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Anti-Infective Drugs Advisory Committee Meeting Clinical Trial Designs for Community Acquired Pneumonia

Anti-Infective Drugs Advisory Committee Meeting Clinical Trial Designs for Community Acquired Pneumonia. April 1 & 2, 2008 Edward Cox, MD MPH Director, Office of Antimicrobial Products OND/CDER/FDA. Welcome. Welcome Topic for discussion

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Anti-Infective Drugs Advisory Committee Meeting Clinical Trial Designs for Community Acquired Pneumonia

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  1. Anti-Infective Drugs Advisory Committee MeetingClinical Trial Designs for Community Acquired Pneumonia April 1 & 2, 2008 Edward Cox, MD MPH Director, Office of Antimicrobial Products OND/CDER/FDA

  2. Welcome • Welcome • Topic for discussion • Clinical trial designs for Community Acquired Pneumonia (CAP) • Primary purpose of the meeting • To seek the Advisory Committee’s advice on informative, safe, and ethical trial designs to evaluate the safety and efficacy of antibacterial drugs for the treatment of CAP • Work through the key parameters in the design of a CAP trial • Very interested to hear the scientific rationale, evidence relied upon and reasoning in arriving at recommendations for clinical trial designs for CAP

  3. Background - 1 • Antibacterial drugs discovered many years ago • Represented a major advance in medicine • Antibacterial therapy incorporated into clinical practice before sophisticated clinical trial designs • Standard of care for CAP for years • Some of the information that tells us about effect of antibacterial drugs in CAP (compared to “no treatment”) is from literature from many years ago

  4. Background - 2 • Science of clinical trials in New Drug Applications (NDAs) has also advanced • Microbiologically focused label • Respiratory tract infections (RTI) • composite data from a variety of RTIs • Lower respiratory tract infections (LRTI) • composite data ABECB & CAP • Community acquired pneumonia (CAP) • trials specific for CAP • noninferiority design w/ margin of 10 to 15% • margin choice based upon convention rather than clear justification based upon evaluation of available data • oral agents – mild to moderate severity

  5. CAP Indication INDICATIONS AND USAGE • [Drug Name] is indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below: Community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus,Moraxella catarrhalis, Legionella pneumophila,Chlamydophila pneumoniae, or Mycoplasma pneumoniae

  6. Some Drugs with a CAP or Related Indication • Microbiologically “focused” • penicillin G, penicillin V, tetracycline, oxytetracycline, doxycycline, minocycline, demeclocycline, clindamycin, lincomycin, streptomycin • Respiratory tract infections(past indication - composite) • ampicillin, cephalexin, cefazolin • amikacin, gentamicin • Lower respiratory tract infections(past indication - AECB & CAP) • amoxicillin, amoxicillin/clavulanate, piperacillin, piperacillin/tazobactam, ticarcillin/clavulanate • erythromycin • cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefaclor cefuroxime injection, • imipenem/cilistatin, - aztreonam - tobramycin • ciprofloxacin - metronidazole (Bacteroides) • Community-acquired pneumonia • amoxicillin/clavulanate • cefdinir, cefditoren pivoxil, cefpodoxime proxetil, loracarbef, • azithromycin, clarithromycin, telithromycin • ofloxacin, levofloxacin, moxifloxacin, gemifloxacin, • linezolid

  7. Importance & Challenges - 1 • Public Health need for new therapeutic options • antimicrobial resistance • Need informative trials to characterize safety and efficacy • weigh risks and benefits • Importance of having new drugs in this area also supports the importance of adequately characterizing safety and efficacy • Quality information to inform appropriate use

  8. Importance & Challenges - 2 • Community acquired pneumonia • risk of progression or extension of infection • Clinical Trials of CAP should • not expose patients to significant risk • be informative • be ethical & acceptable • strategies to minimize risk • provisions for “rescue therapy” • patient selection • DSMB

  9. Drug Product Approval • 1938: Federal Food, Drug and Cosmetic Act required pre-clearance of drugs for safety & pre-market notification but did not include evaluation of efficacy • 1962: FDC Act amended to add requirement for demonstration of effectiveness based upon “substantial evidence” • “Substantial evidence” defined in FDC Act 505(d) as: “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

  10. Adequate and well controlled studies 21 CFR § 314.126 Adequate and well-controlled studies. (a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. • Active treatment concurrent control… • The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. • 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 of test drug and active control can mean either that 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.

