1. 1 Data from Studies in One Indication Supporting Studies in a Different Indication March 5, 2003 Anti Infective Drugs Advisory Committee Meeting Edward Cox, M.D., M.P.H. Deputy Director, Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 FDA Meetings on Resistance General July, 1998 October, 1998 October, 1999 February, 2002 IDSA/PhRMA/FDA Workshop - November, 2002 Product-specific –SynercidFebruary, 1998 –LevaquinOctober, 1999 –ZyvoxApril, 2000 –AugmentinESJanuary, 2001 –KetekJanuary, 2003 –FactiveMarch, 2003

3. 3 February 20, 2002 AC Meeting Suggestion to consider the degree to which a study performed in one indication could support safety and efficacy in another indication so that multiple studies would not be required in each indication in a multi-indication new drug application (NDA).

4. 4 Responses to Resistance - PHS Action Plan Prevention Research Surveillance Product development –“... streamline the regulatory process” (Action Item 82) –“Identify ways... to promote the development of... priority AR products...” (Action Item 80) Source: http://www.cdc.gov/drugresistance/actionplan/aractionplan.pdf

5. 5 21 CFR § 201.57 (c) (2) All indications shall be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless the requirement is waived under § 201.58 or § 314.126(b) of this chapter.

6. 6 Adequate and Well-controlled Studies Reproducibility –variability in clinical trials –bias in a clinical trial –chance findings Performing more than one study may lead to greater certainty regarding the results observed

7. 7 Selected Indications for Antimicrobial Drugs - Bacterial Infections CAP HAP ABECB ABS uSSSI cSSSI uUTI cUTI AOM cIAI Acute Bacterial Meningitis Acute or Chronic Bacterial Prostatitis Bacterial Vaginosis Empiric Therapy of Febrile Neutropenia Streptococcal Pharyngitis Tonsilitis uGC Acute pelvic infections

8. 8 Understanding the Rationale Explore the science behind the practice of considering data from outside of the target indication Expert clinician’s perspective on antimicrobial choices based upon available data Use of data from “related indications” considered in Guidance and Draft Guidance documents Science-based considerations If we can clearly describe the rationale(s) for use of the evidence from studies in other indications, can we develop criteria as to how such information may be used to support clinical studies in other indications for the purposes of drug development

9. 9 Guidance - Points To Consider - 1992 Discusses circumstances within a multi-indication NDA where one trial may be adequate for an indication within the overall drug development program describes relationships between several indications –uUTI relying upon cUTI –Acute Prostatitis relying upon cUTI –uIAI relying upon cIAI –cIAI complemented by GYN infections –GYN infections complemented by cIAI http://www.fda.gov/cder/guidance/index.htm

10. 10 IDSA/FDA Guidelines - 1992 Whenever possible, there should be more than one comparative randomized study for a proposed indication. In some situations, however a single well-controlled study may suffice. A single trial may be sufficient for additional indications when a new agent has been shown to be effective in more than one trial for a major indication existing within the same anatomic location or organ system and caused by similar microorganisms. Examples provided – CAP trials with efficacy shown for S. pneumoniae and H. influenzae  single trials for otitis media, bronchitis, or sinusitis due to these species. –uUTI due to E. coli may not provide adequate assurance of efficacy for systemic infections due to E.coli, e.g., bacteremia from an intraabdominal source. Clin Infect Dis. Vol. 15, Supp. 1. November, 1992

11. 11 Draft Guidances - 1998 cUTI study data may provide support for a study for acute or chronic bacterial prostatitis CAP or HAP study data with concordant microbiology may provide support for a study of ABECB CAP study data may provide support for a study of HAP http://www.fda.gov/cder/guidance/index.htm

12. 12 Example Indications - NDAs Sporanox (injection/oral solution) approved for empiric antifungal therapy for febrile neutropenia based upon one trial and supportive data from treatment trials of fungal infections Studies for prevention indications for Pneumocystis carinii pneumonia and Mycobacterium avium were supported by data from treatment studies

13. 13 Other Examples Can CAP support HAP? Can uUTI support CAP? Can cSSSI support HAP?

14. 14 Factors to Consider Likely microbial etiologies Tissue penetration Severity of disease Host factors

15. 15 Proposed Criteria - 1 1. Natural history of the disease under study - what is the spontaneous resolution rate and what is the morbidity / mortality without treatment? 2. Factors other than the antimicrobial which may affect outcome in a given indications –surgical debridement –adjunctive therapies - ABECB 3. Characteristics of the study drug, e.g., pharmacokinetics of the drug - does it reach site of infection? –tissue levels –effects of pH

16. 16 Proposed Criteria - 2 4. Monomicrobial vs. polymicrobial nature of infection –enterococci in a polymicrobial intraabdominal infection 5. Similar site of infection –Lung for CAP and HAP 6. Host effects –Host differences in CAP vs. HAP 7. Similarity in spectrum of organisms causing disease –differences in organism most commonly associated with CAP vs. HAP

17. 17 Other Considerations Directionality of support? –Severe disease supporting less severe disease? –Less severe disease supporting more severe disease? –Examples: IV CAP to IV HAP vs. PO CAP to IV HAP Similarity of dose, duration, and formulation –What is the role for supportive data derived from different dosing regimens? Weight of evidence that supporting data can provide to a study in another indication

18. 18 Practical Issues Greater dependence on the single clinical study in the subject indication –high quality, rigorous design, well-performed study A highly interdependent program may have less resiliency if an unexpected finding is encountered Unexpected findings in the supporting clinical study may influence the target indication Sufficient quantity of data to adequately characterize safety Ability of the clinical database to adequately address unexpected safety findings Other issues?

19. 19 A Hypothetical Example Dependent development program 2 studies in CAP 1 study in HAP 1 study in cSSSI & supportive data Efficacy data Safety data

20. 20 Relating Indications (?) Related by Organ System CAP  HAP CAP  ABECB cSSSI  uSSSI cUTI  uUTI cUTI  Prostatitis ABS  AOM AOM  ABS Other Relationships. CIAI  cSSSI cSSSI  CIAI cSSSI  HAP HAP  cSSSI