P. aeruginosa, are linked to
functional or anatomical dysfunctions, to instrumentation, catheterization or to
recent use of antibiotics. Risk factors for complicated UTI include male gender,
elderly age category, previous or actual hospitalization, pregnancy, duration of
symptoms >7 days, presence of stones, indwelling catheter, recent
instrumentation, anatomical abnormalities, history of UTI in childhood,
immunosuppression or recent use of antibiotics. These infections require a
prolonged antibiotic treatment to be cured.
Acute pyelonephritis is characterized by fever, lumbar pain, nausea, and
vomiting. Lower UTI symptoms may be absent. Pyuria and significant bacteriuria
(in 20% <105cfu/ml) are always present, blood cultures are positive in 15-20%.
Fifty percent of acute pyelonephritis is uncomplicated and observed mainly in
young women. The other 50% are found mainly in elderly men with prostate
hyperplasia with recent or indwelling catheters. Patients with acute
pyelonephritis should be hospitalized if complicated Or severely ill, unstable,
immunocompromised, pregnant, or if they are children or men. Patients are
usually treated for 14-21 days in the absence of major complications.
Doripenem is likely to present with increased effectiveness in the treatment of
complicated UTI and pyelonephritis due to its high rate of urinary excretion [*]
and its good activity against urinary tract pathogens, especially P. aeruginosa
and S. aureus.
3.3 COMMUNITY-ACQUIRED PNEUMONIA (CAP)
Community-acquired pneumonia (CAP) remains a common and persistent cause of
morQl2Hity and mortality. Between 2 and 3 million cases of CAP result in
approximately 10 million physician visits, 500, 000 hospitalizations, and 45,000
deaths annually in the U.S.(4) Mortality ranges from 2% to 30% in hospitalized
patients, with an average mortality of 14%, in clinical studies. In contrast,
mortality is estimated to be less than 1% in patients who are not
hospitalized.(5,6)
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Doripenem 28 Aug 02
Streptococcus pneumoniae accounts for the majority of cases of pneumonia in
patients over 50 years old. Twenty-five percent of S. pneumoniae are
nonsusceptible to penicllin.
Gram-negative aerobic pneumonia is usually a nosocomial infection.
Community-acquired, Gram-negative pneumonia is rare and more likely to occur in
patients who have been recently hospitalized or are on steroids or
immunosuppressive drugs. However, Klebsiella and P. aeruginosa can occur in the
alcoholic or debilitated elderly patient without additional risk factors. These
infections are associated with a high mortality. Doripenem may constitute an
effective, empiric broad spectrum antibiotic therapy for such infections, [*].
Doripenem is likely to be effective in the treatment of CAP due to its activity
against S. pneumoniae, including penicillin-intermediate and
penicillin-resistant strains. Further, administration of radiolabeled doripenem
to mice and rats has shown substantial and rapid distribution to lung tissue.
3.4 COMPLICATED INTRA-ABDOMINAL INFECTIONS
The treatment of intra-abdominal infections and peritonitis is based on sound
surgical technique and source control, potent antibiotics with a spectrum that
ensures the killing of anaerobic and aerobic pathogens, and adjuvant intensive
care treatment.
In clinical trials, treatment is generally considered successful if resolution
of signs and symptoms of infection is achieved with a single course of
antibiotics and if only one operation is required to control the infectious
process. Treatment is generally considered a failure in clinical trials if
antimicrobial therapy is changed because of lack of response, if additional
operations are required to control the local infectious process, or if any
adverse reaction occurs requiring a change of antibiotic therapy.
The characteristics of clinical failure in antibiotic studies have been disputed
for their relevance for daily clinical practice. Regardless of which antibiotics
are used initially, change or addition of other antibiotic agents is likely in a
large proportion of patients. In clinical practice, changing an antibiotic
regimen is not a failure. Re-operation, whether scheduled or dictated by the
clinical course, is a success if it results in a living, healthy patient. The
rate of treatment success with a single operation and single course of
antibiotics may be as low as 48%.
Doripenem may prove to be an effective treatment for complicated intra-abdominal
infections because of its broad spectrum of activity against aerobic and
anaerobic bacteria.
