Guidance for Industry 

Acute Bacterial Otitis Media: 

Developing Drugs for 

Treatment 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact John Alexander at 301-796-1400. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

January 2008 

Clinical Antimicrobial 

Revision 1 

I:\3892dft.doc 

12/31/07
Guidance for Industry 

Acute Bacterial Otitis Media: 

Developing Drugs for 

Treatment 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

January 2008 

Clinical Antimicrobial 

Revision 1 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. DEVELOPMENT PROGRAM ....................................................................................... 3

A. General Considerations .................................................................................................................3

1. Early Phase Clinical Development Considerations .........................................................................3

a. Animal models ..........................................................................................................................3

b. Patient-reported outcome instruments.......................................................................................3

2. Definition of AOM/ABOM................................................................................................................4

3. Efficacy Considerations ...................................................................................................................4

4. Safety Considerations.......................................................................................................................5

B. Specific Efficacy Trial Considerations .........................................................................................6

1. Study Design.....................................................................................................................................6

2. Study Population ..............................................................................................................................7

3. Study Inclusion Criteria ...................................................................................................................7

a. Patient history and characteristics .............................................................................................8

b. Signs and symptoms..................................................................................................................8

c. Pneumatic otoscopy...................................................................................................................8

d. Tympanometry..........................................................................................................................9

e. Baseline tympanocentesis .........................................................................................................9

4. Study Exclusion Criteria ..................................................................................................................9

5. Randomization, Stratification, and Blinding..................................................................................10

6. Dose Selection ................................................................................................................................10

7. Choice of Comparators ..................................................................................................................10

8. Concomitant Medications...............................................................................................................11

9. Efficacy Endpoints..........................................................................................................................11

a. Evaluation of clinical response ...............................................................................................11

b. Clinical relapse or recurrence .................................................................................................13

c. Adverse events or receipt of additional antibacterial therapy .................................................13

d. Microbiological response........................................................................................................14

10. Study Visits and Timing of Assessments ....................................................................................15

a. Entry visit ................................................................................................................................15

b. On-therapy visits.....................................................................................................................16

c. Early follow-up visit................................................................................................................17

d. Late follow-up assessment ......................................................................................................17

e. Safety evaluations ...................................................................................................................17

11. Statistical Considerations..........................................................................................................18

a. Analysis populations ...............................................................................................................18

b. Noninferiority margins............................................................................................................19

c. Sample size..............................................................................................................................19

d. Missing data ............................................................................................................................19

e. Interim analyses and data and safety monitoring boards.........................................................20

f. Other analyses of interest and secondary endpoints ................................................................20

g. Statistical analysis plan ...........................................................................................................20

12. Ethical Considerations ..............................................................................................................21

i 
C. Other Considerations...................................................................................................................22

1. Labeling Considerations ................................................................................................................22

2. Antimicrobial Resistance Claims ...................................................................................................22

3. Recurrent or Persistent ABOM ......................................................................................................22

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Guidance for Industry1 1 

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Acute Bacterial Otitis Media: 

Developing Drugs for Treatment 

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8 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

9 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

10 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

11 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

12 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

13 the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 

treatment of acute bacterial otitis media (ABOM). Specifically, this guidance addresses the Food 

and Drug Administration’s (FDA’s) current thinking regarding the overall development program 

and designs of clinical trials for drug products to support an indication for treatment of ABOM.2

 

It is the intention of this guidance to serve as a focus for continued discussions among the 

Division of Anti-Infective and Ophthalmology Products and the Division of Special Pathogen 

and Transplant Products and pharmaceutical sponsors, the academic community, and the public.3

 

This guidance does not address the development of drugs for other purposes or populations, such 

as prevention of ABOM or treatment of patients with tympanostomy tubes in place. As the 

science of this indication evolves, this guidance may be revised as new information 

accumulates.4

This guidance revises the draft guidance for industry Acute Otitis Media — Developing 

Antimicrobial Drugs for Treatment published in 1998. Once final, this guidance will be 

considered the FDA’s current thinking regarding the development of drugs for the treatment of 

1

 This guidance has been prepared by the Division of Anti-Infective and Ophthalmology Products and the Division 

of Special Pathogen and Transplant Products in the Center for Drug Evaluation and Research (CDER) at the Food 

and Drug Administration. 

2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 

products regulated within CDER unless otherwise specified. 

3

 In addition to consulting guidance documents, sponsors are encouraged to contact the divisions to discuss specific 

issues that arise during the development of antimicrobial drug products. 

4

 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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ABOM. It also supersedes, with regard to the development of drugs to treat ABOM, more 

general guidance issued many years ago (i.e., Clinical Evaluation of Anti-Infective Drugs 

(Systemic) and Clinical Development and Labeling of Anti-Infective Drug Products, as well as 

the joint FDA/Infectious Disease Society of America’s General Guidelines for the Clinical 

Evaluation of Anti-Infective Drug Products).

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This guidance does not contain discussion of the general issues of clinical trial design or 

statistical analysis. Those topics are addressed in the ICH guidances for industry E8 General 

Considerations for Clinical Trials and E9 Statistical Principles for Clinical Trials. This 

guidance focuses on specific drug development and trial design issues that are unique to the 

study of ABOM. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

There have been a number of public discussions regarding the design of clinical trials to study 

ABOM since the FDA last published draft guidance on the development of antimicrobial drugs 

for the treatment of ABOM in 1998.6 These discussions have primarily focused on the 

appropriateness of noninferiority trial designs for ABOM and other important study design issues 

such as the following: 

• Inclusion criteria 

• Application of appropriate diagnostic criteria 

• Use of appropriate definitions of clinical outcomes 

• Timing of outcome assessments 

• Use of concomitant medications 

• Role of microbiological outcomes 

Important changes from the 1998 draft guidance that are based on these discussions have been 

incorporated into the appropriate sections below. 

5 Beam, TR, DN Gilbert, and CM Kunin, 1992, General Guidelines for the Clinical Evaluation of Anti-Infective 

Drug Products, Infectious Disease Society of America and the Food and Drug Administration, Clinical Infectious 

Diseases, Nov.15, Supplement 1:S5-32. 

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 The design of ABOM clinical trials was the subject of the July 11, 2002, meeting of the Anti-Infective 

Drugs Advisory Committee. A transcript of that meeting is available at 

www.fda.gov/ohrms/dockets/ac/02/transcripts/3875T2.doc. 

