# Presentation: 869405

## Study Considerations: Acute Bacterial Otitis Media

- Recurrent / Treatment Failure
- Rosemary Johann-Liang, M.D.
- Division of Special Pathogen and Immunological Drug Products

- FDA AIDAC 7/11/02

**Notes:**
Good Morning

I am delighted to speak before the committee one more time.  My topic for today is very different from yesterday however.

This morning’s talk before we break for lunch will be on Recurrent and/or Treatment Failure Acute Bacterial Otitis Media.

## Study Considerations: Revisiting the Guidance

- FDA AIDAC 7/11/02

**Notes:**
As we consider revisiting the Otitis Media guidance, we have heard quite a lot about clinical trial designs this morning.

I would like to draw your attention now onto the types of children who will populate the clinical trials.

Specifically we will be discussing the proposal for an additional indication that would study the population of children with recurrent and / or treatment failure AOM.

## Targeted Populations: AOM

- Current Draft Guidance
- Proposal for change
- Discussion of definitions
- Types of Trials
- Items for Discussion

- FDA AIDAC 7/11/02

**Notes:**
I will be following this outline.

The relevant sections in the current guidance will be first shown, then the rationale and proposal for change will be presented.

This will be followed by the discussion of definitions, and the types of trials for the indications.

I will end with some issues we hope will be included in the committee’s discussions this afternoon.

## 1998 Draft Guidance / 1992 Points-to-Consider

- One indication:  AOM
- Exclusion Criteria includes
- systemic anti-infective drug product in the previous 7 days prior to enrollment (clinical-only study)
- systemic anti-infective drug product in the previous 3 days prior to enrollment (clinical/microbiological study)
- patient receiving antimicrobial prophylaxis for recurrent otitis media
- penicillins/aminopenicillins, cephalosporins, macrolides approved with all-comers with above exclusions

- FDA AIDAC 7/11/02

**Notes:**
The 1998 Draft Guidance taken after the 1992 Points-to-Consider lays out Study Considerations for ONE all-comers indication of AOM.

There is no differentiation of different populations.

However, there are exclusion criteria and they include the following.
_
_
_
Various B-lactams and macrolides have been approved thus far under one indication by studying all-comers population with these exclusion.

## Proposal for change Recent AIDAC Advice

- Dr. Leggett (11/2001) “...there was a thing about not being able to use antibiotics within the last 7 days of the last month.  I think that would be another way to actually enrich the resistant population because isn’t that who we have the trouble with, the more severe illness and the more resistant pathogens?”
- Dr. Wald (11/2001)  “....I think that groups of children that we should be studying are children with severe disease..”

- FDA AIDAC 7/11/02

**Notes:**
You all have been telling us that changes need to take place to the current guidance.

Of the various recommendations for change by the committee, these are a few of the advise we have heard regarding populations to study.

Dr. Legget’s statement from the November 2001 committee meeting,
----

Dr. Wald’s statement ,
------

## Proposal for change Challenge of antibiotic resistance

- Underlying factor: PRSP  *(diagram not to scale)*

-                   **All AOM**

**       ****Severe**

**Recently Treated**

**PRSP**

- FDA AIDAC 7/11/02

**Notes:**
So in thinking about this in a picture format,
(I have to interject a disclaimer at this point:  All My PP diagrams in this talk are conceptual, Not proportional, and not drawn to scale)

We have the all-comers population for AOM in the large green oval.  You are telling us that the recently treated population should NOT be excluded, in-fact, they should be perhaps preferentially studied.  You are also telling us that the population with severe disease should be especially studied.

What is the driving force behind these proposals for change?
I think you will all agree with me that  the underlying factor is RESISTANT PATHOGENS, specifically at this point, PRSP.  PRSP is a critical factor OM disease in general, but a problem of greater magnitude in these sub-populations.

## Proposal for change 

- FDA AIDAC 7/11/02

**Notes:**
Rising to meet the challenge of resistant pathogens in otitis media disease, drug development programs are already on-going.

I would like to spend the next several slides briefly reviewing with you the lessons we have learned and are continuing to learn from these two examples of drug development programs.

