IDSA / ISAP / FDA Workshop on Antimicrobial Drug

Development

Update 2004

Edward Cox, MD MPHODE IV

Center for Drug Evaluation and ResearchUS Food and Drug Administration

April 15, 2004

Update 2004 - Outline

• Scientific meetings• Guidance development• Work with Focus Technologies database• Criteria for resistant pathogens of public

health importance• Critical path initiative• Preserving the utility of existing antimicrobial

agents

Scientific Meetings - 1March 4th and 5th, 2003 - FDA Anti Infective Drug

Products Advisory Committee• Patterns of antimicrobial resistance in

Streptococcus pneumoniae and drug labeling– Science-based resistant pathogen claims– Use of data from Focus Technologies contract– High rate of cross resistance between penicillin

resistant strains and other classes of drugs – multi-drug resistant Streptococcus pneumoniae (MDRSP)

• Developing criteria for resistant pathogens of public health importance

• Relating clinical data from one disease to another

Drug Drug YY

Evaluating Cross-Resistance

Drug XDrug X

S, SS, S

S, IS, I

S, RS, R

I, SI, S

I, II, I

I, RI, R

R, SR, S

R, IR, I

R. RR. R

MIC MIC

Correlations in MIC Distributions between Penicillin and Cefuroxime Tested against S. pneumoniae (2000 – 2002)

Total n = 9,779Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R

5

Total n = 5387Total n = 5387

Correlations in MIC Distributions between Levofloxacin and Penicillin Tested against S. pneumoniae (2000-2002)

Total n = 9,779Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R

6

Scientific Meetings - 2

March 4th and 5th, 2003 - FDA Anti Infective Drug Products Advisory Committee

• Patterns of antimicrobial resistance in Streptococcus pneumoniae and drug labeling

• Developing criteria for resistant pathogens of public health importance– Criteria refined for resistant pathogens of public health

importance in a particular indication– The pros and cons of a list were discussed

• Relating clinical data from one disease to another

Criteria for Resistant Pathogen/ Indications of Public Health Importance

1. Limited available therapies due to multi-drug resistance of the organism

2. Organism causes serious and severe disease3. Drug to which organism is resistant is commonly

used in disease under study4. Organism of sufficient prevalence in population

with disease under study5. Drug used to control spread of disease in

population 6. Clinical correlation of in vitro resistance with

poor clinical outcomes

How to Use the Criteria

• Pathogen would not need to fulfill all of criteria to be a resistant pathogen of public health importance in a particular indication

• Drug sponsors would need clinical data on treatment of resistant pathogens in the indication of interest– differences in patient characteristics of those with

resistant organisms vs. susceptible organisms• Priority review based upon results of clinical trials• Note that a drug may still be approved but not garner

resistant pathogen claim until sufficient clinical data on the resistant pathogen of interest have been accrued

Previously Granted Resistance Claims• Methicillin resistant S. aureus (MRSA)

– vancomycin in serious infections

– linezolid in HAP and cSSSI

• Vancomycin resistant E. faecium (VRE)– linezolid

– dalfopristin-quinupristin in bacteremia

• Penicillinase-producing staphylococci– nafcillin in serious and severe infections

• Beta-lactamase producing H. influenzae and Moraxella catarrhalis– number of infections with cephalosporins

• Penicillin resistant S. pneumoniae (PRSP)– levofloxacin and moxifloxacin in CAP

• Multi-drug resistant S. pneumoniae (MDRSP)– gemifloxacin, telithromycin in CAP

Scientific Meetings - 3March 4th and 5th, 2003 - FDA Anti Infective Drug

Products Advisory Committee• Patterns of antimicrobial resistance in

Streptococcus pneumoniae and drug labeling• Developing criteria for resistant pathogens of

public health importance• Relating clinical data from one disease to another

– Discussion of the role of using data from one indication to support another indication

– Similar microbial etiologies– Similar tissue distribution– Consider severity disease of one illness to another– Consideration of host factors

Scientific Meetings - 4• September 2003 - BAMSG/FDA workshop on

fungal drug development– Clinical trial design for empiric antifungal therapy in

febrile neutropenic patients– Clinical trial design for investigating combination

antifungal therapy

• October 2003 FDA AIDP Advisory Committee– Acute Bacterial Sinusitis– Diabetic Foot Infections

Scientific Meetings - 5• September 2003 - BAMSG/FDA workshop on fungal

drug development• October 2003 FDA AIDP Advisory Committee

– Clinical trial design for Diabetic Foot Infections• Defining the condition• Microbiologic diagnosis in patients with DFI• Measuring outcomes

– Clinical trial design in Acute Bacterial Sinusitis• Enriching the population for patients with bacterial

sinusitis • Role of microbiologic diagnosis• Superiority trial designs – active + other symptomatic

therapies vs. symptomatic therapies or dose-response

Guidance Development

Updating and Developing New Guidance Documents

•Acute Bacterial Sinusitis•Acute Bacterial Exacerbation of Chronic Bronchitis•Acute Otitis Media•Acute Bacterial Meningitis•Drug Development for Resistant Pathogens

Critical Path Initiative• Critical Path white paper issued March 2004• Recognizes the advances in the basic biomedical

sciences and the high costs of bringing a new medicine to market

• Calls for advances in the applied sciences in medical product development – A better product development toolkit– Tools for assessing safety– Tools for demonstrating medical utility– Tools for characterization and manufacturing

• Addressing the critical path initiative will require the joint efforts of academia, industry, and FDA

http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

Preserving the Utility of Existing Antimicrobial Drugs - 1

Final rule - Labeling Requirements for Systemic Antibacterial Drug Products Intended for Human Use– Issued February 6, 2003– Effective February 6, 2004– Includes statements in labeling about using systemic antibacterial drugs in a way that will reduce the rate of development of antimicrobial resistance and to encourage physicians to counsel their patients about the use of antibacterial drugs– Estimated to impact 669 systemic antibacterial drug product labels

http://www.fda.gov/OHRMS/DOCKETS/98fr/03-2969.pdf

Preserving the Utility of Existing Antimicrobial Drugs - 2

FDA is a co-sponsor of the GetSmart Program with CDC•Education/Outreach Program•Includes television, radio and print public service announcements •Goal is to better inform Americans about when antibiotic treatment is warranted •Campaign launched fall 2003 at ICAAC

http://www.fda.gov/cder/consumerinfo/antibiot-resist-brochure.htm

http://www.cdc.gov/drugresistance/community/default.htm#campaign

Summary - Update 2004

• Scientific meetings on labeling issues and clinical trial design for a number of indications– Drug labeling for resistant S. pneumoniae– Criteria for resistant pathogens of public health importance– Relating clinical data from one disease to another– Trial design for studies of empiric antifungal therapy for

febrile neutropenic patients and combination antifungal therapy

– Trial design for DFI and ABS• Guidance development• Critical path initiative• Preserving the utility of existing antimicrobial agents