Division of Dockets Management (HFA 305) Food and Drug Administration 5630 Fishers Lane Room 1061 Rockville, MD 20852

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1 December 21, 2012 Division of Dockets Management (HFA 305) Food and Drug Administration 5630 Fishers Lane Room 1061 Rockville, MD Re: Comments on Docket No. FDA-2012-D-0973; Draft Guidance for Industry on Complicated Intra-Abdominal Infections: Developing Drugs for Treatment Dear Sir/Madam: The Infectious Diseases Society of America (IDSA) is pleased to submit comments regarding the Food and Drug Administration s (FDA) Draft Guidance for Industry on Complicated Intra-Abdominal Infections: Developing Drugs for Treatment. IDSA represents nearly 10,000 infectious diseases physicians and scientists devoted to patient care, prevention, public health, education, and research in the area of infectious diseases. Our members care for patients of all ages with serious infections, including intra-abdominal infections, meningitis, pneumonia, tuberculosis, HIV/AIDS, antibiotic-resistant bacterial infections such as those caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Gram-negative bacterial infections such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, and emerging infections such as the 2009 H1N1 influenza virus. We greatly appreciate the effort the FDA has put into the new draft guidance on complicated intraabdominal infections (ciai). There is a tremendous public health need now for new drugs to treat these polymicrobial infections that can be caused by diverse aerobic and anaerobic gram-positive and gram-negative bacteria. Feasible, clinically relevant clinical trial guidance in this area is of great importance. There are many favorable elements of the guidance, such as the acceptability of a single adequate and well controlled study with supportive data as evidence of effectiveness (consistent with the FDA s approval of cefepime, ciprofloxacin and trovafloxacin), the use of clinical and microbiological endpoints, as well as the emphasis on proper PK and microbiologic sensitivity data to support the phase III trials. Other areas could benefit from reconsideration, as summarized below. 1. Line : new drugs for treatment of ciai will be administered intravenously and not orally because patients with ciai do not ingest food or drugs orally (i.e., nothing by mouth, or nil per os (NPO) during the course of their illness.

2 PAGE TWO IDSA Comments on Draft GFI on ciai ciai comprises a variety of infectious etiologies that may or may not result in patients remaining NPO for the duration of their treatment course. The most recent IDSA practice guideline for ciai (Solomkin et al, 2010) recommends 4-7 days of treatment for established infection and on at least three prior occasions the FDA has permitted and reviewed ciai applications with IV to oral switches (New Drug Application (NDA) (trovafloxacin), NDA (moxifloxacin) and NDA (doripenem). Establishing a minimum exposure to the IV formulation of a new drug followed by oral switch when the patient can tolerate oral intake would simplify the execution of confirmatory studies. For the purposes of clarity to future drug sponsors, we suggest permitting an IV to oral switch with a minimum exposure to IV treatment of 3 days if the trial subject is clinically improving. 2. Line : Inclusion criteria Listed in this section are systemic signs and symptoms that are targeted as inclusion criteria. Given the lack of specificity of such signs and symptoms, especially in the elderly or diabetic populations, it would be helpful from the perspective of subject enrollment for ciai studies to expand potential supportive signs and symptoms as broadly as possible, including (1) a drop in blood pressure, (2) increased pulse, (3) increased respiratory rate, (4) hypoxemia, (5) altered mental status, and (6) ileus. Expansion of these criteria would improve the generalizability of the study and also would be consistent with prior FDA reviews such as NDA (ertapenem). 3. Line 256: Exclusion criteria The current guidance makes no reference to disease severity as an exclusion criterion. Specifically, high APACHE scores (> 30) have historically been considered as exclusionary by FDA due to the very high likelihood of antimicrobial treatment failure (see NDA , ertapenem or NDA , tigecycline) with a consequent negative impact on the study s assay sensitivity (including subjects that are likely to die of causes other than their infection will undermine the trial s ability to distinguish effective treatments from less efficacious or inefficacious treatments, see ICH E10). We would recommend adding to the draft guidance that patients suffering from ciai be stratified at enrollment based on APACHE score in order to limit baseline imbalances after randomization. 4. Line : concomitant illnesses that may preclude the evaluation of antibacterial drug efficacy (e.g., malignancy, leucopenia, neutropenia) Acute infectious processes can result in white blood cell abnormalities that include leucopenia and neutropenia. It would be valuable to qualify (or simply remove) white blood cell abnormalities from the exclusion criteria and denote actual disease processes such as malignancies. It also would be valuable to more clearly denote immunosuppressant therapy criteria 5. Line : Patients with at least mild to moderate renal impairment and hepatic impairment should be included in drug development programs, and the need for dose adjustment in such patients should be assessed.

