# Presentation: 300091

##  Clinical Trial Design in Acute Bacterial SinusitisConsiderations for Future Guidance

**John H. Powers, MD**
***Lead Medical Officer***
***Antimicrobial Drug Development and Resistance Initiatives***
***Office of Drug Evaluation IV***
***Center for Drug Evaluation and Research***
***U.S. Food and Drug Administration***

## Introduction

**Re-addressing 1998 Guidance**
**Defining the research question in ABS trials**
**Considerations in clinical trials of ABS**
**Defining the disease and Patient population**
**Types of studies**
**Endpoints and Evaluation**
**Proposals for future guidance**

## Re-addressing previous Guidance

**Discussions at previous AIDAC and workshops and international meetings on selection of non-inferiority (NI) margins in clinical trials**
**February 2002**
**November 2002**
**ICH-E10 document**
**Lack of adequate selection of NI margin means cannot ensure adequacy of any drug over placebo in setting of NI trial**
**ICH-E10 suggests other study designs if NI margin unknown**

## Re-addressing previous Guidance

**Agreement to examine previous placebo-controlled trials (PCTs) in each disease state to select appropriate margin**
**review all pertinent studies not just those which show benefit**
**Review of PCTs in acute bacterial sinusitis**
**Assessment of 14 PCTs in ABS in literature showed several issues with selection of margin**

## Re-addressing previous Guidance

**Prior PCTs provide clues that antimicrobials may be effective in shortening duration of symptoms in ABS**
**Accurate assessment of magnitude of benefit of antimicrobials in ABS remains unknown**
**Need to discuss other study designs**
**Other issues with ABS trials became apparent as part of review**

## Research Question

**What are we trying to measure?**
**“****true” benefit of antimicrobials as sole therapy in bacterial disease**
_**OR**_
_**added benefit**_** of antimicrobials above and beyond effect of standard non-antimicrobial therapies in patients with bacterial disease**
**no need for antimicrobials if decongestants, saline and anti-inflammatory agents are effective alone**
**other therapies do not result in antimicrobial resistance**
**ABS fifth most common reason for prescribing antimicrobials in ambulatory setting**
**McCaig L et al. JAMA 1995;273:214-9.**

## Defining the Disease

**Antibacterials would logically have greatest effect in patients with bacterial disease**
**recent FDA labeling rule**
**Others have hypothesized “no proof” that antibacterials have no effect in viral disease**
**previous PCTs would seem to contradict this**
**use anti-inflammatory drugs if anti-inflammatory effects of antimicrobials predominate give issue of resistance**
**use in non-bacterial disease would seem to contradict current appropriate use guidelines**

## Defining the Disease

**Effects of inclusion of patients likely to recover spontaneously**
**in NI trial, biases conclusion toward non-inferiority when there may be true differences between drugs**
**in PCT, biases conclusion toward no difference from placebo when there may be important differences**
**inclusion of higher proportions of patients with spontaneously resolving disease will result in less measured treatment effect of antimicrobials**
**may explain results of many of previous PCTs**

## Defining the Disease

**Review of literature on correlation of clinical signs and symptoms or radiography and sinus puncture**
**more rigorous criteria seem to select for higher proportion of patients with bacterial disease**
**most rigorous criteria still would allow inclusion of 20% to 40% of patients without bacterial disease**
**no adequately-sized prospective, reproduced studies to allow adequate selection criteria**
**7 days of symptoms in clinical practice but evaluation in clinical trial may be different**
**antibacterials may exert greatest effect early in disease**

## Defining the Disease

**Sinus puncture remains gold standard**
**procedure considered unpalatable by many**
**newer procedures may obviate some of this discomfort and similar in performance to sinus endoscopy (through nose instead of oral approach)**
**lack of accuracy with sinus endoscopy especially for certain organisms e.g. *****Staphylococcus aureus***
**previous studies on nasopharyngeal and throat cultures show high level of discordance**
**Wald E et al. Pediatrics 1986; 77:795-800.**
**middle meatus not normally sterile site**
**Klossek JM et al. J Laryngol Otol 1996;110:847-9.**

## Defining Disease

**Sinus puncture may be therapeutic by itself**
**drainage of closed space infection**
**Effect would be evenly distributed across arms of a trial**
**Effect of puncture should be small relative to effect of antimicrobials**
**otherwise one could question benefit of antimicrobials in this setting**
**Antimicrobials should address residual inflammation caused by tissue invasion of pathogens**