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73 III. DEVELOPMENT PROGRAM 

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A. General Considerations 

1. Early Phase Clinical Development Considerations 

New drugs being studied for ABOM should have preclinical data documenting activity against 

the most commonly implicated pathogens for ABOM (i.e., S. pneumoniae, H. influenzae, and M. 

catarrhalis). 

a. Animal models 

Several animal species, including the mouse, rat, and chinchilla, have been used to evaluate 

antimicrobial activity in vivo. However, with increasing study of the role of genetic factors in 

the pathogenesis of ABOM and a better understanding of the susceptibility of various strains of 

mice to bacterial infections, the mouse model has assumed increasing prominence in studying the 

pathogenesis and treatment of ABOM. Pathological and histological responses to antibacterial 

treatment have been shown in the previously mentioned species as well as other species. 

Although animal models may contribute to demonstrating proof of concept in the treatment of 

ABOM (or for comparing in vivo activity of different antimicrobials), the results should be 

carefully interpreted when being used to help design subsequent human studies. Animal studies 

should not be considered a substitute for the clinical trials in patients with ABOM that should be 

conducted to evaluate safety and efficacy of the drug. 

It is important to understand the pharmacokinetics, metabolism, and distribution of the test drug 

in the animal being studied to be able to use the data from the animal model to inform the design 

of studies in other animal models or subsequent clinical studies (e.g., data from animal studies 

can be one of the components considered in selection of doses that will be evaluated in 

subsequent clinical studies). 

b. Patient-reported outcome instruments 

There should be a well-defined and reliable method of assessing patient response in ABOM 

studies. Sponsors should anticipate the need for appropriate instruments to evaluate clinical 

response (e.g., well-developed patient-reported outcome (PRO) or caregiver-reported outcome 

instruments) early in the clinical development process. If an adequate instrument is not available 

for studying ABOM, we recommend that the new instrument development process begin well in 

advance of phase 3 clinical trials so that the instrument can be ready for incorporation into the 

phase 3 protocol. 

PRO instruments can be used to measure patient symptoms and self-reported signs; for small 

children and individuals who cannot respond reliably for themselves, a caregiver-reported 

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outcome instrument can be used to measure patient signs as observed by the caregiver.7 Both 

types of instruments may be appropriate for use in a single study depending on the patient 

population enrolled. 

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For more information regarding the development of such outcome measures, see the draft 

guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 

Development to Support Labeling Claims.

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2. Definition of AOM/ABOM 

Previously, the FDA’s clinical definition of acute otitis media (AOM) was “inflammation of the 

middle ear manifested by localized signs or symptoms.” To better identify individuals most 

likely to benefit from antimicrobial therapy, this guidance defines ABOM as “recent or acute 

onset of inflammation of the middle ear accompanied by the presence of a bacterial pathogen in 

middle ear fluid.” This definition excludes asymptomatic patients with isolated middle ear 

effusion identified by pneumatic otoscopy (i.e., otitis media with effusion). 

3. Efficacy Considerations 

FDA review of previous ABOM studies has not been able to establish a reliable estimate of the 

magnitude of benefit for treatment of ABOM by antimicrobials (a precondition for a 

noninferiority trial).9,10 Accordingly, only superiority trials are currently recommended for 

ABOM studies.11

The goal of ABOM clinical trials should be to demonstrate an effect of antibacterial therapy on 

the clinical course of ABOM caused by H. influenzae, S. pneumoniae, or M. catarrhalis. If 

pharmaceutical sponsors wish to add additional organisms to this indication, they should provide 

7

 It is important to distinguish between signs and symptoms in the context of PRO instruments to avoid any 

confusion with the use of these terms in the subsequent text. PRO instruments can capture signs or symptoms 

reported by the patient. A caregiver-reported outcome instrument by definition is not a PRO but may be the best 

option to capture patient outcomes for younger children who may not be able to directly articulate their subjective 

state clearly. For example, pain intensity measurement as experienced by a young child can be inferred and reported 

by a caregiver based on the child’s behavior, in which case it is measured as a sign rather than as a true symptom. 

When signs or symptoms are discussed in the following text, in most contexts they include the subjective state of the 

patient but may be limited to signs (excluding symptoms) when captured by a caregiver rather than a patient.

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 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a 

guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

9

 See the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials

(http://www.fda.gov/cder/guidance/index.htm). 

10 Most previous placebo-controlled studies of ABOM have been clinical studies of AOM where a bacterial 

pathogen has been presumed; only one prior trial has performed tympanocentesis at baseline (i.e., documenting 

ABOM at baseline). However, the conclusion of these studies taken together remains that a reliable estimate of the 

magnitude of benefit that would be expected in a new active-controlled study is uncertain. 

11Marcy, M, G Takata, P Shekelle, et al., 2001, Management of Acute Otitis Media, AHRQ Evidence 

Report/Technology Assessment No. 15 (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.21026). 

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data sufficient to substantiate the clinical relevance of the particular organism as a pathogen in 

ABOM. 

The number of studies that should be conducted in support of an ABOM indication depends on 

the overall development plan for the drug product under consideration. If the development plan 

for a drug product has ABOM as the sole marketed indication, then at least two adequate and 

well-controlled trials establishing safety and efficacy should be conducted for this indication. 

When two studies are conducted for an ABOM indication, we strongly recommend that at least 

one study be conducted with tympanocentesis performed on all patients (see section III.B.2., 

Study Population, and section III.B.3., Study Inclusion Criteria). A design with microbiological 

information on all patients offers the strongest likelihood of success by ensuring that all patients 

in the primary analysis population have a documented bacterial infection and that an adequate 

number of patients with each of the common bacterial pathogens has been enrolled (i.e., S. 

pneumoniae, H. influenzae, and M. catarrhalis). Microbiological confirmation also permits 

analysis of treatment response by individual pathogen. Although tympanocentesis is 

recommended for the second study as well, clinical criteria alone can be sufficient for defining 

the primary analysis population in a second trial that is conducted as a superiority study. If only 

a single clinical trial is anticipated in support of an ABOM indication, then tympanocentesis 

should be performed on all patients in that study. 

A single study for an ABOM indication may be appropriate if there are data from other clinical 

studies demonstrating effectiveness in other respiratory tract diseases and there is additional 

supportive information such as pharmacokinetic (PK) and pharmacodynamic studies 

demonstrating concentration of the antibacterial drug in the middle ear fluid at a level expected 

to be active against the common pathogens causing ABOM. For example, evidence of efficacy 

from community-acquired pneumonia (CAP) trials may be supportive of a single superiority trial 

of ABOM because of the overlapping bacterial pathogens and greater seriousness of CAP 

relative to ABOM. 

Currently, there are no surrogate markers accepted by the FDA as substituting for clinical 

outcomes in ABOM studies. Sponsors who wish to propose a surrogate marker for clinical 

outcome or the initial diagnosis of ABOM should discuss this with the FDA early in the drug 

development process. 

