1 Nonprescription Drugs AC Meeting March 23, 2005 Testing of Healthcare Antiseptic Drug Products...

1Nonprescription Drugs AC MeetingNonprescription Drugs AC MeetingMarch 23, 2005March 23, 2005

Testing of Healthcare Testing of Healthcare Antiseptic Drug ProductsAntiseptic Drug Products

Michelle M. Jackson, Ph.D.Microbiologist

Division of Over-The-Counter Drug Products


ObjectivesObjectives

• Discuss proposed monograph requirements - simulation testing procedures - surrogate endpoints

• Discuss Industry Coalition’s (SDA / CTFA*) position

* The Soap and Detergent Association and The Cosmetic, Toiletry, and Fragrance Association Industry Coalition (“Industry Coalition”)


What Makes a Good Clinical What Makes a Good Clinical Simulation Test MethodSimulation Test Method

• Simulates as close as possible actual use conditions

• Design characteristics:– test product: final formulation

– vehicle control arm (negative control): determine reduction due to mechanical action of handwashing only

– active control arm (positive / internal control): used as an internal reference to validate the study

• Measures desired product performance

• Reproducible

Indications Current TFM

Healthcare Personnel Handwash

• Test product• Active control

Surgical Hand Scrub • Test product• Active control• Vehicle

Patient Preoperative Skin Preparation

• Test product• Active Control


Healthcare Personnel HandwashHealthcare Personnel HandwashLabel Indication:• Handwash to help reduce

bacteria that potentially can cause disease.

Testing Process:• Predicts the reduction of

organisms that may be achieved by washing hands after handling contaminated objects.

• Measures reduction of transient organisms after single or multiple uses.

Bacterial Reduction (log10)

2-log CFU / 1st Wash

3-log CFU / 10th Wash

TFM Endpoints:


Healthcare Personnel HandwashHealthcare Personnel HandwashMethodologyMethodology

• Inclusion Criteria– 18-69 years of age– Good health– No clinical evidence of skin disorders

• Exclusion Criteria– Diagnosed with a medical condition– Sensitivity to antimicrobial products– Pregnant or nursing

• Washout period (7 days)– Non-antimicrobial kits


Healthcare Personnel HandwashHealthcare Personnel HandwashMethodologyMethodology

• Outline of test procedures:– Practice: Wash with bland soap– Baseline: Contaminate hands & sample– Wash 1: Contaminate hands; perform wash &

sample– Wash 2: Contaminate hands & perform wash

– Wash 9: Contaminate hands & perform wash– Wash 10*: Contaminate hands; perform wash & sample– Decontaminate: Sanitize hands with 70% alcohol

* Cumulative Effect: progressive decrease in the numbers of microorganisms recovered following repeated application of a test product.


Healthcare Personnel HandwashHealthcare Personnel Handwash

Courtesy of Hill Top Research Inc.

• Inoculation of S. marcescens

• Rub all over surface of the hands (45 seconds)

• Allow to air dry




• Add antimicrobial test formulation

• Lather and wash all over surface of the hands

• Rinse hands (30 secs)




• Hands are placed in plastic bags

• Add sampling fluid* • Bags are tightly secured above the wrist

• Hands are massaged for 1 minute

*Neutralizers: chemical reagent used to inactivate microbiocidal properties of an antimicrobial agent.




• Aliquot of sampling fluid is withdrawn & diluted in dilution fluid*

• Surface plating* within 30 minutes of sampling (Microbial Enumeration)

* Neutralizers are incorporated




• Colony forming units (CFUs) of S. marcescens from two dilution plates

• S. marcescens produces a red pigment



HandwashIndustry Coalition’s

Proposal Reduction (log10)

FDA TFM Proposal

Reduction (log10)

Wash 1 1.5 2

Wash 10* No criteria 3

* Cumulative Effect: progressive decrease in the numbers of micro-

organisms recovered following repeated application of a test product.


Surgical Hand Scrub

Label Indication:• Significantly reduces the

number of microorganisms on the skin prior to surgery.

• Reduces incidence of post- surgical infections.

Testing Process:• Measures immediate and

persistent reduction after single or repetitive treatments.