## Defining Disease

**Sinus punctures are not done in clinical practice**
**Prior PCTs with clinical entry criteria show minimal if any benefit for antimicrobials in ABS**
**Clinical trials versus clinical practice**
**many procedures done in setting of clinical trial that are not done in clinical practice**
**drug efficacy trial versus “strategy” trial**
**FDA mission is to approve *****effective***** drugs for disease under study**
**Two reasons why “strategy” trial may fail to show a difference**
**drug is not effective in disease under study**
**strategy for selecting patients is not specific**

## Defining Disease and Sample Size

**Clinical enrollment criteria requires very large sample size or very large treatment effect to show a difference between drug and placebo**
**Example:**
**assume 35% of patients in trial have bacterial disease**
**assume cure rate in viral disease is 80% in both arms and cure rate with bacterial disease is 80% with antibacterial agent and 65% in placebo**
**THEN**
**Cure rate with clinical enrollment criteria 80% vs. 75% with sample size of >2900 patients**
**Cure rate with sinus puncture defined disease 80% vs. 65% with sample size of 370 patients**

## Types of Trials

**Current guidance (two studies)**
**Microbiological based non-comparative trial with “presumed eradication” based on clinical outcome (“micro” study)**
**Clinical based NI study with clinical inclusion and outcome criteria (“clinical only” study)**

## Types of Trials

**Issues with previous Guidance studies**
**“****Micro” study **
**presumes correlation of microbiological and clinical outcome that has never been shown in ABS**
**examples of other diseases with less than optimal correlation with micro and clinical outcomes (e.g AOM)**
**Johann-Liang R et al. Pediatr Infect Dis J 2003;22:936-7.**
** ****Pre and post therapy microbiological data very helpful in ascertaining contribution of drug to treatment effect**
**less helpful when used as *****sole *****measure of efficacy**
**“****Clinical only” NI study**
**may include significant proportion of patients with non-bacterial disease**
**timing of measurement of endpoints may not be optimal**
**selecting NI margin in NI trials**

## Prior Placebo Controlled Trials

**Medline search for PCTs plus references of relevant trials**
**Evaluated 14 PCTs from medical literature**
**Varying quality of studies**
**blinding in  **
**randomization **
**sinus puncture *****with *****culture in only two but analyzed patients with and without positive culture together in primary anaylsis**
**numbers of patients with positive cultures small**
**Wide variations in methods precludes meta-analysis**

## Prior Placebo Controlled Trials

**Widely varying methods of assessment of outcomes (patients versus sinuses)**
**clinician’s assessment of symptomatic cure**
**non-validated scoring systems for symptomatic cure**
**radiological scoring systems**
**“****ostial patency” by pressure measurements**
**changes in nasal cytology**
**Timing of assessment of cure varies widely**
**various fixed time points from days to weeks after EOT**
**time to resolution of symptoms**
**two used Kaplan-Meier curve but differing measures of outcome (one used pain only and other used non-validated symptom scale)**
**several used “modified” time analysis of early fixed time points**

## Study

**Antimicrobial Efficacy ( 95% CI)**

**1**

**3**

**4**

**2**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**13**

**14**

**15**

**16**

**Study**

## Prior Placebo Controlled Trials

**Only two show benefit over placebo defined as lower bound of 95% CI above zero**
**Two with sinus puncture data **
**one shows much better outcome in subgroup with bacterial disease (+25% vs. +3%)**
**other trial shows worse outcome in subset with bacterial disease ( -12.0% vs. +2.3%)**
**both subsets with small numbers of patients**
**Point estimates in majority of studies show small benefit, on the order of approximately 4%**

## Types of Trials

**ICH-E10 suggests choosing trial design other than NI trial if NI margin unknown**
**cannot ensure benefit of any drug over placebo**
**cannot scientifically justify picking margin without data**
**Other types of trial designs**
**dose-response trial**
**“****placebo” controlled trial**
**more accurate to refer to as superiority trial vs. “other symptomatic therapies”**
**give other appropriate medications other than antimicrobials for symptom relief**