4. Safety Considerations 

There should be sufficient evidence of drug safety from ongoing or completed clinical studies of 

other respiratory infections in adults before initiating ABOM studies in children, even if ABOM 

is the sole indication being pursued by a sponsor. Antibacterials with clinically significant 

toxicity identified in earlier studies should not be considered appropriate for study of this 

indication. PK studies in children also should be completed before initiating ABOM efficacy 

studies. 

A sufficient number of pediatric patients should be studied at the exposure (dose and duration) 

proposed for use to draw appropriate conclusions regarding drug safety. Although it may be 

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possible to derive some of this information from studies of the new drug in adults when exposure 

is similar or greater than is anticipated for treatment of ABOM, there also should be sufficient 

evidence of safety in children independent of adults. The total number of pediatric patients 

needed in a drug development program that includes an ABOM indication should be discussed 

with the FDA early in the drug development process. 

Safety evaluations and assessments specifically should take into consideration the patient 

populations (e.g., pediatric patients 6 months of age and older) that are likely to be treated for 

ABOM. Protocols for ABOM should clearly specify the age-appropriate methods to be used to 

obtain safety data during clinical studies. Age- and sex-appropriate normal laboratory values 

should be included with clinical measurements when reporting laboratory data. Additional 

safety evaluations may be appropriate because of the preclinical and clinical profile of the 

specific drug under study. Longer term assessment of adverse events after discontinuation or 

completion of the antimicrobial also should be considered depending on the specific drug being 

studied and the potential for long-term or delayed adverse effects. 

B. Specific Efficacy Trial Considerations 

1. Study Design 

Currently, we recommend only superiority trials for ABOM studies. Sponsors who are 

considering a noninferiority trial for ABOM should justify the proposed noninferiority margin to 

the FDA as early as possible during protocol development and before study initiation. This 

situation is discussed further in section III.B.11., Statistical Considerations. 

Superiority studies in the treatment of ABOM can consist of the following forms: 

• Double-blinded, placebo-controlled study with a background of optimized

nonantimicrobial therapy — This design tests the safety and efficacy of an 

antimicrobial as an addition to a standardized regimen of analgesic medications 

compared to the same standardized regimen plus placebo. 

• Delayed versus immediate therapy — Patients in both study arms receive an active 

therapy, but administration of the comparator treatment is delayed relative to the 

experimental drug (i.e., one group is started on placebo but then switched to active 

therapy after a protocol-defined interval). The active therapy can be the same 

experimental antimicrobial in both study arms. Both groups remain blinded to treatment 

assignment for the entire study; to demonstrate efficacy, immediate therapy should be 

superior to delayed therapy. 

• Dose-response — Patients in each study arm receive different antimicrobial doses (or 

dosing regimens) together with standardized nonantimicrobial therapy. To demonstrate 

efficacy, the arm receiving a higher dose (or more intensive therapy) should be superior 

to the lower dose (or less intensive) regimen. 

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• Superiority of the study antimicrobial to another antimicrobial — Patients in one 

arm receiving the test drug (with standardized background nonantimicrobial therapy) are 

compared to patients in a control arm receiving another antimicrobial drug (with 

standardized background nonantimicrobial therapy). To demonstrate efficacy, the arm 

receiving the test antimicrobial should demonstrate superiority to the arm receiving the 

control antimicrobial. 

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A three-arm study with the experimental treatment group, an active control arm (e.g., an 

antibacterial drug approved for ABOM), and a placebo-controlled group permits the 

demonstration of superiority and also can provide risk-benefit information relative to an 

approved comparator. 

At the present time, the FDA does not recognize different forms of ABOM based on disease 

severity at presentation. However, we recognize that investigators may be less likely to enroll 

patients presenting with severe disease in a placebo-controlled trial than patients with milder 

symptoms, and that enrollment of hospitalized patients may be incompatible with a placebocontrolled study. We also recognize that treatment of severe disease is where an antimicrobial 

treatment effect may be greatest. If sponsors wish to study patients with severe disease (or 

hospitalized patients), we strongly encourage discussion with the appropriate review division 

regarding protocol design. 

2. Study Population 

ABOM clinical trials should enroll male and female children, usually from 6 months of age and 

older. ABOM should be diagnosed by a combination of signs and symptoms, including 

pneumatic otoscopy and tympanometry/electroacoustic reflectometry at the time of enrollment. 

Tympanocentesis should be performed at enrollment (i.e., before the initiation of study 

treatment) in studies where microbiology information is being obtained as part of the study 

design; if bilateral ABOM is present on exam, tympanocentesis should be performed only on the 

more involved ear. 

3. Study Inclusion Criteria 

All signs, symptoms, and test results at baseline (and during time on study) should be recorded. 

The minimum subset of specific signs and symptoms needed for enrollment should be defined in 

the study protocol as part of the inclusion criteria for the study.12

12 It is essential that the inclusion criteria for a superiority study be selected to yield a strong likelihood that a patient 

has disease attributable to a bacterial pathogen; this is particularly important for the success of a trial without 

mandated tympanocentesis. A protocol also can specify different criteria for the diagnosis of ABOM for different 

age groups if this improves the overall positive predictive validity for bacterial disease. 

At entry, patients also should display a minimum criterion for signs and symptoms to enable a clinically meaningful 

difference between placebo and active therapy to be detected by the study. For example, if response as measured by 

a caregiver-reported outcome instrument is the primary study endpoint, then each patient at enrollment should have 

a minimum decrement in score on this instrument adequate to allow for a possible conclusion of improvement over 

time. 

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The following are inclusion criteria that can be used in ABOM trials. 

a. Patient history and characteristics 

The following patient demographic characteristics should be used for a better chance of selecting 

patients more likely to have bacterial disease before undergoing baseline tympanocentesis: 

• Younger age: less than 5 years 

• Fever: temperature greater than 38.5 degrees Celsius 

• Biphasic illness: symptoms of ABOM preceded by predisposing infections, such as 

rhinitis, pharyngitis, and tonsillitis 

b. Signs and symptoms 

Infants and younger children often present with nonlocalizing symptoms of otitis media; older 

children are more likely to articulate symptoms referable to the ear. Signs or symptoms that may 

be present in all children with ABOM include the following: 

• Ear pain or earache 

• Ear fullness 

• Decreased hearing 

The following signs may be observed in infants or neonates: 

• Head rolling 

• Ear tugging 

• Ear rubbing 

Additional generalized signs and symptoms in infants that are consistent with a diagnosis of 

ABOM but are otherwise nonspecific include: 

• Fussiness or irritability 

• Inconsolability 

• Decreased appetite 

• Sleep disturbance 

c. Pneumatic otoscopy 

Otoscopic findings considered consistent with ABOM include: 

