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DIVISION OF ANTI-INFECTIVE DRUG PRODUCTS
POINTS TO CONSIDER
CLINICAL DEVELOPMENT AND LABELING OF
ANTI-INFECTIVE DRUG PRODUCTS
SPECIFIC INFECTIONS
- Uncomplicated urinary tract infections
- Complicated urinary tract infections
- Uncomplicated skin and skin structure infections
- Complicated skin and skin structure infections
- Community-acquired pneumonia
- Nosocomial pneumonia
- Acute bacterial exacerbations of chronic bronchitis
- Secondary bacterial infections of acute bronchitis
- Acute otitis media
- Acute sinusitis
- Streptococcal pharyngitis
- Bacterial meningitis
- Uncomplicated gonococcal urethritis/cervicitis
- Non-gonococcal urethritis/cervicitis
- Acute prostatitis
- Endocarditis
- Uncomplicated intra-abdominal infections
- Complicated intra-abdominal infections
- Gynecologic infections (non-STD or PID)
- Pelvic inflammatory diseases
- Bacterial vaginosis
- Osteomyelitis (acute & chronic)
- Acute bacterial arthritis
- Empiric therapy in febrile neutropenia
- Helicobacter pylori-Associated Peptic Ulcer Disease [DRAFT] (March 1995 Addendum; Revised: 9 June, 1995)
(Please see Section VIII for some study conduct issues related to these trials, especially regarding numbers of sites and percentages of patients from a given site.)
(1) Uncomplicated Urinary Tract Infections (Cystitis)
(Scenario One)
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. In a study of this infection, an evaluable patient should be both clinically and microbiologically evaluable. Although, generally, the primary effectiveness parameter in this study should be microbiologic outcome at 5 to 9 days after the cessation of therapy, the study should establish the general correlation between clinical cure and bacterial eradication in these patients. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling for this infection should be as per Section III of this document.
(Scenario Two)
If the dosage and duration of therapy are the same for complicated urinary tract infections and effectiveness in complicated urinary tract infections is established as below for similar microorganisms, only one statistically-adequate and well-controlled trial, performed at at least two different centers with no more than 55% of the evaluable patients from any one center, should be sufficient to establish effectiveness in uncomplicated urinary tract infections. Any pathogen listed in the complicated infection label should be incorporated into the label for the uncomplicated infection claim, if the pathogen is generally accepted to be associated with uncomplicated urinary tract disease. This suggestion is not intended to suggest that similar dosing regimens for uncomplicated and complicated urinary tract infections should be studied. Applicants should determine the most effective and least toxic dose for each indication.
(Both scenarios)
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in uncomplicated urinary tract infections should also be submitted. Such studies should include, but not be limited to, tissue distribution studies that demonstrate that, at the dosing regimen requested in the NDA, the investigative agent diffuses into urine in quantities adequate to achieve and maintain urine levels equal to or above the expected MIC90's of the claimed pathogens for an acceptable period of time.
If an applicant chooses to perform more than one adequate and well-controlled trial in this specific infection, specific pharmacokinetic and pharmacodynamic data relative to this indication should not ordinarily be necessary, though clearly it is of interest.
(2) Complicated Urinary Tract Infections and Pyelonephritis
 One statistically adequate and well-controlled trial establishing equivalence or superiority to an approved agent and one open trial that establishes statistical equivalence to the success rate of the approved agent in the first complicated UTI trial or to an effectiveness rate agreed upon with the Division are suggested.
For the second trial, the applicant should demonstrate that the patient demographics, the disease severity, the exclusion/inclusion criteria, the evaluability criteria, and the primary effectiveness parameters were not substantively different from those in the adequate and well-controlled first trial. The second trial should be performed by different investigator(s) than those involved in the first trial and the site(s) should represent geographically different area(s).