## Types of Trials

**Antimicrobials plus other symptomatic therapies vs. other symptomatic therapies**
**no issue of selection of appropriate NI margin in superiority trial**
**trial has own internal validity since direct comparison rather than indirect comparison with no antimicrobial therapy**
**PCTs suggested by independent reviews**
**“****Given the small number of trials with heterogeneous results, additional placebo-controlled trials are needed to evaluate the efficacy of antibiotics.”**
- Williams JW Jr et al. Cochrane Database Syst Rev. 2003;(2):CD000243

## Types of Trials

**Ethical consideration given rare but serious adverse events associated with ABS**
**Balances risk of adverse outcomes of ABS with risks of  adverse outcome with antimicrobials**
**serious adverse events e.g. anaphylaxis**
**spread of antimicrobial resistance**
**No data on antimicrobials decreasing risk of complications**
**would require very large sample size given rare events**
**complications may be due to altered anatomy or host factors **

## Types of Trials

**Other infectious diseases with higher mortality and complications studied as PCTs**
**new influenza drugs studied as PCTs despite availability of older drugs**
**mortality of influenza in outbreak setting ranges from 10 to 600 per 100,000 persons in healthy and chronically ill respectively **
**Barker WH et al Arch Intern Med 1982;142:85.**
**Selection of exclusion criteria to minimize risk**

## Types of Trials

**Exclusion criteria to minimize risk**
**exclude frontal and sphenoidal disease**
**? exclude patients with certain organisms**
**brain abscess associated with microaerophilic streptococci (*****S. anginosus***** group) in 70%**
***S. pneumoniae***** and *****H. influenzae***** in <1%**
**Chun CH et al Medicine 1986;65:415-31**
**Kao PT et al. J Microbiol Immunol Infect 2003;36:129-36.**
**excluding “severe” disease**
**but has several associated issues**

## Types of Trials

**“****Severe” disease**
**severity defined as clinical characteristics predicting worse outcome (regardless of therapy) e.g PORT criteria for community- acquired pneumonia**
**Fine MJ et al N Engl J Med 1997;336:243-50.**
**no criteria exist for ABS**
**criteria used in previous trials (fever) may select for bacterial disease**
**patients with facial swelling may have periorbital cellulitis which may be considered a separate disease**
**patients with “severe” disease may be most likely to benefit from antimicrobials**

## Trial Design and Sample Size

**More**** ****conservative**** ****assumptions:**
**Non-inferiority (********=.05): ****2700**
**Placebo w/ 10 Day Endpoint (.80 v. .70): ****780**
**Placebo with time-to-resolution: ****520**
**More ****aggressive**** assumptions:**
**Non-inferiority (********=.10): ****670**
**Placebo w/ 10 Day Endpoint (.80 v. .65): ****370**
**Placebo with time-to-resolution: ****250**
**Current sample sizes of ABS databases from NDAs**
**680 patients/drug in “clinical only” trials (range 142 to 1965)**
**580 patients/drug in “micro” trials (range 192 to 1103)**

## Types of Trials

**Implications for pharmaceutical industry**
**current trial design affords low risk of failure as difficult to distinguish any drug from placebo**
**ABS is large market and proof that ABS does not need treatment in some portion of patients would decrease market size**
**opportunity for smaller trials and more streamlined development program**
**use of supportive data from CAP trials allows opportunity for one rigorous ABS trial**
**less data but higher quality data**

## Endpoints and Timing

**Most appropriate measurement would examine resolution of signs and symptoms of disease**
**several PCTs evaluated time to return to normal daily activities which may be patient dependent**
**radiographic scores not validated and not correlated with clinical signs and symptoms**
**correlation with microbiolgical endpoints and clinical outcomes not demonstrated to date**
**Time to resolution of disease may be most appropriate in self-resolving diseases**
**influenza and traveler’s diarrhea trials**

## Endpoints and Timing

**Nicholson KG et al. Lancet 2000;355:1845-1850.**

## Proposal for Future Guidance

**1) Define population with bacterial disease by sinus puncture**
**would not necessarily require 7 days of symptoms**
**perhaps improve selection criteria for clinical practice**
**2) Superiority trial design of symptomatic therapy vs. symptomatic therapy plus antimicrobial**
**discussion of appropriate exclusion criteria**
**role of antimicrobial resistance**
**3) Endpoint of time to resolution of symptoms**
**similar to previous trials of influenza**
**requires validation of patient diaries**