3 PAGE THREE IDSA Comments on Draft GFI on ciai Does the Agency intend to state: Patients with at least mild to moderate renal or hepatic impairment should be.? We support that modification. 6. Line : If the organism is not sensitive to the investigational or control drug, those drugs would be discontinued and replaced with appropriate antibacterial drug therapy. One of the intended purposes of a clinical trial is to link microbiologic observations with clinical outcomes so that susceptibility interpretive criteria ( breakpoints ) can be defined. At Phase 3 of development, a set of proposed breakpoints will have been defined, but these require confirmation by Phase 3 data. In addition, the vast majority or registrational ciai trials will be blinded, so a patient may already be receiving efficacious therapy. Finally, microbiological sensitivity data for the investigational agent (or even susceptibility testing results for the comparator agent) may not be available until after treatment has been completed (e.g., with the use of a central laboratory for testing, especially as regards anaerobic pathogens). Finally, as noted below in 10, outcomes depend on multiple factors, not just microbiological data/sensitivities. (Note that only sensitivity can be assessed for the investigational drug until breakpoints are established.) Accordingly, in prior trials, the investigator has been charged with assessing the progress of the patient based on clinical criteria and making changes to antimicrobial therapy (or other interventions) based on the presence or absence of satisfactory progress. 7. Line : Thus, although we recommend that clinical trials attempt to enroll a considerable proportion of patients who have not received prior nontrial antibacterial drugs, we conclude from these data in the subgroup of patients that would fulfill the definition of ciai that the administration of a nontrial antibacterial drug for not more than 24 hours during the 72 hours preceding trial entry in ciai trials is not likely to have a large effect Rather than limiting nontrial antibacterial drug administration to 24 hours, we would recommend expanding this limitation to 48 hours during the preceding 72 hours prior to trial entry in those patients with isolates resistant to non-trial therapy. 8. Line : The primary endpoint of clinical success is defined as the complete resolution of the baseline signs and symptoms attributable to ciai at a fixed time point approximately 28 days following randomization. The use of attributable signs and symptoms does not constitute an objective assessment of outcome. The outcome must be well-defined and reliable and, once subjects are enrolled, protocol-specific criteria, not investigator criteria, are utilized to determine outcome. The use of randomization would eliminate concerns of attribution as has been previously noted in multiple NDA reviews by the Agency. 9. Line 389: Persistence of clinical symptoms of ciai Does the Agency intend to state: Persistence of clinical symptoms and/or signs of ciai? We support that modification.

4 PAGE FOUR IDSA Comments on Draft GFI on ciai 10. Line : The microbiological intent-to-treat population (micro-itt population) All randomized patients who have baseline bacterial pathogens that cause ciai and against which the investigational drug has antibacterial activity. The historic definition utilized by FDA regarding the micro-itt (m-itt) population has been the subset of treated patients that met disease definition and who had a baseline pathogen identified, regardless of susceptibility to study agent. The new definition proposed in the current ciai draft guidance is problematic for the following reasons: 1. It is unclear how validated antibacterial activity would originate to guide any such post-randomization intervention. For example, in the two registration trials (301 and 306, see Clinical Infectious Diseases Vol. 41, pages S354-66, 2005) comparing tigecycline to imipenem for ciai, pooled results showed similar eradication rates (33 of 39 for tigecycline and 31/36 for impenem) for subjects that had Pseudomonas aeruginosa isolated even though tigecycline has no activity against P. aeruginosa, demonstrating that multiple factors impact treatment outcome independent of microbiologic data. 2. To adopt this new definition of m-itt could result in significant loss of subjects postrandomization between the ITT and m-itt populations which would introduce new statistical concerns regarding missing data. 3. Rather than excluding subjects based solely on MIC data, clinical evaluation of subjects should occur at the time of MIC evaluation and only if they are not clinically responding they should be removed from the study. 11. Line : The micro-itt population with bacterial pathogens in the antibacterial spectrum of the investigational drug should be considered the primary analysis population. Historically the FDA has stated that use of the m-itt alone as the only analysis for noninferiority (NI) assessment can result in potential biases (see doripenem statistical review, page 11). Given the concerns regarding this new definition of m-itt as well as the potential biases in this particular indication (surgical drainage can impact outcome independent of microbiologic sensitivity), it would be important to expand the primary outcome assessment from the m-itt. Co-primary analysis populations of the m-itt population and the Microbiologically Evaluable (ME) population should be considered, as below. 12. The non-inferiority (NI) margin. A very thorough and impressive appendix is included in the document which provides justification of a NI margin for ciai. We congratulate the FDA for doing such a thorough job and for taking on this complex task. The recommended NI margin by FDA (M2) is 10%, and we thank the FDA for clarity regarding the NI margin. 13. Lines : The risk-benefit considerations depend on the population being studied and the safety profile of the drug being investigated. For example, in areas where a drug demonstrates meaningful therapeutic advantage in patients with unmet need, a greater degree of risk may be offset by the benefit provided in an overall evaluation of risk and benefit. The FDA s focus on risk-benefit is appropriate and appreciated given the seriousness of ciai.

5 PAGE FIVE IDSA Comments on Draft GFI on ciai IDSA hopes that these comments are useful to FDA as the agency moves forward to finalize the ciai guidance. Should you have any questions, please contact Robert J. Guidos, IDSA s Vice President for Public Policy and Government Relations, at rguidos@idsociety.org or Sincerely, David A. Relman, MD FIDSA President