For studies of this infection, an evaluable patient should be both clinically and microbiologically evaluable. Although the primary effectiveness parameter in these studies should be microbiologic outcome, the study should establish the general correlation between clinical cure and bacterial eradication in these patients. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
The Division recognizes that pyelonephritis can be either an uncomplicated or complicated clinical disease. The Division suggests that it be studied with complicated urinary tract infections as dosing regimens for pyelonephritis and complicated urinary tract infections are routinely similar. If there is not a sufficient number of patients with pyelonephritis successfully treated with the investigative agent (minimum: 30 patients/arm/study), the listing should not include pyelonephritis.
(3) Uncomplicated Skin and Superficial Skin Structure infections
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. It is suggested that the numbers of evaluable patients with simple abscesses, impetiginous lesions, furuncles, and cellulitis should be at least 20% each so that this general claim could be granted. NDA's with critical studies, in which only one or two specific types of uncomplicated skin and skin structure infections were studied, should receive a listing only for those one or two specific types of infection. Protocols used to study an investigative product for treatment of these infections should have very clear inclusion, exclusion, evaluability criteria, and outcome definitions as the primary effectiveness parameter for this infection should be clinical outcome. Nonetheless, at least 50% of the clinically evaluable patients should also be microbiologically evaluable in order that adequate numbers of evaluable cases with specific pathogens are available to assess general effectiveness for specific pathogens.
(1) The simple growth of transient or resident skin flora in a culture should not constitute a microbiologically evaluable patient. Pathogens listed in the INDICATIONS AND USAGE section of the product label should be those established in the submitted data that also reflect contemporary beliefs about pathogenicity in these types of skin infections. In addition, the microbiologic culture sample should be obtained in such a manner that biologically meaningful conclusions can be reached based on the data.
(3) Analysis of treatment outcomes in these infections should be stratified by the presence or absence of therapeutic surgical intervention(s). In certain circumstances where it appears the surgical treatment was required as an adjunct or follow-up therapy due to failure of the investigative agent to successfully treat the uncomplicated skin infection, the patient should be evaluated as a treatment failure.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity should be submitted. Such studies would include, but not be limited to, tissue distribution studies that demonstrate that, at the dosing regimen requested in NDA, the investigative agent diffuses into skin and superficial skin structure tissues or other validated surrogate marker in quantities adequate to achieve and maintain skin and superficial skin structure levels equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
If an applicant chooses to perform more than one adequate and well-controlled trial in this indication (e.g., to establish a sufficient overall safety data base for the product), specific pharmacokinetic/-dynamic data relative to this indication should not ordinarily be necessary.
(4) Complicated Skin and Soft Tissue Infections
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product or to an approved method of treating these types of infections is suggested. Under this heading should be considered infected ulcers, burns, and major abscesses or other skin structure infections requiring significant surgical intervention along with antimicrobial drug therapy, and infections of the deeper soft tissues. Numbers of patients with each type of these infections should be such that a general claim could be granted. NDA's with critical studies, in which only one or two specific types of these infections were studied, should receive a listing only for those one or two specific types of infection. Protocols used to study an investigative product for treatment of these infections should have very clear inclusion, exclusion, and evaluability criteria and outcome definitions as the primary effectiveness parameter for this infection should be clinical outcome. Nonetheless, at least 70% of the clinically evaluable patients should also be microbiologically evaluable in order that adequate numbers of evaluable cases with specific pathogens are available to assess general effectiveness for specific pathogens. Analysis of treatment outcomes in these infections should be stratified by the presence or absence of therapeutic surgical intervention(s). In certain circumstances where it appears the surgical treatment was required as an adjunct or follow-up therapy due to failure of the investigative agent to successfully treat the infection, the patient should be evaluated as a treatment failure.