High-dose formulation of Augmentin
and
The Development of fluoroquinolones in pediatrics

## Proposal for change Drug Development, “High-Dose”Augmentin

- Developed w/ PRSP in mind
- Some enrichment stategies used to maximize patients with bacterial AOM esp. PRSP
- Label: Augmentin ES-600®
- “..is indicated for the treatment of pediatric patients with **recurrent or persistent acute otitis media** .........**characterized by the following risk factors: antibiotic exposure for AOM within the preceding 3 months, AND either of the following: age **_**<**_** 2 years, daycare attendance”**

- This “recurrent or persistent” sub-population not pre-defined and inserted post development to differentiate 14:1 from 7:1 formulation
_**Lesson Learned**_**: this population needs to be pre-defined.**

- FDA AIDAC 7/11/02

**Notes:**
High-dose Augmentin, the 14:1 formulation was presented to this committee in January of last year.  As you are aware,  this high dose formulation was developed with PRSP in mind and enrichment strategies were used in its clinical trials to maximize patients with bacterial disease, especially PRSP.  
However, the restricted “sub-population” that this formulation is currently labeled for was Not prospectively defined and therefore not the defined population studied during development. 
How does this label currently read?
This “recurrent and persistent” indication was inserted post development following this committee’s advice that this 14:1 formulation should be differentiated from the 7:1 formulation and should not be used for routine AOM.
Th e lesson learned here was that the population that the indication will be labeled for needs to be pre-defined.

## Proposal for changeDrug Development, Fluoroquinolones for Peds

- 1989:  Specific Underlying Dz, older child                 Cystic Fibrosis, Cancer, >6 years
- 1993:  Expand diseases and age                                        CF, Cancer, Sickle Cell, CompUTI, COMsupprativa,etc.    Unanimous: not for investigation in routine indications
- 1997:  Continue development for severe indications     Treat “the sicker sub-populations” of generally well children with gram-positive resistant organisms

- FDA AIDAC 7/11/02

**Notes:**
Next,
I would like to walk you through a timeline of a series of recommendations by this anti-infective drugs advisory committee on the development of fluoroquinolones in pediatrics.

The story starts in 1989, where the committee recommended that mainly due to safety concerns, fluoroquinolone development in pediatrics should be restricted to older children with severe underlying diseases of cyctic fibrosis and cancer needing therapy for gram negative resistant organisms

The committee met again in 1993 regarding this matter and recommended expanding the types of diseases and age but again unanimously voted that this class of drugs was not for investigation in routine indications.

By 1997, there is a change.  There was again the recommendation to continue the pediatric study of these drugs for severe indications.  However, the committee began to discuss the development of these drugs to treat “the sicker sub-populations” of generally well children due to the increasing emergence of gram positive resistant pathogens.

## Proposal for change Drug Development, Fluoroquinolones for Peds

- Dr. McCracken’s Statement  (1997 AIDAC Meeting) *“...the fluoroquinolones could then be evaluated in hospitalized pediatric patients with community or hospital-acquired pneumonia and possible middle ear or sinus infections caused by resistant pathogens, PRSP, i.e. ****in recurrent or persistent OM...”***
- 2002 and beyond:  At least one fluoroquinolone undergoing development for AOM for the specific sub-population of “Recurrent/ Non-responsive OM”
*Arguedas A et al.  Gatifloxacin Treatment of Recurrent/Non-Responsive Acute Otitis Media.  41st ICAAC ****2001****: Abstract G-1534*

- FDA AIDAC 7/11/02

**Notes:**
This is a statement by Dr. McCracken from that committee meeting. ---------------

Currently, development of FQ for use in pediatrics, not just for severe indications, but also for “sicker sub-populations” in routine indications such as AOM is on-going.
One example is the Gatifloxacin development program, parts of which was presented at the 41th ICAAC.  That “sicker sub-population” within the AOM being studied with gatifloxacin is Recurrent/ Non-responsive AOM.