  11. Active Controls & Noninferiority - 1 Case# 1: Large treatment effect Low spontaneous resolution rate Test Inactive (e.g. placebo) Active Control Response rate

  12. Active Controls & Noninferiority - 2 Test Case #2: Unclear treatment effect High spontaneous resolution rate Active Control Inactive (e.g. placebo) Response rate

  13. Active Controls & Noninferiority - 3 Case# 1: Large treatment effect Low spontaneous resolution rate Test Inactive (e.g. placebo) Active Control Response rate Test Case #2: Unclear treatment effect High spontaneous resolution rate Active Control Inactive (e.g. placebo) Response rate

  14. CAP Trials • Quantitative estimate of the effect of the active control drug over placebo in a current day study based upon what we know from previously conducted studies • treatment effect • Treatment effect reflects the types of patients and how studied • severity of disease, type of disease • endpoint & timing of assessment • other factors • Accounting for uncertainty – discounting, judgments, rationale • Goal of informative trial designs

  15. CAP Trials in NDAs • Inpatient studies of CAP • Intravenous antibacterial drugs with or without an oral formulation (“step-down” therapy) • additional studies with the oral formulation typically done • Indication • CAP • Outpatient studies of CAP • Oral antibacterial drugs • Indication • mild to moderate CAP

  16. Key Topics • Review what we know and don’t know about CAP and issues in clinical trial design • treatment effect based upon available data • what population • what endpoint (when to assess) • other key parameters • Address key issues in clinical trial design for CAP & describe possible informative CAP trial designs • studies of IV drugs - - studies of oral drugs • endpoints • what population • can noninferiority studies be done? • can superiority studies can be done?

  17. Overview of the 2-Day Meeting • Agenda – Day #1 • IDSA/FDA CAP workshop • IDSA perspective • ATS/ACCP statement • Ethical considerations • Noninferiority trials in CAP

  18. Overview of the 2-Day Meeting • Agenda – Day #1 (continued) • Historical data on CAP • Contemporary CAP trials • Approaches to setting an NI margin • Exposure-Response analysis for CAP • Critical considerations in CAP trial design • Day # 2 • A clinician’s scientific approach to pneumonia • Considerations in design of CAP studies • Questions and discussion • Questions for the AC