Analyses of the data should also generally confirm (by means of comparing the direction of the independent 95% confidence intervals testing) the successful outcome rates established for the overall clinically evaluable and for the clinically and microbiologically evaluable subset of patients. Likewise the analyses should establish the correlation between clinical cure and bacterial eradication in the clinically and microbiologically evaluable subset of patients.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity should be provided. Such studies would include, but not be limited to, tissue distribution studies that demonstrate that, at the dosing regimen requested in the NDA, the investigative agent diffuses into skin and deeper soft tissues or other validated surrogate marker in quantities adequate to achieve and maintain skin and superficial skin structure levels equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
If an applicant chooses to perform more than one adequate and well-controlled trial in this indication (e.g., to establish a sufficient overall safety data base for the product), specific pharmacokinetic/-dynamic data relative to this indication should not ordinarily be necessary.
(5) Community-acquired Pneumonia
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product and one open trial are suggested.
The adequate and well-controlled trial should preferably be performed in the United States for purposes of U.S. product approval. In this trial, the primary effectiveness endpoints should be clinical and radiographic endpoints; however, microbiologic evaluations (culture and gram stain) should also be performed on each patient. Isolation of a pathogen from the baseline sputum culture should not be required for overall evaluability; however, rigid case definitions, including specific entry sputum microscopy and radiographic findings [specific to the type(s) of community acquired pneumonia being studied] should be included in the trial design.
Patients should be analyzed in two separate groups: (1) those who were clinically evaluable (whether or not microbiologically evaluable) and (2) those who were clinically evaluable and microbiologically evaluable. Analyses of the data should also generally confirm (by means of comparing the direction of the independent 95% confidence intervals testing) the successful outcome rates established for the overall clinically evaluable and for the clinically and microbiologically evaluable subset of patients. Likewise the analyses should establish the correlation between clinical cure and bacterial eradication in the clinically and microbiologically evaluable subset of patients.
Also suggested is a second study, which may be an open trial, involving at least 2 investigators in different geographic areas (no one center contributing more than 55% of the evaluable patients) in which 80 evaluable patients are studied. In this trial, the microbiologic etiology of the pneumonia should be confirmed for each patient. For this second trial, the applicant should demonstrate that the patient demographics, the disease severity, the exclusion/inclusion criteria, the evaluability criteria, and the effectiveness parameters were not substantively different from those in the adequate and well-controlled first trial. The second trial should be performed by different investigator(s) than those involved in the first trial, and the site(s) should represent geographically different area(s). The results of this trial should be consistent with the results obtained in the controlled trial and demonstrate consistency in the action of the drug in treating this infection.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
In situations where atypical microorganisms causing community-acquired pneumonia are evaluated or when different susceptibility patterns are expected for specific microorganisms in different populations, different comparative agents and/or different patient populations may be selected for the two trials that should corroborate one another in the establishment of effectiveness in treating this infection. In these circumstances, it should be appropriate to perform two studies that investigate outcomes in both the clinically evaluable patients and in the clinically and microbiologically (i.e., the pathogen is confirmed by an approved laboratory test methodology) evaluable subset of patients. Analyses of the data should confirm (by means of comparing the direction of the independent 95% confidence interval testing or by appropriate other analysis if the subgroups can be combined from the two separate studies) the successful outcome rates established for the overall clinically evaluable and for the clinically and microbiologically evaluable subset of patients.
(6) Nosocomial Pneumonia
One well-controlled trial that establishes effectiveness equivalent (meets standard 95% confidence interval approach) or generally equivalent (difference in absolute success rates no greater than 5% less effective in clinical parameters) to an approved comparator agent or to a prospectively agreed upon comparator treatment regimen is suggested. The 5% referred to in the "generally equivalent" comment is not a 95% confidence interval; rather, it is the calculated difference between the absolute successful clinical outcome rates of the evaluable patients in the two arms of this trial. It is suggested that at least 80 patients would be in each treatment arm. In studies of this infection, an evaluable patient should be clinically, radiographically, and microbiologically evaluable. Rigid case definitions, including specific entry sputum microscopy and radiographic findings should be included in the trial design.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
(7) Acute Bacterial Exacerbations of Chronic Bronchitis
 Two trials are suggested.