Clearly however, the committee has pointed out throughout the timeline that I have just presented to you that FQ are not for study in routine cases in routine indications due to safety issues (especially arthrotoxicity), the fact that many other alternatives drugs are available, and the worry of more resistance if this class of drugs are used widely in pediatrics.

## Proposal for change:  SummaryWhat we have heard and learned

- Enrich the population for Acute *Bacterial *Otitis Media, especially PRSP AOM
- Study “recurrent and/or persistent” disease
- Do not exclude recent antibiotic use
- Drug DP for PRSP: Not for routine use
- safety issues
- Other drugs available for routine OM
- Save the new drug, curb more drug resistance
- The Need for Pre-defined Populations

- FDA AIDAC 7/11/02

**Notes:**
So to summarize what we have heard from you and the lessons learned regarding populations for study in AOM,
You have told us to
Enrich the populations for study for better yield of patients with bacterial disease, especially those with PRSP; and that this may be accomplished in part by studying the sub-population of children with “recurrent and/ or persistent” disease And to Not exclude children recently exposed to antibiotics.
Furthermore, you have told us that the drug development programs geared toward treatment of resistant pathogens, especially PRSP should not be pulled together for study in routine use.  This is due to safety issues at the individual level and judicious use of drugs to curb more resistance at the public health level.

All in all, what we have learned is that this “not-for-routine” subpopulation of AOM need to be precisely defined as we move forward in developing drugs for resistant pathogens 

## Proposal for Change: An Answer

- FDA AIDAC 7/11/02

**Notes:**
So bringing together all that you have told us through multiple advisory meetings, we have a possible solution to propose.                                              The proposal is for an additional indication termed “recurrent  and / or treatment failure AOM”.  This is a population driven concept.  I think it is fair to say that we would all agree that the child coming into the office with an occasional episode of AOM is a distinct population in comparison to the child that seems to live in the office with multiple and frequent episodes of AOM requiring repeated and cycling of antibiotic therapy.  
The proposal for change then is that we go from the one all-comers indication that is currently in the guidance to two indications relevant to the targeted populations.  One for routine AOM and one for recurrent/treatment failure AOM.  This would in turn facilitate drug development programs by pre-defining the appropriate populations for clinical trials.   For  example, a “regular-dose” b-lactam being studied here for routine AOM going on to be labeled for this indication at the time of approval; while high dose formulations or FQ being studied here will eventually be labeled for the indication of  recurrent / TF at the time of approval.    It is also possible for a drug without particular safety or resistance concerns and having necessary efficacy parameters maybe able to pursue both indications concurrently with data from both programs complementing and supporting the overall development program.

## Proposal for Change: An Answer

-     Two indications would represent two distinct populations with RESISTANCE factor overlap *(diagram not to scale)*

**AOM**

**R/TF AOM**

**PRSP**

- FDA AIDAC 7/11/02

**Notes:**
A simple illustration of this concept may be as follows.
(Again I want to remind you of the Not-to-scale nature of my PP  illustrations)

In choosing the clinically distinct populations as the bases for separating out the indications, we will be able to clinically distinguish the population that will be studied under routine AOM here on the large pretty pink color on the right from the population with recurrent and/ or treatment failure disease here on the smaller green oval to the left. 
The resistance factor will overlap both populations but will have a greater overlap for the “not-for-routine” indication

## Precise Definitions

- Define the elements of the additional indication
- Reach a consensus about the definitions
- Clarify terms to avoid confusion

- FDA AIDAC 7/11/02

**Notes:**
With that  change in general concept in mind, let’s spend a few minutes on defining the elements of the additional indication 
so that as we revise the guidance, we can reflect the consensus that was reached on this concept and be precise with our definition.
Defining exactly what we mean by the terminology used would provide a clear channel for communication by all interested parties and avoid confusion.

## Definitions: RecurrentIs this what we heard?

_**>**_** 3 episodes of AOM over the last 6 months  OR **
_**>**_** 4 episodes of AOM over the past year**
- generally accepted and used definition
- children with underlying factors
- young children with anatomical immaturity
- clinically: thought of as a distinct population
- microbiologically: subset with  PRSP?