3.5 GYNECOLOGIC INFECTIONS
There are several types of gynecologic infections of the upper female genital
tract, including any combination of endometritis, salpingitis, tubo-ovarian
abscess, pelvic peritonitis, and post-surgical infections. Sexually transmitted
organisms, especially N. gonorrhoeae and C. trachomatis, are implicated in most
cases; however, microorganisms that can be part of the vaginal flora (e.g.,
anaerobes, G. vaginalis, H. influenzae, enteric Gram-negative rods, and
Streptococcus agalactiae) also can cause acute pelvic infections in women.
Diagnosis of gynecologic infection usually is based on clinical findings.
Although the clinical diagnosis of gynecologic infection is often imprecise,
treatment should be initiated as soon as the presumptive diagnosis has been
made, because prevention of long-term sequelae has been linked directly with
immediate administration of appropriate antibiotics. Treatment regimens for
gynecologic infections must provide empiric, broadspectrum coverage of likely
pathogens. Antimicrobial coverage should include N. gonorrhoeae, C. trachomatis,
anaerobes, Gram-negative facultative bacteria, and streptococci. Although the
need to eradicate anaerobes from women who have gynecologic infection has not
been determined definitively, the evidence suggests that this may be important.
Anaerobic bacteria have been isolated from the upper-reproductive tract of women
who have gynecologic infection, and data from in vitro studies have revealed
that anaerobes such as Bacteroides fragilis can cause tubal and epithelial
destruction. Doripenem may prove to be an excellent empiric treatment for
gynecologic infection because of its activity against Gram-negative and
anaerobic bacteria.
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Clinical Development Plan
Doripenem 28 Aug 02
4. DEVELOPMENT STRATEGY
4.1 OVERALL STRATEGY
Doripenem was licensed from Shionogi & Co., Ltd, Japan, where it is currently in
Phase III clinical development. [*]. Results of these programs demonstrated
minimal safety concerns and favorable pharmacokinetics and clinical and
bacteriological efficacy. All reports of these studies are being translated into
English and will be submitted with the US IND. In parallel with these
activities, a Phase 1 multiple dose escalation study is being conducted in the
UK and results of this study will also be submitted as part of the US IND. [*].
The overall objective of the doripenem, development program is to conduct large,
well controlled studies in a limited number of major indications such as CAP and
complicated UTI for the US registration application.
The Japanese Phase 3 study results maybe recognized as supportive evidence of
efficacy, [*]
4.2 OVERVIEW OF PPI-SPONSORED CLINICAL STUDIES
Table 2 briefly summarizes the proposed PPI-sponsored clinical development
program
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TABLE 2 OVERVIEW OF STUDIES
Doripenem Comparator Dose(s) N Enrolled (N Estimated Data
Study (Phase) Objective/Design Dose(s) (mg) (mg) Evaluable/Arm) Study Start Base Closure
--------------------------------------------------------------------------------------------------------------------------
XXXX-01 [*] [*] [*] [*] [*] [*]
(Phase I)
--------------------------------------------------------------------------------------------------------------------------
XXXX-02 [*] [*] [*] [*] [*] [*]
(Phase I)
--------------------------------------------------------------------------------------------------------------------------
XXXX-03 [*] [*] [*] [*] [*] [*]
(Phase II)
--------------------------------------------------------------------------------------------------------------------------
XXXX-04 [*] [*] [*] [*] [*] [*]
(Phase III)
--------------------------------------------------------------------------------------------------------------------------
XXXX-05 [*] [*] [*] TBD [*] [*]
(Phase III)
--------------------------------------------------------------------------------------------------------------------------
XXXX-08 [*] [*] [*] TBD [*] [*]
(Phase III)
--------------------------------------------------------------------------------------------------------------------------
XXXX-09 [*] [*] [*] TBD [*] [*]
(Phase III)
--------------------------------------------------------------------------------------------------------------------------
XXXX-06 [*] [*] [*] TBD [*] [*]
(Phase 3)
--------------------------------------------------------------------------------------------------------------------------
XXXX-07 [*] [*] [*] TBD [*] [*]
(Phase III)
--------------------------------------------------------------------------------------------------------------------------
XXXX-10 [*] [*] [*] [*] [*] [Q2 2005]
(Phase I)
--------------------------------------------------------------------------------------------------------------------------
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Doripenem 28 Aug 02
4.3 HIGH LEVEL TIMELINE
The following figure summarizes high-level timelines for the development
program.