• Bulging or fullness of the tympanic membrane (convexity of the plane of the eardrum), 

with loss of anatomic landmarks on visualization 

• Opacification of the tympanic membrane regardless of color 

• Erythema of the tympanic membrane 

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• Abnormal tympanic membrane mobility on biphasic pneumatic otoscopy; a tympanic 

membrane in the neutral position or retracted is not sufficient evidence of ABOM as 

these findings are not specific enough to distinguish the disease from otitis media with 

effusion 

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d. Tympanometry 

Entry tympanometry and/or electroacoustic reflectometry are recommended for all children at 

baseline and may help select patients to undergo tympanocentesis. If tympanometry is used, 

appropriate results for inclusion include either type B or positive pressure peak curves. 

e. Baseline tympanocentesis 

The microbiological diagnosis of ABOM is based on isolating a bacterial pathogen by 

tympanocentesis at baseline. Gram stain of the aspirate material with examination for white 

blood cell (WBC) count also should be performed, with culture as well as antimicrobial 

susceptibility testing of all bacterial isolates. 

Tympanocentesis should be performed only by individuals with expertise in this procedure. 

Study sponsors should have mechanisms in place to ensure that study centers where this 

procedure will be performed and the individuals at these centers have sufficient experience and 

training to perform tympanocentesis. 

4. Study Exclusion Criteria 

The following patients should be excluded from trials for the treatment of ABOM: 

• Patients with otitis externa 

• Patients with tympanostomy tubes at the time of study entry13

• Immunocompromised patients or patients with other medical conditions that may affect 

interpretation of the effect of study medications 

• Patients on any medications that may affect the interpretation of study outcome (e.g., 

inhaled steroids) 

• Patients with craniofacial abnormalities 

• Patients with concomitant infections other than ABOM that may influence the assessment 

of drug efficacy and safety 

• Patients who are allergic to any of the study medications 

• Erythema of the tympanic membrane without other evidence of otitis media14

13 Patients with an acute, recent tympanic membrane perforation related to the present episode of ABOM can be 

enrolled if other entry criteria are met. 

14 Although nonspecific as an isolated finding, the absence of diffuse erythema has a relatively high negative 

predictive value for bacterial otitis media. 

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Patients who have received antimicrobial therapy for the current episode of ABOM or within the 

previous 4 weeks should be excluded unless the trial is designed specifically to study treatment 

failures. 

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5. Randomization, Stratification, and Blinding 

Patients should be randomized for receipt of study drugs at enrollment. All studies should be 

double-blinded for study therapy and assessment of outcome unless there is a clearly compelling 

reason why this cannot be done. PRO endpoints are rarely convincing without double-blinding. 

Stratification by age is recommended since younger patients (i.e., younger than 2 years of age) 

may have lower cure rates than older patients. Other possible stratification factors include 

unilateral versus bilateral disease, and the presence or absence of otorrhea. 

6. Dose Selection 

The PK of the drug in children should be established before initiating efficacy studies in 

children; studies also should assess any PK changes with age. Data from phase 2 dose-ranging 

studies can be integral to selecting an appropriate dose for phase 3 clinical trials. 

Data from studies with tympanocentesis demonstrating drug penetration into middle ear fluid 

also can be valuable before progressing to phase 3 studies. 

7. Choice of Comparators 

To date, review of previous placebo-controlled studies of ABOM15 have not shown a risk to 

placebo-treated recipients that make future placebo-controlled trials unethical;16 overall risk 

from placebo treatment may be similar to that associated with antibacterial therapy since lowfrequency severe events (e.g., pseudomembranous colitis or serious allergic reactions) have been 

observed with almost all antibacterial drugs. The occurrence of common but less-severe adverse 

reactions (e.g., diarrhea) from antibacterial drugs also can be relevant in assessing the riskbenefit to patients in a placebo-controlled trial where the expected treatment effect may be small. 

An early clinical assessment for treatment failure at 48 to 72 hours, followed by rescue therapy, 

should be incorporated into the study design so that individual patients are treated at the time a 

failure outcome is assigned; this process may serve to mitigate concerns regarding inclusion of a 

placebo arm in an ABOM trial. 

15 Studies of AOM and ABOM are used synonymously in this context since earlier studies of ABOM were primarily 

studies of AOM with a clinically diagnosed presumed bacterial etiology. 

16 Most previous placebo-controlled studies of ABOM did not perform tympanocentesis at baseline; therefore, the 

true incidence of bacterial infection in these trials is unknown. Without this information, the incidence of 

suppurative complications from untreated ABOM in the setting of a documented pathogen is also uncertain. 

Similarly uncertain is whether antibacterial therapy would prevent these complications. This concern is also 

addressed in section III.B.12, Ethical Considerations. 

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391 8. Concomitant Medications 

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All patients should receive effective analgesia for pain associated with ABOM. The use of 

antihistamines, decongestants, or other therapies is discouraged. However, if other treatments 

are permitted in the study, their use should be carefully standardized across study groups; the 

lack of standardization of concomitant medications can introduce an important source of 

confounding in clinical trials if there are imbalances in receipt of nonantimicrobials between trial 

groups. Such confounding may occur even if the number of patients receiving concomitant 

medications is similar between study groups but the reasons for administering concomitant 

medications differ. Confounding also may occur when the patients in one group who receive 

concomitant medications differ in baseline characteristics from those patients who do not receive 

concomitant medications. Therefore, sponsors should make every attempt to control for 

potential confounders such as concomitant medications. This can be accomplished through a 

protocol-specified nonantimicrobial background regimen with the dose and frequency of use 

similar for all patients in the trial; however, the use of standardized, nonantimicrobial therapy in 

the protocol should be based on experimental evidence that the treatment is effective. At a 

minimum, the protocol should specify appropriate options for nonantimicrobial therapies during 

the study. 

Assessment of the need for concomitant medications as an endpoint may not be an accurate 

surrogate for persistent patient signs or symptoms unless the presence of such signs or symptoms 

is confirmed by a patient- or caregiver-reported outcome tool that shows continued signs or 

symptoms at the time of administration of the concomitant medication. Effort should be made to 

capture all concomitant medication use on a patient- or caregiver-reported tool and to relate this 

information to patient signs or symptoms. 

9. Efficacy Endpoints 

a. Evaluation of clinical response 

The primary emphasis of the study should be the effect of the antimicrobial drug on outcomes 

that are clinically important to patient symptoms and functioning. Assessment of clinical 

response at each time point should not be limited solely to signs or symptoms identified at the 

time of enrollment. For example, if a patient is enrolled with ABOM in one ear and develops 

ABOM in the opposite ear during therapy while symptoms referable to the first ear are still 

improving, that patient should not be considered a clinical success. Patient outcome should be 

based on response per patient rather than per ear (i.e., outcome is measured identically regardless 

of whether unilateral or bilateral disease is present). 