- FDA AIDAC 7/11/02

**Notes:**
First the definition for “recurrent”
Are we correct in hearing from you that “recurrent” OM is part of the “sicker subpopulation”?
The generally accepted and used definition for recurrent AOM is as shown here.
This population of children includes children with various underlying and predisposing factors to AOM including young children with anatomical immaturity.  Clinically, this definition would encompass the children thought of as a distinct entity.  Microbiologically however, when the literature is carefully scrutinized, this population defined precisely as above may not have a significantly higher rates of PRSP when compared to age-controlled children with routine AOM.

## Definitions: Treatment FailureIs this what we heard?

**During therapy:  No improvement observed in signs and symptoms of AOM after at least 48 hours of antibiotic management                                              OR **
**Post therapy:  Presentation with signs and symptoms of acute otitis media within 7 days of completing a course of antibiotics for acute otitis media**
- Microbiologically: subset with  PRSP
- Inclusive of accepted definition of Persistent AOM (3rd day) AND exclusive of the time point (beyond 1 week after EOT, hard to differentiate re-infection vs. new-infection)

- FDA AIDAC 7/11/02

**Notes:**
Next the definition of Treatment Failure.

Are we correct in hearing from you that children recently treated with antibiotics or early treatment failure should not be excluded from clinical trials for AOM but rather be studied vigorously since this is the population that microbiologically appears to have higher rates of resistance.

One definition that we can use may be as proposed here.

This definition is inclusive of the accepted definition of persistent AOM (signs and symtoms continuing on the 3rd day after start of therapy) while being exclusive of the time point beyond 1 week after end of treatment where it becomes very hard to differentiate re-infection from new-infection. 

## Definitions: need for precision

**Descriptive names for “sub-populations”**
**	****  ****not clearly defined**
- “difficult-to-treat OM”
- “otitis-prone children”
- “hard-to-treat OM”
- children “at-risk”

**Inclusion Criteria included** in recent protocols to study “stepped-up” therapy for these  “sub-populations”
- _<_ 24 months
- daycare attendance
- 3 or more siblings

- FDA AIDAC 7/11/02

**Notes:**
Now that we have proposed some definitions for what the elements of the new indication might be, I want to clarify what the new indication is not synonymous with.

Some terms that we have been seeing in recent protocols that are used as names for “sub-populations” of AOM are 
____, _____, _____, ______
These terms are not clearly defined and may lead to confusion.

For example, protocols wanting to study “hard-to-treat” or “difficult-to-treat” AOM with “high-dose” formulations or FQ would list under the inclusion criteria: < or + to 2 years, daycare attendance, 3 or more siblings etc.    This would mean that even with a first time otitis, just by being a 6 month old baby,  that baby will be exposed to a drug like a FQ for example, which I don’t think is what anybody wants at the moment.

## Definitions: Enrichment overall

- Use these listings as enrichment strategies for bacterial OM for both indications

- AOM

- PRSP

- R/ TF AOM

- FDA AIDAC 7/11/02

**Notes:**
These listings are then not the elements of the proposed new indication bur rather enrichment strategies for increased yield of patients with bacterial OM, especially PRSP OM  for both indications.

Again the two distinct populations are shown here in the pink and green ovals with the resistance factor overlapping both populations.  The enrichment groups are overlaying  both indications and the resistance factor shown here in purple.  

Taking into account all the definitions that has just been discussed, I would like to walk through a series of possiblescenerios in the next slide.

## Definitions: Enrichment overall

- Use these listings as enrichment strategies for bacterial OM for both indications

- AOM

- PRSP

- R/ TF AOM

**Younger than 2 yrs**

**Daycare attendance**

- FDA AIDAC 7/11/02

**Notes:**
These listings are then not the elements of the proposed new indication bur rather enrichment strategies for increased yield of patients with bacterial OM, especially PRSP OM  for both indications.

Again the two distinct populations are shown here in the pink and green ovals with the resistance factor overlapping both populations.  The enrichment groups are overlaying  both indications and the resistance factor shown here in purple.  