4.4 DESCRIPTIONS OF PPI-SPONSORED CLINICAL STUDIES
Detailed descriptions of the first three of these studies follow.
4.4.1 XXXX-01
[*]
4.4.1.1 OBJECTIVES
- Assess the safety and tolerability of doripenem administered
intravenously to healthy subjects
- Investigate the pharmacokinetic profile of doripenem in a [*]
population
4.4.1.2 DESIGN
Dose-escalation, randomized study with [*]
Eligible subjects will be admitted to the study unit on [*]. A summary of the
dosing regimens follows.
DOSE COHORT DOSE REGIMEN
-----------------------------------------
[*] [*] [*]
-----------------------------------------
[*] [*] [*]
-----------------------------------------
[*] [*] [*]
-----------------------------------------
[*] [*] [*]
-----------------------------------------
4.4.1.3 PRIMARY ENDPOINTS
Safety
Adverse event -information will be collected daily and xxxxx xxxxx will be
measured before and after each infusion. Blood and urine sample for clinical
laboratory analysis will be collected periodically throughout the study and
there will be [*].
Pharmacokinetic
Blood and urine samples will be collected at predetermined times throughout the
study for pharmacokinetic analysis.
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Doripenem 28 Aug 02
4.4.1.4 SELECTION OF CONTROL GROUP
[*]
4.4.1.5 NUMBER OF SUBJECTS
Up to [*] healthy subjects between [*] years of age will be enrolled.
4.4.1.6 RESPONSE VARIABLES
Safety will be assessed through [*]. All data collected will be assessed for
severity, changes from baseline and their relationship to treatment with study
drug.
Pharmacokinetic assessments will be determined from [*] samples.
4.4.1.7 METHODS TO MINIMIZE OR ASSESS BIAS
Subjects within each cohort will be randomly assigned to [*].
4.4.2 XXXX-02
[*]
4.4.2.1 OBJECTIVES
Assess the safety, tolerability and pharmacokinetics of doripenem administered
intravenously in subjects with [*]
4.4.2.2 DESIGN
Single-dose study with [*].
Subjects will be admitted to the [*] the morning prior to study drug
administration and will be maintained in the [*] for pharmacokinetic analysis
for a minimum of [*] following infusion. Subjects will return to the [*] on [*]
for the final follow-up visit.
[*]:
[*] [*] [*] [*] [*]
[*] [*] [*] [*] [*]
[*] [*] [*] [*] [*]
[*] [*] [*] [*] [*]
4.4.2.3 PRIMARY ENDPOINTS
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Doripenem 28 Aug 02
Safety
Adverse event information will be collected daily and xxxxx xxxxx will be
measured [*] from the day of infusion up to [*] thereafter. Blood and urine
sample for clinical laboratory analysis will be collected periodically
throughout the study and there will be [*].
Pharmacokinetic
[*] samples will be collected at predetermined times throughout the study for
pharmacokinetic analysis.
4.4.2.4 SELECTION OF CONTROL GROUP
The control group within each cohort will be subjects with [*].
4.4.2.5 NUMBER OF SUBJECTS
Up to [*] subjects between [*] years of age will be enrolled.
4.4.2.6 RESPONSE VARIABLES
Safety will be assessed through [*]. All data collected will be assessed for
severity, changes from baseline and their relationship to treatment with study
drug. Pharmacokinetic assessments will be determined from [*] samples.
4.4.2.7 METHODS TO MINIMIZE OR ASSESS BIAS
Control subjects within each cohort will be matched to [*] subjects by age and
weight.
4.4.3 XXXX-03
[*]
4.4.3.1 OBJECTIVES
The primary objective of this study is to: Determine the microbiological
response of patients with [*] following [*] of treatment with either of [*]
dosing regimens of doripenem infusions at [*] post-therapy Secondary objectives
of this study are to: Determine the clinical response of patients with [*]
following [*] of treatment with either of [*] dosing regimens of doripenem
infusions at [*] post-therapy Evaluate the safety of doripenem, in patients with
[*] Obtain doripenem pharmacokinetic data in patients with [*].