One statistically adequate and well-controlled trial establishing equivalence or superiority to an approved product is suggested. In this trial, an evaluable patient should be both clinically and microbiologically (any putative pathogen) evaluable. Analysis of the data should confirm the general correlation between clinical improvement and bacterial eradication (or suppression) in the evaluable patients.
Also suggested is a second study, in which clinical effectiveness should be used as the only primary effectiveness endpoint; however, microbiologic studies should be performed on each patient but pathogen isolation at baseline or susceptibility to either trial drug should not be required for overall evaluability. This trial should preferably be performed in the United States for purposes of U.S. product registration. Patients, in this trial, should be analyzed in two separate groups: (1) those who were clinically evaluable (whether or not microbiologically evaluable) and (2) the subset of patients who were clinically evaluable and microbiologically evaluable. This trial should employ rigorous entry and evaluability criteria to insure the likelihood of bacteria being responsible for the exacerbation. Analyses of the data should confirm (by means of comparing the direction of the independent 95% confidence interval testing) the successful outcome rates established for the overall clinically evaluable and for the clinically and microbiologically evaluable subset of patients. Likewise, the analyses should establish the general correlation between clinical improvement and bacterial eradication (or suppression) in the clinically and microbiologically evaluable subset of patients.
Only Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae (based on acceptable clinical and microbiologic responses for these three microorganisms in the clinical trials) should presently be listed as pathogens amenable to therapy with the investigative agent in this infection. As evidence accumulates that other microorganisms are pathogenic in this disease, consideration should be given to their addition to the list.
If effectiveness in either of the two pneumonia claims is established by the product at the same dosing regimen (dose and duration) for the three clinically relevant (AECB) microorganisms, only the one "clinically plus microbiologically evaluable" study should be sufficient to establish the effectiveness of the antimicrobial drug product in the treatment of this infection.
(8) Secondary Bacterial Infection of Acute Bronchitis
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. In this trial, an evaluable patient should be both clinically and microbiologically evaluable. Analyses of the data should confirm the general correlation between clinical cure and bacterial eradication in the evaluable patients.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
In order to establish, by means of this one trial, effectiveness of the antimicrobial product in treating this infection, the applicant should also have data to support effectiveness in the treatment of "Acute bacterial exacerbations of chronic bronchitis" as outlined previously in this document.
(9) Acute Otitis Media
 Two trials are suggested.
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested.
In this trial, rigid case definitions should be used with specific subjective and objective diagnostic parameters and effectiveness parameters clearly defined prospectively. This trial should not ordinarily enroll children less than 6 months of age. Baseline tympanocentesis need not be performed in this study; however, tympanocentesis of patients judged to be therapeutic failures is strongly encouraged to document potential specific bacterial pathogens not adequately treated in the trial. This trial should preferably be performed in the United States for purposes of U.S. product approval.
Also suggested would be one open study utilizing tympanocentesis or other validated bacterial etiologic detection methodology at baseline to establish microbiologic etiology. This study should establish acceptable microbial and clinical outcome in at least 25 patients with H. influenzae, in at least 25 patients with S. pneumoniae, and in at least 15 patients with M. catarrhalis. Post-therapy tympanocentesis is strongly encouraged in those patients judged to be therapeutic failures so that bacterial persistence or superinfection could be determined. In this trial, outcomes on all patients enrolled should be reported, not just those patients with the bacterial pathogens mentioned previously in this paragraph.
It would be expected that this trial would be performed by at least two investigators in geographically diverse regions. As etiologic patterns change, the requisite microorganisms listed would also change.
Pathogens listed in the final product label should be those of the three listed above that had acceptable eradication rates. If a product failed to have acceptable clinical and microbiologic effectiveness against all three microorganisms, the product should be listed only for those microorganism(s) that it eradicated. It should also receive a "restricted" listing as "not a product for first line therapy". This restriction should be based on the empiric nature of the treatment of this disease at the present time, and the need for true first-line therapies to be efficacious against all of the presently common bacterial pathogens associated with this infection. To receive an unrestricted label in this infection, the investigative product should be compared to a product with an unrestricted label in the "clinical only trial" outlined previously in this section.