Taking into account all the definitions that has just been discussed, I would like to walk through a series of possiblescenerios in the next slide.

- FDA AIDAC 7/11/02

**Notes:**
This is an illustration of a hypothetical AOM drug development schema.

Having used enrichment strategies to increase the chance of having a patient with bacterial OM,  a 6 month old infant in daycare fulltime who also by the way meets the cuteness criteria is identified.

If this baby is in the office with his first episode of AOM, or has now grown to be still-cute 9 month old and is having a second episode of AOM, for both of these scenerios, the infant will be studied under the indication of routine AOM enrolling in drug trials seeking first line therapy.

If this baby has treatment failure OM (meeting the pre-defined definitions) or is now 12 months and is always in your office because this is the fourth episode of AOM, this infant will be studied under the indication of R/TF AOM enrolling in drug trials seeking “stepped-up” therapy.

## Targeted Populations <=>Relevant Indications <=>Drug Development Programs<=>

- Types of Trials

- FDA AIDAC 7/11/02

**Notes:**
So I have presented to you what you have told us about targeted populations and have laid out for you our responsive proposal of relevant indication corresponding to appropriate drug development programs that can move forward with prospectively defined populations that needs consensus on precise definitions.  In the next slide, I would like to highlight some particulars about the types of trials that would be part of the drug development program for the additional indication.

## Types of Trials: Recurrent/Treatment Failure AOM

- FDA AIDAC 7/11/02

**Notes:**
We would be looking for well-controlled single or double tympanocentesis trials with non-inferiority or superiority design with pathogen specific diagnosis by tympanocentesis at entry.  For single tap studies, the primary outcome assessment will be clinical at end-of-therapy and for double tap studies, the primary outcome assessment will be on-treatment micro and end-of-therapy clinical.

These two types of trials may be supplemented by empiric or actual use therapy trials which to increase the safety information for the product.  This type of trial is particularly encouraged for NMEs, drugs with specific safety issues, or drugs with limited safety data and should be inclusive of children with various underlying conditions.
Non-comparative double-tap trials may be another supplemental study in cases where efficacy data on a specific organism for example needs more support.
Relevant studies from other indications may also provide supplemental information.

## Acute Bacterial Otitis Media Study Considerations: 

- Summary Overviewand Items for Discussion

- FDA AIDAC 7/11/02

**Notes:**
Finally, I would like broaden our considerations regarding types of trials to ABOM overall.

- FDA AIDAC 7/11/02

**Notes:**
As we consider revisiting the Guidance on AOM, 
this is a summary overview of our overall proposal.
We have heard from you that AOM should be studied in microbiologically-driven and comparative manner with populations enriched to yield the patients having bacterial disease. Under the indication of routine AOM, drug development programs for “regular-dose” B-lactams, macrolides, etc. can proceed.  The types of trials for study in this indication include Single Typanocentesis trials, double tympanocentesis trials, placebo-controlled trials and other supplemental studies.  Under the indication of R/ TF AOM, drug development progrmas for “high-dose”formulations, fluoroquinolones, etc. can proceed.  The types of trials for study in this indication include single Tympanocentesis trials, Double Tympanocentesis trials, Empiric Therpay Safety Trails and other supplemental studies. 

We have arrived at this overall conceptual proposal in response to your recent recommendations for change by incorporating what you have told us and the lessons that we have learned.  We would like to turn this proposal back to you now for discussion and further advise.  

## Items for Discussion: Proposed Additional Indication of R/TF AOM

- Definition for “Recurrent” AOM
- Definition for “Treatment Failure” AOM
- Do these two groups fit the population to pre-define for “not-for-routine” drug development programs w/ PRSP emphasis?
- Is it reasonable to have these two groups be placed together in the new indication?
- Are the types of trials for this indication appropriate? Any other types of studies?

- FDA AIDAC 7/11/02

**Notes:**
Some items for discussion are listed here for you.
We would like to know if you agree with the definitions for “recurrent” AOM
the definition for “treatment failure”AOM
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I thank you so much for your attention and look forward to your discussions this afternoon.