Development of Drugs for Acute Otitis Media and Acute Bacterial - - PowerPoint PPT Presentation

Development of Drugs for Acute Otitis Media and Acute Bacterial Sinusitis

Solange Rohou, MD

1 EFPIA - AOM-ABS comments

AOM and ABS: Key Issues

• Are placebo-controlled superiority studies

appropriate or feasible if the etiology is highly likely to be bacterial?

• Can an active-control superiority study deliver

when a new compound is compared to a well- dosed -lactam?

– Is it ethical to enrich for isolates resistant to the comparator agent?

• Are there other approaches to consider?

EFPIA - AOM-ABS comments 2

Are placebo-controlled superiority studies appropriate or feasible? A focus on AOM

• A serious disease, but we lack key data

– AOM can have serious consequences: Mastoiditis and suppurative intracranial events* – But, only when bacteria are the causative agents – And, mild cases often show spontaneous resolution

• The historical data are of poor quality

– EMA guidance: “Antibacterial agents have not consistently demonstrated superiority vs. placebo in well-conducted randomised studies.” – EFPIA agrees

• But, there are now new data

EFPIA - AOM-ABS comments 3

*Klein 2011 NEJM 364:168-9

AOM is a treatable disease

• Amoxicillin-clavulanate vs. placebo

– Two independent studies*, ~150/arm in each study – High quality diagnosis: Fluid, inflammation, symptoms

• Tähtinen: Amox-clav therapy reduced failure rate

– 30/161 children (18.6%) vs. 71/158 children (44.9%) – 95% CI: 16-36%, Hazard ratio 0.38 (95% CI: 0.25-0.59)

• Hoberman: Reduced clinical failure at or before

– Day 4–5 visit (4 vs. 23%; 95% CI:12-27, P<0.001) – Day 10–12 visit (16 vs. 51%; 95% CI: 25-45; P<0.001)

• Adverse events

– Diarrhea more common with antibiotics – Mastoiditis in a placebo-treated child

EFPIA - AOM-ABS comments 4 * Tähtinen et al. NEJM 364:116-26, 2011; Hoberman et al. NEJM 364:105-15, 2011

AOM: Equipoise is now gone

• The endpoints in these studies

– Were composite and need further analysis – But, all sub-components are consistent with overall effect

• With these data

– Equipoise before was limited: 207/498 eligible patients declined enrollment in the Hoberman trial – Equipoise is now gone: Accompanying editorial (Klein 2011): “Is acute otitis media a treatable disease? Yes.”

• Future studies will require an active comparator

– Lower bound of effect size certainly > 10% – High-quality data that do not require further discounting – Margin can be selected based on clinical reasoning

EFPIA - AOM-ABS comments 5

AOM: Superiority designs?

• EMA draft guidance:

– Demonstration of superiority … based on clinical cure rates is unlikely to be feasible – … it may be appropriate that the demonstration of superiority is based on alternative relevant variables (e.g., time to specific clinical response)

• We think superiority is unlikely via either path

– We will use a well-recognized, relevant, approved comparator regimen – We cannot enroll if resistance to the comparator is either likely or known – Little reason to anticipate superiority in this setting vs. a properly dosed beta-lactam

EFPIA - AOM-ABS comments 6

AOM: Other designs?

• Delayed (rescue) therapy

– Lack of equipoise makes this very difficult

• Add-on therapy

– This has the problems of a superiority design

• Consequences

– Development for this indication is unlikely until feasible active-control non-inferiority designs are agreed – As this is a key gateway indication for oral-only RTI drugs, loss of the ability to gain initial market access may reduce investment in the area – As resistance emerges, there will be no new agents

EFPIA - AOM-ABS comments 7

ABS: Parallel issues, less data

• ABS: Do we still have equipoise?

– As for AOM, existing data are poor quality* – But, suppurative complication risk is similar to AOM – Bacteria in a closed space are always worrisome

• All other issues parallel those for AOM

– Superiority design, etc.

• Consequences

– Development for this indication is unlikely at present

EFPIA - AOM-ABS comments 8 *Cochrane database systematic review. 2009, issue 3

Conclusions

• Antibiotic stewardship and vaccines may slow rate of

emergence of resistance

– But, new drugs will be needed, must anticipate need now

• Active-controlled studies appear to be required

– Equipoise is gone for AOM – Equipoise probably limited for ABS

• Non-inferiority design appears possible for AOM

– Need to work through the statistics

• Resolving these issues is important

– These are key gateway indications for oral-only RTI drugs – Emerging resistance is likely and new agents will be needed

EFPIA - AOM-ABS comments 9