It is likely that in the setting of ABOM studies outcome assessment will include assessment of 

clinical signs recorded by a caregiver. Caregiver-reported outcome instruments should be 

limited to observable signs and should exclude items that ask about concepts that can be known 

only by the patient (e.g., pain intensity). 

If improvement or resolution of signs or symptoms is the primary outcome measure of a study, 

then assessment over time on this measure should be the primary efficacy analysis. An 

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alternative can be to use response at fixed time points as the primary study endpoint. However, a 

fixed time endpoint may not be as sensitive a measure of treatment effect as a time-to-resolution 

analysis. For example, clinical outcome at greater than 7 days after onset of therapy may not 

show a difference between treatment arms since most patients will be clinically cured by this 

time regardless of the administration of antimicrobials. Sponsors who choose to use response at 

a fixed time point as the primary outcome (i.e., as the test-of-cure assessment) should provide 

evidence to support the selection of that specific time point. 

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Measuring clinical response in an ABOM trial can be approached in two ways: as a binary 

response (i.e., success or failure based on complete resolution of symptoms) or as a meaningful 

response as defined by a composite sign or symptom (PRO) scale score. 

1. Primary clinical outcome based on complete resolution of symptoms

• Clinical success. Clinical success can be documented when a patient exhibits 

complete resolution of disease-specific clinically meaningful signs and symptoms 

present at enrollment and the absence of new symptoms attributable to ABOM. 

• Clinical failure. Clinical failure can be documented as follows: 

− Development of complications of ABOM such as meningitis or mastoiditis. 

− Lack of complete resolution of disease-specific clinically meaningful symptoms 

or development of new symptoms attributable to ABOM. 

− Treatment with nonstudy antibacterial drugs for ABOM or a related condition. 

Patients designated as clinical failures at an early time point should also be designated as 

clinical failures for all subsequent follow-up visits. 

If clinical response is based on complete resolution of symptoms, we recommend that the 

primary efficacy endpoint be time to clinical success, defined as above for the period 

from the start of study drug to complete relief of symptoms. The use of an appropriate 

PRO tool is preferred even when outcome is evaluated categorically as complete 

resolution since this can yield greater assurance that symptoms are being assessed 

consistently across patients.17 If an alternative to a PRO is used, the method of 

assessment should be a well-defined and reliable method of assessing patient response. 

2. Primary clinical outcome based on a scale

If a PRO instrument is used for measuring responses that will be based on a scale score, 

then the score rather than an endpoint of complete symptom resolution should be used as 

17 For more information regarding the development of PRO measures, see the draft guidance for industry PatientReported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. When final, this 

guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check 

the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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the outcome variable. An outcome scale can be used for describing categorical responses 

(e.g., success, improvement, and failure) at each time point if the criteria for the 

categories have been well-developed and validated.

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18

The amount of improvement determined to be clinically meaningful (and, therefore, 

appropriate for regulatory decisions) should be determined during instrument 

development and discussed with the FDA before study initiation. Statistically significant 

differences between comparator regimens can be insufficient for demonstrating benefit if 

the differences have not been shown to be clinically meaningful. 

Nonspecific symptoms may persist in children after treatment for ABOM and possibly 

confound a study endpoint requiring complete resolution of symptoms; accordingly, use 

of an accepted PRO response instrument that has been developed with an adequate 

responder definition that takes into consideration these types of symptoms is strongly 

recommended in ABOM studies. 

b. Clinical relapse or recurrence 

Patients who experience clinical improvement without complete resolution of symptoms but then 

worsen should be considered clinical failures (i.e., there should be no separate category for 

relapse). Patients who experience complete resolution of symptoms of ABOM for at least 48 

hours and then experience further symptoms indicative of ABOM before the early or late followup visit should be considered clinical recurrences for that follow-up visit. 

Clinical recurrence can be evaluated as a secondary endpoint. Tympanocentesis (or repeat 

tympanocentesis if performed at entry) in patients who experience further symptoms after 

success may be valuable, as this would allow a differentiation between patients who may still 

harbor the initial pathogen compared to patients who have acquired a new pathogen or have a 

noninfectious etiology for new symptoms, although in both instances this should be considered a 

clinical recurrence. Bacterial isolates obtained from clinical recurrences should be subjected to 

an appropriate in vitro method (e.g., pulse field electrophoresis gel) to determine if the original 

isolate and the isolate obtained from the recurrence episode are indistinguishable. 

c. Adverse events or receipt of additional antibacterial therapy 

Patients who discontinue therapy because of an adverse event should be evaluated at the time of 

discontinuation of the study medication. These patients should not be considered withdrawn 

from the study in terms of overall evaluation; investigators should continue to follow all such 

patients at study visits as scheduled and continue to record information on both safety and 

efficacy outcomes. If at the time study medication is discontinued the patient is alive, without 

complications, and does not receive additional antimicrobial therapy, then the patient should be 

18 If a PRO instrument is used for assessing the primary study endpoint, then it may be possible to use time to reach 

a specific criterion of clinical improvement as the primary efficacy outcome (i.e., before complete resolution of 

symptoms). However, use of such a measure as the primary efficacy analysis should be discussed with the FDA 

before study initiation. 

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evaluated following the protocol criteria; discontinuation of therapy because of an adverse event 

should not automatically be considered a clinical failure. 

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Patients who receive another antibacterial drug while on study drug should be considered failures 

at the time the second antibacterial drug is administered unless a second unrelated infection has 

been documented and it is known that the second antibacterial drug does not have activity 

against pathogens known to cause ABOM. 

d. Microbiological response 

Although microbiological outcome provides useful information regarding the biological activity 

of antimicrobials, microbiological outcome is not a direct measure of benefit to patients and, 

therefore, should be viewed as being supportive but not as a substitute for clinical outcome in a 

specific trial.19

If follow-up cultures are obtained from patients, the cultures can be most useful if samples are 

obtained after the completion of drug therapy and a sufficient time interval so that drug levels in 

middle ear fluid will be unlikely to affect culture results (i.e., based on PK and 

pharmacodynamic considerations). Cultures with no growth obtained while on therapy may 

represent suppression rather than elimination of organisms. 

Although information from repeat tympanocentesis can be valuable if these procedures were 

performed, we recognize that performing repeat procedures on patients who are clinically well 

may not be acceptable; accordingly, follow-up microbiological data are likely to be incomplete 

and unable to fully characterize the concordance of clinical and microbiological outcomes. 