(10) Acute Sinusitis
 Two studies are suggested.
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. In this trial, rigorous case definitions with specific clinical and either radiographic or ultrasonic entry criteria and endpoints as the primary effectiveness parameters should be used. Sinus aspiration need not be performed in this study, although aspiration of patients judged to be therapeutic failures should be strongly encouraged to document any bacterial pathogen(s) not adequately treated in the trial. This trial should preferably be performed in the United States for purposes of U.S. product approval.
Also suggested would be one open study utilizing sinus aspiration. This trial should establish successful microbial, clinical, and radiographic or ultrasonic outcome in at least 100 patients. This study should establish acceptable microbial and clinical outcome in at least 25 patients with H. influenzae, in at least 25 patients with S. pneumoniae, and in at least 15 patients with M. catarrhalis. Post-therapy sinus aspiration is strongly encouraged in those patients judged to be therapeutic failures so that bacterial persistence or superinfection could be determined. In this trial, outcomes on all patients enrolled should be reported, not just those patients with the bacterial pathogens mentioned previously in this paragraph. This trial should be performed by at least two investigators in geographically diverse regions, and no one center should contribute more than 55% of the evaluable patients.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document. If a product failed to eradicate the major bacterial pathogens associated with this infection, the product should also receive a "restricted" listing as "not a product for first line therapy". This restriction should be based on the empiric nature of the treatment of this disease at the present time and the need for true first-line therapies to be efficacious against the major bacterial pathogens associated with this infection.
(11) Streptococcal Pharyngitis
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. Despite statistical equivalence to an approved product, any product with an absolute eradication rate at follow-up of <85% should not ordinarily be approved as a first line therapy for this infection. Although the primary effectiveness parameter in this study should be microbiologic eradication, the study should establish the general correlation between clinical cure and bacterial eradication in these patients.
In studies of this infection, an evaluable patient should be clinically and microbiologically evaluable.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity should also be submitted. Such studies should include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into tonsillar tissues in quantities adequate to achieve and maintain tonsillar tissue concentrations equal to or above the expected MIC90's of the claimed pathogen for an adequate period of time.
If an applicant chooses to perform more than one adequate and well-controlled trial in this indication (e.g., to establish a sufficient overall safety data base for the product), specific pharmacokinetic/-dynamic data relative to this indication should not ordinarily be necessary.
(12) Bacterial Meningitis
 In pediatrics, one statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. Follow-up to determine neurologic sequelae following treatment is suggested to determine final therapeutic effectiveness of a drug product.
In adult meningitis, one open trial that establishes equivalence to a previously agreed upon mandatory microbiologic eradication rate and clinical cure rate is suggested. The minimally acceptable cure rate should be determined by the particular disease (patient age and microorganisms being studied). Follow-up to determine neurologic sequelae following treatment is also suggested to determine final therapeutic effectiveness of a drug product.
In both pediatric and adult meningitis, adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity should be submitted. Such studies should include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into cerebrospinal fluid in quantities adequate to achieve and maintain cerebrospinal fluid levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document.
(13) Uncomplicated Gonococcal Urethritis/Cervicitis
 Effectiveness against this disease entity should be established in both men and women. Effectiveness could be established by two open trials - one trial for each gender (or one trial enrolling adequate numbers of both men and women).
One trial should involve at least 100 men, and one trial should involve at least 100 women.
Bacterial eradication rate should be the primary effectiveness endpoint, and at least 95% bacterial eradication should be expected in both trials (or for both genders if one trial is performed) in order to support the claim for this infection. Initial resistance of a given isolate to the investigative agent should not ordinarily make that patient non-evaluable. Patients could be stratified by presence or absence of resistance to the pathogen and then analyzed. Such an approach may result in a restricted indication, depending on the data outcome.