  19. For questions 1 and 2: To rely on noninferiority studies for new drugs to treat CAP, we must be able to estimate the effect size a control drug would have on the primary endpoint used in the current trial. The Agency has presented information on the historical experience that suggest a reduction in mortality with point estimates ranging from 18 to 25% in the observational studies and from approximately 10 to 19% in controlled trials. These data are derived from patients with pneumococcal / lobar pneumonia. Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  20. Question 1a: 1. Can these data be utilized to select a noninferiority margin for a contemporary CAP study for an IV drug in hospitalized patients? a) To what severity of pneumonia or type of patients would it apply and how should severity be defined? Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  21. Question 1b-1c: b) Should a microbiological diagnosis be necessary for inclusion in the primary analysis population for the trial, and if so, what organisms should be included (e.g., S. pneumoniae, other microbes)? c) Should strategies be utilized to enrich the population for patients with a particular microbial etiology (e.g., S. pneumoniae, or other microbes)? Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  22. d) Please discuss whether the evidence which shows a treatment effect based on mortality can be linked to endpoints which are used in current non-inferiority CAP trials (i.e. clinical success/failure). If so, how? (Note: the possible components of the clinical failure endpoint might include some of the following mortality, receiving rescue therapy, lack of resolution of clinical signs and symptoms such that additional antibacterial therapy is administered, lack of resolution of signs and symptoms at the time the primary endpoint is assessed.) Question 1d: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  23. e) The historical evidence for a treatment effect is based on studies which evaluated penicillin, sulfonamides, and tetracyclines. Given the need to preserve the treatment effect (the effect of the comparator agent over placebo or no treatment) in a future study, what are appropriate choices for comparator agents? Please explain the basis and information that supports the recommendation for comparator agents for a future study. Question 1e: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  24. f) What is your best estimate of the treatment effect size (M1) that the historical data support for treatment of hospitalized CAP (based on severity selected in part a of this question, above) in a future CAP trial and what is your recommendation for a noninferiority margin that preserves a portion of the treatment effect (i.e., M2) for a CAP trial in this population with the endpoints discussed above? Question 1f: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  25. Question 2: • 2. Given the information presented, mostly from historical data on the treatment effect of drugs for CAP in patients with pneumococcal / lobar pneumonia, please address the following questions on trials of outpatient CAP (studies using an oral drug). Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  26. a) Can a treatment effect be reliably quantified for a noninferiority study of outpatient CAP (i.e., for an oral drug)? • To which patient population would this information apply with regards to disease severity and microbiological etiology? • What endpoint(s) should be utilized? • iii. What is the proposed noninferiority margin and what data support the proposed noninferiority margin? Question 2a: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  27. b) Can placebo-controlled trials be carried out in less severely ill patients with CAP? • i. If yes, how can risk to patients be minimized? What patient population could be enrolled? What endpoints should be evaluated? Question 2b: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  28. c) Can you suggest any alternative study designs that could be utilized which would allow for an informative trial of outpatient CAP (i.e., an oral drug) to be conducted? Please describe. Question 2c: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  29. 3. In a setting of hospitalized CAP as described in question 1 (above), one could study therapy with an intravenous formulation administered initially with subsequent “step down” therapy to an oral formulation as a means to support the use of the oral and IV formulations for severe disease. Question 3: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  30. This leaves the question of whether the finding of efficacy for severe CAP would provide evidence of efficacy that could be used to support efficacy of the oral formulation for less severe (i.e., mild and moderate CAP). Do you believe the finding of efficacy in more severe CAP supports the drug’s effect in less severe CAP, even though the drug has not been directly studied in less severe CAP? Question 3 continued: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  31. 4. If the available evidence for setting a noninferiority margin in current CAP trials is derived primarily from studies of patients with CAP due to S.pneumoniae, should noninferiority studies include patients with other etiologies of CAP? Question 4: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  32. If not, what additional data/studies are needed to show that antibacterial drugs are effective for specific organisms? When addressing this question please consider the following organisms: • Chlamydophila pneumoniae • Haemophilus influenzae • Legionella pneumophila • Mycoplasma pneumoniae • Staphylococcus aureus • Klebsiella pneumoniae Question 4 continued: Anti-Infective Drugs Advisory Committee meeting April 1 & 2, 2008

  33. Key Issues from the FDA-IDSA Workshop John Alexander, MD, MPH Medical Team Leader, Division of Anti-Infective and Ophthalmology Products, CDER

  34. FDA-IDSA Workshop • Held January 17-18, 2008 • Goals • Examine critical issues in: • The design and conduct of trials of the safety and efficacy of antibacterial drugs in the treatment of CAP • The implications of emerging scientific tools that assist in the diagnosis of the etiology of CAP • Discuss clinical trial design and statistical considerations in demonstrating efficacy in clinical trials of CAP.

  35. CAP Scenarios • Day 1 – CAP not requiring hospitalization 35 y/o male, 3 days of URI, purulent sputum, coughing fever (38.3 C), RR 18, “crackles” at R base CXR – bilateral LL infiltrates, R>L • Day 2 – Hospitalized CAP, not requiring ICU 65 y/o female, mild COPD, diabetes, HTN, smoker (35 PY) ↑ sputum, ↑ dyspnea, fever (39.2 C), RR 24, O2 sat= 89% RA definite L crackles, no rubs, PORT=IV, CURB-65=2 CXR – LLL consolidation, air bronchogram, large heart

  36. CAP Presentations – AC Reprise • Criteria for NI Trials and Clinical Importance • NI Trials Submitted in the Recent Past • Historical Data on Treatment Effect • PK/PD Relationship • Clinician’s Perspective • Consultant’s Perspective • IDSA Perspective • Open Public Hearing – Industry Presentations • AC Presentations Informed by CAP Workshop

  37. CAP Presentations – Diagnostics • Improved Detection of S. pneumoniae • Molecular Diagnostics for Viral and Bacterial Pathogens • Etiology of Outpatient CAP • Etiology of Hospitalized CAP • Procalcitonin – Biomarker for CAP

