1. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 1 Factive® (gemifloxacin) Proposed for the treatment of Acute Bacterial Sinusitis Oscient Pharmaceuticals, NDA 21-158/S-006 Renata Albrecht, MD Director, Division of Special Pathogen and Transplant Products CDER Renata Albrecht, MD Director, Division of Special Pathogen and Transplant Products CDER

2. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 2 OutlineOutline Proposed Indication –Acute Bacterial Sinusitis (ABS) Approved Indications –CAP and ABECB Review of NDA 21-158/S-006 Adequate and well controlled studies Question(s) to committee Proposed Indication –Acute Bacterial Sinusitis (ABS) Approved Indications –CAP and ABECB Review of NDA 21-158/S-006 Adequate and well controlled studies Question(s) to committee

3. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 3 Proposed Indication “Acute Bacterial Sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, S.aureus (methicillin susceptible strains only), K. pneumoniae and E. coli.” The proposed dosage regimen is 320 mg qd PO for 5 days. “Acute Bacterial Sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, S.aureus (methicillin susceptible strains only), K. pneumoniae and E. coli.” The proposed dosage regimen is 320 mg qd PO for 5 days.

4. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 4 Approved Indications “Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.” “Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae**” “Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.” “Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae**”

5. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 5 Gemifloxacin ABS Studies StudyDurationComparatorDesign 0097 daysCefuroxime axetil R, DB, NI* 0107 daysTrovafloxacinR, DB, NI 1865 vs. 7 daysGemifloxacinR, DB, NI 2065 daysNoneOL** 3335 daysNoneOL *Randomized, double-blind, non-inferiority study ** Open-label study

6. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 6 Four studies reviewed previously Nonapproval letters: –2000 (Studies #009, #010) 7 days –2002 (Studies #186, #206) 5 days “concluded gemifloxacin is effective in treating…acute bacterial sinusitis (ABS)” Concern regarding cutaneous reactions Conclusion that benefit did not outweigh risk for this indication Nonapproval letters: –2000 (Studies #009, #010) 7 days –2002 (Studies #186, #206) 5 days “concluded gemifloxacin is effective in treating…acute bacterial sinusitis (ABS)” Concern regarding cutaneous reactions Conclusion that benefit did not outweigh risk for this indication

7. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 7 How was efficacy demonstrated? Active controlled, noninferiority designs Ambulatory patients with baseline: –Signs and symptoms of sinusitis –Radiographic findings –(Some with bacteria from sinus tap culture) –Evaluate on Rx, end of Rx, and follow-up Success defined as resolution of clinical and radiographic findings after treatment Met conditions outlined in the protocols Active controlled, noninferiority designs Ambulatory patients with baseline: –Signs and symptoms of sinusitis –Radiographic findings –(Some with bacteria from sinus tap culture) –Evaluate on Rx, end of Rx, and follow-up Success defined as resolution of clinical and radiographic findings after treatment Met conditions outlined in the protocols

8. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 8 What were the safety concerns? Cutaneous reactions –Primarily rash –Consistently more frequent in gemi arms than control (across indications) –Increased with duration of treatment –More common in 40 yo –More common in women than men –Spectrum ranged from mild to severe Cutaneous reactions –Primarily rash –Consistently more frequent in gemi arms than control (across indications) –Increased with duration of treatment –More common in 40 yo –More common in women than men –Spectrum ranged from mild to severe

9. Rash Rates by Treatment Duration, Age and Gender Duration of Therapy (days) Percent reporting rash 3 5 7 10 14 3 5 7 10 14 0 5 10 15 20 25

10. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 10 Approval vs Nonapproval Decisions (1) CAP and ABECB: –Serious diseases, high morbidity/ mortality for CAP, risk of patient decompensation with ABECB. –In clinical trials most patients >40 yo, male >50%. –Despite higher incidence of rash with gemifloxacin, benefit judged to exceed risk –AC meeting 2003 recommended approval Approval April 4, 2003 CAP and ABECB: –Serious diseases, high morbidity/ mortality for CAP, risk of patient decompensation with ABECB. –In clinical trials most patients >40 yo, male >50%. –Despite higher incidence of rash with gemifloxacin, benefit judged to exceed risk –AC meeting 2003 recommended approval Approval April 4, 2003

11. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 11 Approval vs Nonapproval Decisions (2) ABS not approved in 2000 (7 day regimen) and in 2002 (5 day regimen) –Potentially serious morbidity? –Most patients female in clinical trials, mean age ~ 40 years –Rash: 7 day regimen > 5 day > (comparators) –Despite conclusion that gemifloxacin was effective, the overall recommendation was that the indication not be approved because the risk of adverse events exceeded benefit for treatment of ABS ABS not approved in 2000 (7 day regimen) and in 2002 (5 day regimen) –Potentially serious morbidity? –Most patients female in clinical trials, mean age ~ 40 years –Rash: 7 day regimen > 5 day > (comparators) –Despite conclusion that gemifloxacin was effective, the overall recommendation was that the indication not be approved because the risk of adverse events exceeded benefit for treatment of ABS

12. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 12 ABS, February 2005 (1) The Factive applications were submitted before 2003 AC on acute bacterial sinusitis Agreed that judged by the pre-2003 parameters the drug was effective Reiterated concerns that rash was more common with gemifloxacin, and requested large comparative safety study to demonstrate convincingly that the incidence of skin reactions, particularly serious skin reactions, was clinically acceptable and no greater than comparator. The Factive applications were submitted before 2003 AC on acute bacterial sinusitis Agreed that judged by the pre-2003 parameters the drug was effective Reiterated concerns that rash was more common with gemifloxacin, and requested large comparative safety study to demonstrate convincingly that the incidence of skin reactions, particularly serious skin reactions, was clinically acceptable and no greater than comparator.

13. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 13 ABS, February 2005 (2) Stated that did not grant MDRSP for ABS –“A placebo-controlled trial demonstrating efficacy in ABS secondary to MDRSP would be required.” Stated that did not grant MDRSP for ABS –“A placebo-controlled trial demonstrating efficacy in ABS secondary to MDRSP would be required.”

14. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 14 Current Submission NDA 21-158/S-006 New efficacy application: Submitted November 2005 Accepted for review March 2006 New efficacy application: Submitted November 2005 Accepted for review March 2006

15. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 15 Review of ABS FDA review involves examination of the information submitted for both efficacy and safety, and includes review of both new information and previously reviewed information in the application Includes clinical study information and post-marketing information since approval in 2003 FDA review involves examination of the information submitted for both efficacy and safety, and includes review of both new information and previously reviewed information in the application Includes clinical study information and post-marketing information since approval in 2003

16. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 16 SafetySafety Clinical trial data from 8119 patients who received gemifloxacin (including 6775 patients in initial NDA 21-158) Clinical trial data from 5248 patients on comparator drugs (included in initial NDA 21-158) Post marketing safety information (Interim study reports submitted since June 2006) Clinical trial data from 8119 patients who received gemifloxacin (including 6775 patients in initial NDA 21-158) Clinical trial data from 5248 patients on comparator drugs (included in initial NDA 21-158) Post marketing safety information (Interim study reports submitted since June 2006)

17. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 17 EfficacyEfficacy All three comparative ABS studies used non- inferiority trials design. Since 2002, there have been a number of public meetings and workshops on use of noninferiority trials and necessity to justify noninferiority margin. At October 2003 AC meeting on ABS committee recommended superiority trial designs for ABS since an appropriate noninferiority margin could not be determined from available published placebo- controlled studies. All three comparative ABS studies used non- inferiority trials design. Since 2002, there have been a number of public meetings and workshops on use of noninferiority trials and necessity to justify noninferiority margin. At October 2003 AC meeting on ABS committee recommended superiority trial designs for ABS since an appropriate noninferiority margin could not be determined from available published placebo- controlled studies.

18. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 18 Noninferiority (similarity) trial design Used for many infectious diseases trials. Appropriate for diseases whose spontaneous resolution without antimicrobial treatment is low (e.g. bacterial meningitis, bacterial pneumonia) So, if clinical success is reproducibly 80% on antimicrobial, there is a 30% benefit of antimicrobial therapy. A margin of <30% for lower bound of 95% C.I. excludes that the effect may be due to placebo. Choosing a margin of <15% preserves at least half the benefit. But, if clinical success is >70% in placebo arm (>80% for drug), the benefit is only <10%, and a much smaller margin must be selected to assure that the effect seen in the study is not due to placebo Used for many infectious diseases trials. Appropriate for diseases whose spontaneous resolution without antimicrobial treatment is low (e.g. bacterial meningitis, bacterial pneumonia) So, if clinical success is reproducibly 80% on antimicrobial, there is a 30% benefit of antimicrobial therapy. A margin of <30% for lower bound of 95% C.I. excludes that the effect may be due to placebo. Choosing a margin of <15% preserves at least half the benefit. But, if clinical success is >70% in placebo arm (>80% for drug), the benefit is only <10%, and a much smaller margin must be selected to assure that the effect seen in the study is not due to placebo

19. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 19 What is benefit of antimicrobial over placebo in ABS? Review of published placebo-controlled studies in acute sinusitis –17 articles published since 1964 Eight published after 2000 (6 adult, 2 peds) Why is this important? –Challenges in determining benefit of antimicrobial over placebo Review of published placebo-controlled studies in acute sinusitis –17 articles published since 1964 Eight published after 2000 (6 adult, 2 peds) Why is this important? –Challenges in determining benefit of antimicrobial over placebo

20. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 20 21 CFR 314.126(b)(2)(iv) Adequate and Well Controlled studies Active treatment concurrent control trials “If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity…can mean either than both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous, placebo-controlled studies of the active control drug.” Active treatment concurrent control trials “If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity…can mean either than both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous, placebo-controlled studies of the active control drug.”

21. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 21 Laws and Regulations Substantial evidence means… “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts…, on the basis of which it could fairly and responsibly be concluded…that the drug will have the effect it purports or is represented to have …” For approval, need “substantial evidence” Substantial evidence means… “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts…, on the basis of which it could fairly and responsibly be concluded…that the drug will have the effect it purports or is represented to have …” For approval, need “substantial evidence”

22. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 22 Review of NDA 21-158/S-006 Efficacy –Although Factive determined to be effective in ABS in 2000, 2002, the indication was turned down due to an unacceptable safety profile –As we examine efficacy in 2006, need to consider developments since 2002 Safety –Concerns regarding ADR profile and signal in 2000, 2002 led to nonapproval –As we examine safety in 2006, need to consider safety data from clinical studies and post-marketing Efficacy –Although Factive determined to be effective in ABS in 2000, 2002, the indication was turned down due to an unacceptable safety profile –As we examine efficacy in 2006, need to consider developments since 2002 Safety –Concerns regarding ADR profile and signal in 2000, 2002 led to nonapproval –As we examine safety in 2006, need to consider safety data from clinical studies and post-marketing

23. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 23 Today’s Agenda Oscient Presentations FDA presentations: –Update on sinusitis drug development (Dr. Powers) –Safety and efficacy of Factive for sinusitis (Dr. Tierney) –Post-marketing reports for gemifloxacin (Dr. Mosholder) Open public hearing Questions to the committee Oscient Presentations FDA presentations: –Update on sinusitis drug development (Dr. Powers) –Safety and efficacy of Factive for sinusitis (Dr. Tierney) –Post-marketing reports for gemifloxacin (Dr. Mosholder) Open public hearing Questions to the committee

24. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 24 Question(s) to the Committee Do the safety and effectiveness data presented demonstrate an acceptable risk/benefit profile for the use of Factive™ (gemifloxacin) as treatment of patients with acute bacterial sinusitis?

25. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 25 Question(s) to the Committee If yes, are there any special caveats, warnings or limitations that should be included in the label? Do you have any specific risk- management recommendations for Factive® (gemifloxacin) post approval? If no, are there other studies or other information that could demonstrate that benefit outweighs the risk for this indication? If yes, are there any special caveats, warnings or limitations that should be included in the label? Do you have any specific risk- management recommendations for Factive® (gemifloxacin) post approval? If no, are there other studies or other information that could demonstrate that benefit outweighs the risk for this indication?

26. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 26 Thank You Bob Temple Ed Cox Steve Gitterman Brenda Marques Leonard Sacks Maureen Tierney John Powers Igor Cerny Jayne Peterson Dornette Spell LeSane Sohail Mosaddegh Bob Temple Ed Cox Steve Gitterman Brenda Marques Leonard Sacks Maureen Tierney John Powers Igor Cerny Jayne Peterson Dornette Spell LeSane Sohail Mosaddegh Bob O’Neill Karen Higgins Cheryl Dixon Gerald Dal Pan Mark Avigan Rosemary Johann-Liang Andy Mosholder Evelyn Farinas OSE Staff DDMAC Compliance