When beta-lactamase production is not a factor (i.e., in non-beta-lactam antimicrobial drug products), evaluation of infections caused by beta-lactamase-producing microorganisms should not be needed. If beta-lactamase production is a factor, greater than 95% bacterial eradication should be demonstrated in a subset analysis of at least 40 patients (at least 20 men and 20 women) from these two trials in order to support specific wording in the INDICATIONS AND USAGE section that states the product is indicated in the treatment of uncomplicated gonococcal urethritis/cervicitis due to beta-lactamase-positive and beta-lactamase-negative strains of N. gonorrhoeae. Without such data, the labeling should be restricted to beta-lactamase-negative N. gonorrhoeae, and the labeling should also have a "not first line therapy" restriction depending on the level of beta-lactamase-positive N. gonorrhoeae in the country at the time of approval of the final product labeling.
Once effectiveness in uncomplicated gonococcal urethritis/cervicitis has been established, effectiveness in gonococcal pharyngitis or proctitis may be established by scanning data bases from the critical studies and from similar uncomplicated gonococcal urethritis/cervicitis studies recognized by the Division as adequate studies. All patients with gonococcal pharyngitis or proctitis should be pooled, and all patients with these diagnoses should be included in the analyzed data. A minimum of 20 patients each of each gender for each additional body site (i.e., rectum, pharynx) where at least 90% bacterial eradication is demonstrated should be sufficient to establish effectiveness in these additional infections. Applicants should be encouraged to study these additional body sites in both men and women; however, individual gender-specific labeling claims could be approved by the Division if the above criteria are met.
(14) Non-gonococcal Urethritis/Cervicitis
Applicants are strongly encouraged to study effectiveness of their antimicrobial drug product in treating this infection in both men and women; however the listing for this infection may be supported independently for either men or women. One statistically adequate and well-controlled multicenter trial in men establishing equivalence or superiority to an approved product is suggested to support the claim in men. One statistically adequate and well-controlled multicenter trial in women establishing equivalence or superiority to an approved product is suggested to support the claim in women.
For this infection, an evaluable patient should be both clinically and microbiologically evaluable. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should presently be limited to specific Chlamydia species, specific Ureaplasma species, and specific Mycoplasma species based on acceptable clinical and microbiologic responses for species of these three genera in the clinical trials. As evidence accumulates that other microorganisms are pathogenic in this infection, the Division would consider including them on the list.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity are also suggested. Such studies should include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into urethral and cervical exudates in quantities adequate to achieve and maintain urethral and cervical exudate levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
(15) Acute Prostatitis
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. In this infection, an evaluable patient should be both clinically and microbiologically evaluable. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be those as per Section III of this document.
It is assumed that the compound would have also established effectiveness in complicated urinary tract infections and that the majority of pathogen are similar. Clearly some potential pathogens, such as species of Chlamydia, should be evaluated on their responses in this study and in investigations of treatment of other infectious sites involving Chlamydia.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity are also suggested. Such studies would include, but not be limited to, tissue distribution studies that demonstrate that the investigative agent diffuses into prostatic secretions and tissues in quantities adequate to achieve and maintain prostatic secretions and tissue levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
(16) Endocarditis
 One open trial of at least 50 patients that establishes a predetermined overall clinical and microbiologic success rates is suggested. For this infection, an evaluable patient should be both clinically and microbiologically evaluable. If there is not a reasonable mix of artificial and native valve, right and left sided disease, and acute versus subacute clinical presentations, such should be noted in the approved labeling by restricting the labeling in the INDICATIONS AND USAGE section of the product labeling to just those types of infection and populations actually studied. This trial should involve at least two investigators in different geographic areas. Pathogens listed would be determined on a case-by-case basis, taking into account various expected success rates for the treatment of specific pathogens.