4.4.3.2 DESIGN
[*]
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The study design is shown schematically in the following figure.
[*] ---> [*] ---> [*]
4.4.3.3 PRIMARY AND SECONDARY ENDPOINTS
The primary efficacy analysis, [*], will be conducted in the microbiologically
evaluable population. The following secondary efficacy analyses will be
conducted:
- [*]
- [*]
- [*]
- [*]
4.4.3.4 SELECTION OF CONTROL GROUP
[*] will be tested.
4.4.3.5 NUMBER OF PATIENTS
Approximately [*] evaluable patients with [*] will be enrolled. It is
anticipated that [*] of all enrolled patients will be non-evaluable for
microbiologic efficacy and that total patient enrolment will therefore be
approximately [*] patients. These patients will, be recruited from approximately
[*]
4.4.3.6 RESPONSE VARIABLES
The TOC microbiological efficacy criteria will be:
- [*].
- [*].
- [*].
- [*]
Patients who experience [*] will be considered microbiological successes.
Patients who experience [*] under study will be considered microbiological
failures.
The TOC clinical efficacy criteria will be:
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- [*]
- [*]
The safety criteria will be:
- Adverse events, [*].
4.4.4 [*]
[*] statistically adequate and well-controlled [*] establishing [*] and [*] that
establishes [*] are required for this indication. If there is not a sufficient
number of patients with [*] successfully treated with the investigational agent
(minimum of [*]) the indication will not be included.
Studies should be adequately powered to demonstrate [*] in the per the protocol
evaluable population. [*].
The primary effectiveness parameter should be [*] outcome at the [*] after
cessation of therapy). Clinical and microbiological outcome should also be
evaluated at the [*] in order to assess relapse and recurrence rates.
NOTE: [*]
4.4.5 [*]
[*] statistically adequate and well-controlled [*] should be conducted
establishing safety and effectiveness (i.e., [*])[*] involving at least [*]
patients from at least [*] areas are required for this indication. The results
of the [*] should be consistent with results of the [*] and demonstrate
consistency in the action of the drug in treating this infection.
Patients should be analyzed in [*] separate groups: those who are [*].
Clinical outcome is the primary efficacy variable for the indication of [*]. The
patient's response to therapy should be based on a comparison of the patient's
[*] to the patient's evaluation at [*] after completion of therapy).
4.4.6 [*]
This indication should encompass [*].
[*] statistically adequate and well-controlled [*] establishing [*] is
suggested. At least [*] of the patients should be microbiologically, as well as
clinically, evaluable. Analysis of the data should generally confirm (by means
of [*]) the successful outcome rates established for the overall clinically
evaluable and for the clinically and microbiologically evaluable subset of
patients. Likewise the analysis should establish the correlation between [*] in
the clinically and
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microbiologically evaluable subset of patients. To establish effectiveness in
treating [*], the investigative agent should also establish effectiveness [*] or
should establish [*].
It should be assumed that an applicant successfully establishing effectiveness
of an antimicrobial drug product for treatment of this infection should also
establish effectiveness of the product [*] in order to support this [*].
[*] are also required. Such studies would include, but not be limited to, [*].
4.4.7 [*]
NOTE: This indication does not include [*]
[*] statistically adequate and well-controlled [*] establishing [*] is
suggested. At least [*] of the clinically evaluable patients should also be
microbiologically evaluable. Analysis of the data should also generally confirm
(by means of [*]) the successful outcome rates established for the overall
clinically evaluable and for the clinically and microbiologically evaluable
subset of patients. Likewise the analysis should establish the correlation
between [*] in the clinically and microbiologically evaluable subset of
patients.
It should be assumed that an applicant successfully establishing effectiveness
of an antimicrobial drug-product for treatment of this infection should also
establish effectiveness of the product [*] in order to support this [*] trial.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data
supportive of [*] in this disease entity are also suggested. Such studies would
include, but not be limited to, [*].
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13.
