1992 Points-to-Consider

1992 Points-to-Consider

Study Considerations: Acute Bacterial Otitis MediaRecurrent / Treatment FailureRosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products

FDA AIDAC 7/11/02

1992 Points-to-Consider

Study Considerations: Revisiting the Guidance

Clinical Trials DESIGN

Pre-Defined, Targeted

POPULATIONSIndication AOM routine Indication AOM :Recurrent / Treatment Failure

FDA AIDAC 7/11/02

1992 Points-to-Consider

Targeted Populations: AOM

Current Draft Guidance Proposal for change Discussion of definitions Types of Trials Items for Discussion

FDA AIDAC 7/11/02

1992 Points-to-Consider

1998 Draft Guidance / 1992 Points-to-Consider One indication: AOM Exclusion Criteria includes– systemic anti-infective drug product in the previous 7 days prior to enrollment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 exclusionsFDA AIDAC 7/11/02 4

1992 Points-to-Consider

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

1992 Points-to-Consider

Proposal for change

Challenge of antibiotic resistanceUnderlying factor: PRSPRecentl y Treated

(diagram not to scale)

Severe

All AOM

PRSP

FDA AIDAC 7/11/02

1992 Points-to-Consider

Proposal for change

Answer to Antibiotic ResistanceDrug Development(already ongoing)"High-dose" FormulationsFDA AIDAC 7/11/02

Fluoroquinolones in Pediatrics7

1992 Points-to-Consider

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”FDA AIDAC 7/11/02

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.

1992 Points-to-Consider

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 seve

re indications Treat “the sicker sub-populations” of generally well children with gram-positive resistant organismsFDA AIDAC 7/11/02 9

1992 Points-to-Consider

Proposal for changeDrug 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 subpopulation of “Recurrent/ Non-responsive OM”Arguedas A et al. Gatifloxacin Treatment of Recurrent/Non-Responsive Acute Otitis Media. 41st ICAAC 2001: Abstract G-1534FDA AIDAC 7/11/02 10

1992 Points-to-Consider

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 PopulationsFDA AIDAC 7/11/02 11

1992 Points-to-Consider

Proposal for Change: An AnswerAdditional Indication: Recurrent / Treatment Failure AOMAll comers AOM to Targeted Populations (Clinically distinct) Child with occasional episode of AOM AOM Routine e.g. penicillins, macrolides, cephalosporins,othersFDA AIDAC 7/11/02

Child with multiple frequent episodes repeated therapy AOM Recurrent/ Treatment Failure e.g. "high-dose" drugs, fluoroquinolones, others12

1992 Points-to-Consider

Proposal for Change: An AnswerTwo indications would represent two distinct populations with RESISTANCE factor overlap (diagram not to scale)

PRSP R/TF AOM

AOM

FDA AIDAC 7/11/02

1992 Points-to-Consider

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

1992 Points-to-Consider

Definitions: RecurrentIs 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 c …… 此处隐藏：4048字，全部文档内容请下载后查看。喜欢就下载吧 ……