Adequate microbiologic data and specific human or animal pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity are also suggested. Such studies would include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into appropriate tissues in quantities adequate to achieve and maintain levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
(17) Uncomplicated Intra-abdominal Infections
 This entity should encompass intra-abdominal infections that do not require surgical intervention (e.g., mild diverticulitis) and should not include gynecologic infections and pelvic inflammatory disease.
Two statistically adequate and well-controlled multicenter trials establishing equivalence or superiority to an approved product or to a prospectively agreed to therapeutic regimen are suggested. In these infections, an evaluable patient should be clinically evaluable only. As there would be no microbiology in these studies, the actual study results citing types of infections studied and actual effectiveness outcomes should be included as part of the INDICATIONS AND USAGE section of the labeling.
If effectiveness in complicated Intra-abdominal infections is established at the same dosing regimen and duration, only one adequate and well-controlled trial in this infection is suggested.
(18) Complicated Intra-abdominal Infections
 This entity should encompass intra-abdominal infections that require surgical intervention, including penetrating and blunt trauma.
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product or to a prospectively agreed to therapeutic regimen is suggested. At least 80% of the patients should be microbiologically, as well as clinically, evaluable. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document. Analysis of the data should generally confirm (by means of comparing the direction of the independent 95% confidence intervals testing) 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 clinical cure and (presumed) bacterial eradication in the clinically and microbiologically evaluable subset of patients. To establish effectiveness in treating anaerobic microorganisms in this infection, the investigative agent should also establish effectiveness against anaerobes in either at least one other infection with significant anaerobic etiologies or should establish an acceptable in vitro susceptibility and animal data effectiveness profile in anaerobic infections.
If there was not a reasonable mix of various intra-abdominal infections, such should be noted in the approved labeling by restricting the wording of the INDICATIONS AND USAGE section to just those types actually studied.
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 (usually at the same dosing regimen and duration) in the treatment of gynecologic infections in order to support this one complicated intra-abdominal infections trial.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of clinical effectiveness in this disease entity are also required. Such studies would include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into various intra-abdominal tissues or fluids in quantities adequate to achieve and maintain intra-abdominal tissue or fluid levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
(19) Gynecologic Infections
[N.B.: This listing does not include sexually transmitted diseases or acute pelvic inflammatory disease.]
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. At least 50% of the clinically evaluable patients should also be microbiologically evaluable. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document. Analysis of the data should also generally confirm (by means of comparing the direction of the independent 95% confidence intervals testing) 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 clinical cure and bacterial eradication in the clinically and microbiologically evaluable subset of patients.
If there was not a reasonable mix of various gynecologic infections, such should be noted in the approved labeling by restricting the wording of the INDICATIONS AND USAGE section to just those types of infections actually studied.
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 (usually at the same dosing regimen and duration) in the treatment of complicated intra-abdominal infections in order to support this one gynecologic infections trial.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of putative effectiveness in this disease entity are also suggested. Such studies would include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into appropriate tissues or fluids in quantities adequate to achieve and maintain tissue or fluid levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate period of time.
(20) Pelvic Inflammatory Disease
 One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product is suggested. At least 50% of the clinically evaluable patients would also be microbiologically evaluable. Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be as per Section III of this document. Analyses of the data should also generally confirm (by means of comparing the direction of the independent 95% confidence intervals testing) the successful outcome rates established for the overall clinically evaluable and for the clinically and microbiologically evaluable subset of patients. Likewise the analyses should establish the correlation between clinical cure and (presumed) bacterial eradication in the clinically and microbiologically evaluable subset of patients.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of putative effectiveness in this disease entity are suggested. Such studies would include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into appropriate tissues or fluids in quantities adequate to achieve and maintain appropriate tissue or fluid levels of antimicrobial compound equal to or above the expected MIC90's of the claimed pathogens for an adequate time period.