  38. Diagnostics * Intensive Care Unit †Influenza A/B, Adenovirus, RSV, parainfluenza # Gram-negative bacilli Lancet 2003 (Dec. 13); 362:1991

  39. Diagnostics • Conventional methods (CM) for bacterial diagnosis are limited • Blood cultures have low yield • Sputum samples not available for all patients • Study of 109 patients with CAP (77 hospitalized)* • Pathogen identified by CM in 54/109 • Transthoracic aspirates identified S. pneumoniae as etiologic agent in 33% (18/55) of patients with unknown cause based on conventional methods • Not practical for clinical trials *Ruiz-Gonzalez et al. Am J Med 1999; 106:385-390

  40. Diagnostics • Binax Now®S. pneumoniae Urinary Ag • Approved – August 1999 • Prospective study suspected S pneumo (sepsis or LRTI) • Sens 90%, Spec 75% vs. blood culture • Spanish Study of CAP* • Concentrated urine samples • 10/13 (77%) bacteremic pneumococcal CAP • 9/14 (64%) non-bacteremic pneumococcal CAP • 69/300 (23%) CAP but no pathogen isolated *CID 2003 (Feb 1); 36:286

  41. Diagnostics • Atypical Pathogens • Legionella • Urinary Ag has replaced other methods for diagnosis (Sens 75-85%; Spec 99% for L. pneumophila 1) • Mycoplasma • MIF - Serologic testing is current standard • Chlamydophila (Chlamydia) • MIF – Poor correlation with culture or PCR* • PCR – Multiple in-house assays (need standardization) CID 2007 (Feb 15); 44:568

  42. Diagnostics • xTAG™ Respiratory Virus Panel • Approved - Jan. 2008 • PCR system for viral DNA/RNA detection • Influenza A(H1 & H3)/B, RSV A/B, Adenovirus, Parainfluenzae (1, 2, 3), Human Metapneumovirus, Rhinovirus • Use for diagnosis of viral infections • ?Exclusion of patients from CAP trials?

  43. Diagnostics • Procalcitonin (PCT) • “Hormokine” produced by parenchymal cells • Increases in response to sepsis • Attenuated by viral infection-related cytokines • “Promising” as biomarker for selecting patients more likely to have bacterial vs. viral pathogen • Limited experience with PCT at a few centers • Not yet used in trials for drug development

  44. CAP Presentations • Pneumonia Severity - PORT Score (a.k.a. PSI) • Developed as a prediction tool for short-term mortality in CAP patients

  45. PORT Score NEJM 1997; 336(4):243-250

  46. PORT Score DemographicsH & PLaboratory age = yrs (M) neoplasia (+30) pH <7.35 (+30) age = yrs – 10 (F) CHF (+10) BUN >30 (+20) nursing home (+10) renal disease (+10) Na <130 (+20) liver disease (+20) glucose >250 (+10) CVD (+10) hct <30% (+10) pulse >125 (+10) p02 <60 (+10) SBP <90 (+20) CXR - effusion (+10) RR >30 (+20) T >40 C or <35 C (+15) altered mental status (+20) NEJM 1997; 336(4):243-250

  47. PORT Score NEJM 1997; 336(4):243-250

  48. PORT Score • Prognostic score for mortality • Includes elements related to severity, but not a true severity score • Good tool for reducing unnecessary hospitalization • Intended to supplement, not override, physician judgment • Tool was studied in treated patients • Would it predict mortality in untreated patients?

  49. Workshop Discussion • Many concerns about non-inferiority trials • Selection criteria, diagnostics, endpoints, analysis • But … non-inferiority could be supported for some CAP patients • Need for clear guidance for CAP studies • For mild pneumonia, more debate about use of NI trials though most still question ethics of placebo control trial or practicality of superiority

  50. Workshop Discussion • Disease Severity • PORT score and CURB-65 both discussed • Clinical Endpoints • Emphasis on PRO tool for mild pneumonia • Objective, but how can PRO measure be related to historic evidence of treatment effect? • Discussed use of mortality for severe pneumonia • Advantage – objective, most related to historic data • Disadvantage – uncommon, treatment alternatives • Composite Endpoint

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