However, we recommend that investigators perform repeat tympanocentesis in patients who are 

clinical failures to document bacteriological failure and evaluate the susceptibility profile of any 

pathogens isolated. 

The possibility that there may be a proportion of patients who are clinically cured but who still 

have bacterial isolates from repeat tympanocentesis calls into question the use of the outcome 

categories based on inferred microbiological outcomes such as presumed microbiological 

eradication. Such analyses do not add to what is already known from analysis of clinical 

outcomes; therefore, there are no recommendations for presumed eradication in this guidance. 

The term eradication also may be inaccurate, as bacteria may be present but below the level of 

detection of culture testing; therefore, the term no growth on culture is considered to be more 

accurate. 

19 Microbiological outcomes may be valuable in studies addressing dosing regimens (i.e., where time to no growth 

on culture is being used as an outcome to optimize dose and/or dosing frequency after clinical benefit has been 

demonstrated). 

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558 10. Study Visits and Timing of Assessments 

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a. Entry visit 

At entry, the investigator should evaluate the patient by performing an appropriate history and 

physical examination. The information recorded on the case report form during the entry 

examination should include the following. 

• History and demographic characteristics 

− Date of visit 

− Age, sex, and weight 

− Underlying medical conditions, if any 

− Current medications, if any 

− History of allergies or allergic symptoms 

− Social environment (e.g., day care attendance), including smoke exposure 

− Number of distinct and well-documented episodes of AOM/ABOM in the previous 

12 months and how this information is obtained (i.e., chart review or recall of 

caregiver); dates, treatment regimens, and outcomes should be recorded 

• Symptoms 

The presence of each symptom, as discussed in section III.B.3., Study Inclusion Criteria, should 

be documented directly as reported by the patient or caregiver. Baseline signs and symptoms 

also can be recorded by patients or caregivers in a validated diary (i.e., a PRO or caregiverreported instrument). 

• Signs at clinic visit 

− Vital signs, including body temperature measurement. 

− Presence of unilateral or bilateral disease. 

− Otoscopic findings for each ear, including position of tympanic membranes, color, 

and mobility on pneumatic otoscopy. The absence of tympanic membrane 

perforation for each ear should be documented. 

− Tympanometry and/or electroacoustic reflectometry for each affected ear. 

− Other laboratory tests (e.g., peripheral WBC count, if obtained). 

• Sample collection 

For studies where microbiological information is being obtained, the entry visit should 

include baseline tympanocentesis with culture of middle ear fluid and susceptibility 

testing of any organisms isolated. All isolates considered to be possible pathogens should 

be saved in the event that additional testing of the isolate is needed. For microbiological 

assessment, the investigator should collect the following information: 

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603 − Identification of the affected ear sampled (i.e., right or left). 

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− A description of how the sample was obtained, processed, and transported to the 

laboratory. 

− Identification of the bacterial isolate and serotype if S. pneumoniae.

20

− In vitro susceptibility testing of the isolates to both the study and control drugs. This 

information should remain blinded while the patient is receiving study medication. In 

vitro susceptibility testing should be performed by using standardized methods such 

as the Clinical and Laboratory Standards Institute methods, unless otherwise justified. 

b. On-therapy visits 

Each patient should have daily on-therapy assessments of signs and symptoms. These 

assessments can be performed by the investigator during a visit to the investigator’s office or by 

a validated PRO instrument. Regardless of how the assessment is conducted (e.g., interview, 

interactive voice response via telephone, diary), the questioning of patients or caregivers should 

be performed in a reproducible and structured way so that any potential biases in the method of 

questioning do not affect study outcome. The ability to detect differences between study 

therapies for a time-to-resolution endpoint may be increased if assessments are done more often 

(e.g., twice daily). Therapy should be continued as described in the study protocol regardless of 

whether symptoms have resolved; however, patients with resolution of symptoms can be 

considered as having achieved clinical success if this is a study-defined outcome (i.e., patients 

with continuing symptoms should be classified as not having achieved clinical success at the 

measured time point). Investigators should attempt to allow a minimum of 48 to 72 hours on 

therapy with the study medication before classifying a patient as a clinical failure; accordingly, 

investigators may wish to include a 48-hour visit to ensure there is not substantial clinical 

worsening at this time. 

Assigning clinical failure and permitting use of rescue antibacterial therapy should be reserved 

for patients who are worsening on their assigned treatment arm; specific criteria to identify these 

patients should be included in the protocol. It is important that investigators distinguish patients 

who are worsening (i.e., where rescue therapy is appropriate) from patients who are slow to 

improve but may still remain on assigned therapy and thereby achieve clinical success at a later 

time point.21 Investigators also may wish to specify a failure endpoint if symptoms have not 

resolved by a certain day on study, even if the symptoms are not clearly clinically worsening at 

that time; this may be most objective if defined as a score remaining above a certain threshold 

for a PRO instrument. 

A repeat tympanocentesis can be performed in patients whose therapy has failed and the sample 

sent for culture and identification and susceptibility testing of isolates. In the case of clinical 

20 The investigator should remain blinded to this information unless the patient has met the criteria for clinical 

failure. 

21 In a time-to-resolution analysis, a patient should be classified as a success at the time of complete resolution of 

symptoms. Although the patients that remain are failures at each time point, failure is not carried forward unless a 

patient has reached a specific failure endpoint (e.g., the need to alter study treatment for rescue therapy). Criteria for 

failure or the need for rescue therapy should be explicitly outlined in the clinical protocol. Patients should not be 

unblinded to original study treatment if a criterion for rescue therapy is met. 

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failure, therapy should then be changed to an appropriate alternative antimicrobial treatment for 

ABOM, with other therapeutic modifications as necessary. Patients who receive rescue therapy 

should continue to have the identical protocol-specified assessments as patients who continue to 

receive their originally assigned treatment. 

Investigators should document findings from on-therapy office visits (e.g., history, physical 

examination, and laboratory test results) on the patient case report form. If the investigator 

contacts the patient by telephone or by another interactive technology, documentation of the 

specific questions asked, how they were asked, and the responses given should be captured on 

the case report form. If a validated diary is used to capture patient symptoms during this study, 

this information also should be recorded on the patient case report form. 

c. Early follow-up visit 

The early follow-up visit should occur after completion of all study medication at a time when 

the drug is expected to clear from the site of infection. For example, if a study drug with a short 

half-life is administered for 5 days, this study visit can occur on day 7 to 10 after initiation of 

therapy. At this visit the investigator should perform a focused medical history and physical 

examination, as well as appropriate laboratory measurements. The investigator also should 

inquire about adverse events. Evaluation of relapse is discussed in section III.B.9., Efficacy 

Endpoints. If clinical failure or relapse is suspected, a specimen should be obtained for bacterial 

culture by tympanocentesis. 

d. Late follow-up assessment 

The late follow-up assessment should occur 10 to 14 days after the completion of all study 

medication (e.g., if study drug is administered for 10 days, this assessment can occur on days 20 

to 25 after initiation of therapy (unless a drug with a long t1/2 has been studied)). For patients 

with no adverse events noted at the early follow-up assessment and who are clinical successes 

(i.e., previous resolution of all symptoms), this assessment can be performed by a telephone 

contact. For patients with adverse events occurring at or after the early follow-up assessment, 

investigators should perform an assessment that includes a medical history, a physical 

examination, appropriate laboratory evaluations, identification of any new adverse events, and 

follow-up on unresolved adverse events. All adverse events should be followed to resolution. 