(21) Bacterial Vaginosis
Two statistically adequate and well-controlled multicenter trials establishing equivalence or superiority to an approved product is suggested. In this infection, an evaluable patient should be expected to be clinically evaluable only. Rigorous entry criteria, including the presence of a homogeneous vaginal discharge that (a) has a pH greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination, should be employed in clinical trials. Gram's stain of vaginal discharge should be performed and results should be consistent with a diagnosis of bacterial vaginosis, including (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells. Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis, Chlamydia trachomatis, N. gonorrhoeae, Candida albicans, and Herpes simplex virus, should be ruled out. It should also be expected that the antimicrobial drug product exhibits acceptable in vitro activity against the major pathogens associated with this clinical entity.
(22) Osteomyelitis (acute and chronic)
 One open trial involving at least 50 evaluable patients using rigorous prospective clinical, radiographic, and microbiologic entry criteria and evaluability criteria (including at least a one year follow-up period) which demonstrates a successful outcome in at least 90% of the acute patients and 70% in the chronic patients is suggested. At least 40 patients should be acute and 30 chronic if the sponsor wishes to receive labeling in the INDICATIONS AND USAGE section of the final product labeling for both types of osteomyelitis. Without the acute/chronic mix, at least 50 patients should be evaluable, and the wording in the INDICATIONS AND USAGE section of the product labeling should be restricted to only that type of infection actually studied.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling would be determined on a case-by-case basis.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of putative effectiveness in this disease entity are also suggested. Such studies should include, but not be limited to, tissue distribution studies that demonstrate the investigative agent diffuses into bone tissues in quantities adequate to achieve and maintain bone tissue levels of antimicrobial compound equal to or above the expected MIC90's of the claimed or prevalent pathogens for an adequate time period.
(23) Acute Bacterial Arthritis
 One open trial of at least 50 evaluable patients using rigorous prospective clinical, radiographic, and microbiologic entry criteria and evaluability criteria that demonstrates a successful outcome in at least 90% of the patients is suggested.
Pathogens listed in the INDICATIONS AND USAGE section of the product labeling should be determined on a case-by-case basis. Gonococcal arthritis should not be an appropriate entity to study for this specific listing. Also, if prosthetic joints are involved, the study should include at least 25 evaluable patients with artificial joints and 25 evaluable patients without artificial joints to support a specific listing for both entities. Otherwise, the listing should be restricted to either artificial or natural joints.
Adequate microbiologic data and specific human pharmacokinetic/-dynamic data supportive of putative effectiveness in this disease entity are required. Such studies would include, but not be limited to, intra-articular tissue distribution studies that demonstrate the investigative agent diffuses into intra-articular tissue in quantities adequate to achieve and maintain tissue levels equal to or above the expected MIC90's of the claimed and prevalent pathogens for an adequate time period.
 (24) Empiric Therapy in Febrile Neutropenic Patients
One statistically adequate and well-controlled multicenter trial establishing equivalence or superiority to an approved product or to a prospectively agreed upon therapeutic regimen is suggested. This trial should use rigorous prospective clinical, radiographic (as appropriate), and microbiologic entry criteria and evaluability criteria.
Prior to approval for this entity, the compound should also have established effectiveness in at least three of the following infections: nosocomial pneumonia, complicated intra-abdominal infections, complicated urinary tract infections, complicated skin and skin structure and soft tissue infections, acute osteomyelitis, or acute bacterial arthritis.
Murray M. Lumpkin, M.D.
Director
Division of Anti-Infective Drug Products
Office of Drug Evaluation II
Center for Drug Evaluation and Research
D. Bruce Burlington, M.D.
Deputy Director, Office of Drug Evaluation II
Deputy Center Director for Medical and Scientific Affairs
Center for Drug Evaluation and Research
March 1995 Addendum : Helicobacter pylori-Associated Peptic Ulcer Disease
1992 Addendum: Dose-Response Testing
Date created: November 26, 1996; last update: July 6, 2005 |