The late follow-up assessment should include questions regarding any symptoms of ABOM to 

ascertain if late relapse or recurrence has occurred; if clinical failure or recurrence is suspected, a 

specimen should be obtained for bacterial culture by tympanocentesis. 

e. Safety evaluations 

The protocol should clearly specify the methods to be used to obtain safety data during the 

course of the study. Both adverse event information and safety laboratory data should be 

collected during the study. Age- and sex-appropriate normal laboratory values should be 

included with clinical measurements when reporting laboratory data. Longer-term assessment of 

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adverse events after discontinuation or completion of the antimicrobial also can be considered 

depending on the specific drug being studied. 

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All patients should be evaluated for safety at the time of each study visit or assessment, 

regardless of whether the test drug has been discontinued.22 All adverse events should be 

followed until resolution, even if time on study would otherwise have been completed. 

11. Statistical Considerations 

Sponsors should designate the hypotheses to be tested before initiation of the trial. These 

hypotheses should be clearly stated in the statistical analysis plan and the trial should be powered 

to detect differences between study arms if group differences exist. If sponsors choose to test 

multiple hypotheses, they should address issues related to the potential increase in obtaining false 

positive results (type I error) because of multiple comparisons, either by adjusting the type I error 

or using a stepwise, closed testing strategy for hypothesis testing. If sponsors use a closed 

testing hypothesis strategy, they should specify the order of hypothesis testing before initiation of 

the trial and the method for controlling the overall Type I error rate. These issues should be 

discussed with the FDA in advance of enrollment in the trial, and should be incorporated into the 

statistical analysis plan as appropriate. 

a. Analysis populations 

The following definitions apply to various populations for analyses in ABOM clinical trials: 

• Safety population — All patients who received at least one dose of drug during the 

study. 

• Intent-to-treat (ITT) population — All patients who are randomized. 

• Modified intent-to-treat (MITT) population (also sometimes referred to as 

microbiological intent-to-treat population) — When tympanocentesis is performed on 

patients as defined in the study protocol, this population is all patients who are 

randomized and who have a pathogen known to cause ABOM isolated at baseline. 

Patients should not be excluded from this population based upon events that occur postrandomization (e.g., loss to follow-up). 

• Per-protocol populations (also referred to as the clinically evaluable or 

microbiologically evaluable populations) — The population of patients who meet the 

definition for the primary analysis population (ITT or MITT population) and who follow 

important components of the protocol as specified (e.g., administration of a specified 

minimum amount of study medication). Traditionally, adequacy of therapy for a perprotocol analysis population has been defined as patients who have received greater than 

or equal to 80 percent (or within 80 to 120 percent) of the prescribed dose amount and/or 

22 For specific safety reporting requirements during clinical trials, see the ICH guideline for industry 

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

(http://www.fda.gov/cder/guidance/index.htm). 

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dosing regimen. Sponsors should document compliance with dosing (e.g., daily 

assessment, caregiver or patient diary, urine testing, return of unused drug, or MEMS 

caps). 

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The ITT populations in the study should be evaluated as well as the population of patients who 

follow important aspects of the protocol (i.e., the per-protocol populations) to ensure consistency 

of results. However, it is also important to note that the per-protocol population analyses are 

subgroup analyses since they exclude patients based upon events that occur after randomization. 

Patients in such subgroup analyses may differ by important factors (both measured and 

unmeasured) other than the drug received; because of this, analyses based on the ITT (or MITT) 

population should be considered the primary study analyses, with analyses based on a perprotocol population reviewed for consistency of results. Results in both populations should 

provide evidence of effectiveness. 

b. Noninferiority margins 

FDA review of previous ABOM studies has not been able to establish a reliable estimate of the 

magnitude of benefit for treatment of ABOM by antimicrobials; because of this, noninferiority 

trials are currently not considered adequate to establish evidence of effectiveness for regulatory 

approval of a new indication for ABOM. For additional information regarding noninferiority 

studies in antibacterial trials, see the draft guidance for industry Antibacterial Drug Products: 

Use of Noninferiority Studies to Support Approval.

23

c. Sample size 

The appropriate sample size for a clinical trial should be based upon the number of patients 

needed to answer the research question posed by the study. The sample size is influenced by 

several factors including the prespecified type I and type II error rates, the expected success rate, 

and the noninferiority margin (for a noninferiority trial) or the amount by which the study drug is 

expected to be superior to the control in a superiority trial. Sample size should be based upon the 

number of patients needed to draw conclusions in the ITT (no tympanocentesis performed) or 

MITT analysis population. 

d. Missing data 

There is no single optimal way to deal with missing data from clinical trials. Sponsors should 

make every attempt to limit loss of patients from the trial. Analyses that exclude patients are 

subgroup analyses, and patients who do not complete the trial may differ substantially from 

patients who remain in the trial in both measured and unmeasured ways. Therefore, sponsors 

should prespecify in the protocol the method of how missing data will be included in the analysis 

of trial results. Sponsors also should present sensitivity analyses in the final study report such as 

including all missing patients as failures, including all missing patients as successes, and 

including all missing data as successes or failures in each study group respectively. 

23 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a 

guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 

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Different rates of missing data or differences in the reasons for missing data across treatment 

arms can be a cause for concern in the interpretation of a clinical trial. If this occurs, it should be 

addressed in the study report. 

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e. Interim analyses and data and safety monitoring boards 

If interim (or futility) analyses will be performed, they should be specified in the analysis plan. 

The purpose of the interim analysis should be clearly stated in the analysis; it is important that 

the interim analysis not affect study conduct and thereby compromise study results. Study data 

also should be examined at the time of interim analysis for any emerging safety signals. We 

encourage sponsors to discuss their plans with the review division before initiation of the trial to 

ensure that the overall study significance tests properly address the effect of interim testing. 

Usually, data and safety monitoring boards (DSMBs) are used to evaluate ongoing safety and 

efficacy issues during clinical trials of diseases with endpoints that measure mortality and/or 

serious morbidity; however, since these endpoints are uncommon in ABOM studies, a DSMB 

may not be needed for an ABOM study. Sponsors can still use a DSMB if they choose to do 

so.

24 If a DSMB is used, a detailed charter with the composition of the committee members and 

the operational details should be provided for review. 

f. Other analyses of interest and secondary endpoints 

Sponsors can present secondary analyses on endpoints such as: 

• Clinical response in unilateral versus bilateral disease 

• Investigator assessment of patient response 

• Response based on patient demographics (e.g., age younger than 2 years old versus 2 

years old and older) 

Analyses of secondary and additional endpoints should be considered exploratory since a trial 

usually is not designed to address the questions raised by these analyses, either because of 

multiple comparisons and/or concerns with subgroup analyses. However, the conclusions of 

such analyses can be strengthened if hypotheses related to these endpoints are prespecified in the 

protocol, if adjustments for multiple comparisons (maintenance of type I error) are outlined in 

the protocol, and if the trial is appropriately powered to determine differences between groups 

related to these variables. Analyses of secondary and additional endpoints can be most helpful 

for identifying areas for study in future trials. 

g. Statistical analysis plan 

The sponsor should submit the statistical analysis plan for any phase 3 ABOM study to the FDA 

before initiation of the trial. 

24 For more detailed guidance, see the guidance for clinical trial sponsors Establishment and Operation of Clinical 

Trial Data Monitoring Committees (http://www.fda.gov/cder/guidance/index.htm). 

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Draft — Not for Implementation 

Clinical and microbiological outcomes from blinded studies also can be used for assessing the 

accuracy of an established or tentative microbiological breakpoint for the treatment under study. 

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12. Ethical Considerations 

Concerns have been expressed in previous discussions regarding ABOM studies that institutional 

review boards (IRBs) or investigators may consider a placebo-controlled study to be unethical. 

The general issue of the ethics of placebo-controlled trials is addressed in section II.A.3. (2.1.3) 

of the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical 

Trials. With the possible exception of a superiority study of the investigational antimicrobial 

compared to another antimicrobial, the other types of superiority studies discussed in section 

III.B.1., Study Design, of this guidance may involve the withholding of known effective 

antimicrobial treatment. For such a clinical investigation to be approvable by a local IRB under 

21 CFR part 50, subpart D, the risk to children randomized to a comparator arm that involves the 

withholding of known effective treatment (whether placebo or delayed therapy) must be no more 

than a minor increase over minimal risk (21 CFR 50.53). Nevertheless, “whether a particular 

placebo controlled trial of a new agent will be acceptable to subjects and investigators when 

there is known effective therapy is a matter of investigator, patient, and institutional review 

board (IRB)/independent ethics committee (IEC) judgment, and acceptability may differ among 

ICH regions. Acceptability could depend on the specific design of the trial and the patient 

population chosen...” (ICH E10). 

For example, given the specific concern of rare infectious complications that may be associated 

with nontreatment of ABOM (e.g., mastoiditis or meningitis), the study design for a placebocontrolled trial should include an early clinical safety assessment for treatment failure at 48 to 72 

hours.25 If necessary, effective antimicrobial rescue treatment can be initiated at that point, thus 

limiting the risk exposure of the children randomized to the placebo-controlled arm of the study. 

This approach involves the investigator having timely access to unblinded culture results if 

cultures are obtained via tympanocentesis. 

Tympanocentesis should be performed only by individuals with expertise in this procedure. 

Study sponsors should have in place mechanisms to assure that study centers performing 

tympanocentesis (and individuals at these centers) have sufficient experience and training to 

ensure that this procedure poses no more than a minor increase over minimal risk to patients (21 

CFR 50.53). Alternatively, the availability of unblinded culture results so that effective 

antimicrobial treatment can be initiated in response to a treatment failure may provide a direct 

benefit to the enrolled children and thus be acceptable under 21 CFR 50.52. In addition, targeted 

therapy based on culture results from repeat tympanocentesis performed to assess clinical 

failures may offer significant health benefit to the affected child. 

Finally, for an isolated single-dose PK study in children, sufficient evidence of drug safety from 

prior studies in adults would be needed so that the risk exposure for children is limited to no 

25 As noted earlier, review of previous placebo-controlled studies of ABOM have not shown a risk to placebotreated recipients that make future placebo-controlled trials unethical; overall risk from placebo treatment may be 

similar to that associated with antibacterial therapy since low-frequency severe events (e.g., pseudomembranous 

colitis or serious allergic reactions) have been observed with almost all antibacterial drugs. 

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more than a minor increase over minimal risk (21 CFR 50.53). Once sufficient data are available 

to select an appropriate dose and duration for the investigational drug, an efficacy trial can 

include either: 1) a population PK approach to supplement the single-dose PK data, or 2) a 

single-dose PK study using the initial (or perhaps subsequent) dose of the investigational 

antimicrobial. Based on a component analysis of risk, the PK component of the efficacy study 

would be acceptable, depending on the exact study design, either as minimal risk (21 CFR 50.51) 

or as a minor increase over minimal risk (21 CFR 50.53). If the PK data are used to adjust the 

dose of the study medication, an IRB may consider this aspect of the study as offering the 

prospect of direct benefit (21 CFR 50.52). 

C. Other Considerations 

1. Labeling Considerations 

The following is an example of a labeled indication for the treatment of ABOM: 

“[Drug] is indicated for the treatment of pediatric patients with acute bacterial otitis media 

due to S. pneumoniae, H. influenzae, or M. catarrhalis.” 

2. Antimicrobial Resistance Claims 

To date, the FDA has not granted resistance claims for ABOM caused by multidrug resistant S. 

pneumoniae. To obtain a claim for resistant pathogens in ABOM, sponsors should present data 

from within their clinical trials to demonstrate the clinical effect of in vitro resistance in this 

disease. Resistance claims should be relevant to ABOM (e.g., amoxicillin resistance is more 

clinically relevant than penicillin resistance in ABOM since amoxicillin is more commonly 

prescribed for ABOM than penicillin). Sponsors seeking resistance claims for ABOM are 

encouraged to contact the review division regarding appropriate study designs for resistant 

pathogens. 

3. Recurrent or Persistent ABOM 

Although this guidance does not address unique aspects of clinical trial design for the study of 

persistent or recurrent ABOM, the principles discussed generally are applicable to clinical trials 

for persistent or recurrent ABOM. Sponsors seeking an indication for persistent or recurrent 

ABOM are strongly encouraged to discuss their drug development plans with the FDA before the 

initiation of clinical studies. 

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