1-log CFU / Day 1 – Wash 1



TFM Endpoints:


Surgical Hand ScrubMethodology

• Inclusion / Exclusion• Washout period for 14 days

Baseline week

1 2 3 4 5 6 7

Testing week

1 2 3 4 5

1 scrub 3 scrubs 3 scrubs 3 scrubs 1 scrub

3 and 5 5 and 7

3 and 7

1

SampleDay 1

SampleDay 2

SampleDay 5

Days

Baseline count > 1.5 x 105

12 hrs – 4 daysbefore initial

testing


Surgical Hand Scrub


• Dispense amount in accordance with the manufacturer’s labeling


Surgical Hand Scrub


• Perform scrub in accordance with the manufacturer’s directions

• Scrub the hands including the nails, fingers, and interdigital spaces


Surgical Hand ScrubSurgical Hand Scrub


• Donning sampling gloves

• Post Treatment Sampling: - One third of the hands in a treatment group are sampled immediately

- Remaining hands wear gloves 3 hrs and/or 6 hrs prior to sampling


Surgical Hand ScrubSurgical Hand Scrub


• Add sampling fluid*

• Fasten glove securely above the wrist

• Massage for 1 minute



Surgical Hand Scrub


• Aliquot of sampling fluid is withdrawn & transferred to dilution tubes* • Surface plating* within 30 minutes of sampling (Microbial Enumeration)



Surgical Hand Scrub

Surgical ScrubIndustry Coalition’s


FDA TFM Proposal

Reduction (log10)

Wash 1 1(No persistence criteria)

1(persistence*)

Wash 2 No Criteria 2

Wash 11 No Criteria 3

* 6-Hour Persistence: prolonged or extended antimicrobial activity that prevents or inhibits the proliferation or survival of microorganisms after product application.



Label Indication:• Helps reduce bacteria that

potentially cause skin infection.

• For the preparation of the skin prior to surgery.

• For the preparation of the skin prior to injection.

Testing Process:• Measures immediate and

persistent reduction after single treatment.


1-log CFU / pre-injection

2-log CFU / abdomen (dry site)

3-log CFU / groin (moist site)

TFM Endpoints:


Patient Preoperative Skin PreparationMethodology

• Inclusion / Exclusion • Washout period for 14 days

• No bathing 24 hrs prior to baselines

• Baseline screening counts– Pre-injections > 1.0 x 103

– Large enough to show> 2 log for Abdomen (dry site)

> 3 log for Groin (moist site)


Patient Preoperative Skin Preparation Preoperative Skin Preparation(Abdominal Site)(Abdominal Site)


• 5”x 5” Area

baseline 30 min

10 min 6 hrs


Patient Patient Preoperative Skin Preparation Skin Preparation (Abdominal Site) (Abdominal Site)


• Baseline sampling

• Cylinder sampling technique

• Add sampling fluid containing neutralizer


Patient Preoperative Skin Preparation (Abdominal Site)


• Application of prep formulation

• Cover area with a sterile gauze pad


Patient Preoperative Skin Preparation (Abdominal Site)

• Treatment samples are taken from the site area using the cylinder sampling technique




Surgical ScrubIndustry Coalition’s


FDA TFM Proposal

Reduction (log10)

Pre-injection 1 1

Abdomen1

(No persistence criteria)2

(persistence*)

Groin2

(No persistence criteria)3

(persistence*)

* Persistence: prolonged or extended antimicrobial activity that prevents or inhibits the proliferation or survival of microorganisms after product application.


Industry Coalition’s Comments

TFM Criteria● “overly stringent”

● inappropriate in antiseptic products with proven clinical benefit because they cannot meet

the current criteria. - Monograph: alcohol & iodine - NDA: chlorhexidine gluconate

● all antiseptic products only need to be effective after a single use.


Performance Criteria

Industry’s ProposalBacterial Reduction

(log10)

FDA TFM Proposal Bacterial Reduction

(log10)


Wash 1 1.5 2

Wash 10 ---- 3

Surgical Hand Scrub*

Wash 1 1 1

Wash 2 --- 2

Wash 11 --- 3

Patient Preoperative Skin Preparation*

Preinjection 1 1

Abdomen 1 2

Groin 2 3

* Industry has recommended removal of the 6-hour persistence criteria for these products.

1.5

----

2

1

1

1

---

---


Other Considerations for Effectiveness Criteria

• Surrogate endpoints– lack of clinical validation– level of residual bacteria on the skin not measured– virulence of the residual bacteria not considered

• Criteria based on earlier NDA data

• Consistently applied to monograph products • Industry deviates from TFM

– variability in testing procedure– not compared to vehicle or active control– statistical analysis


Industry Coalition’s ProposalPoints to Consider

• Majority designed as product comparisons

• Few studies used TFM methodology

• Significant variation in test conduct

• Neutralizer validation data not generally provided

• Generally sample sizes were small

• Alcohol alone (rubs/leave-on) did not meet the 10th wash 3-log reduction


Product compared to reference• Hand wash

– significantly more effective than plain soap– average of 2.8 log*

• Hand rub (leave-on)– not be significantly less effective than 60% IPA– average of 4.6 log*

Product compared to reference• Hand wash

– significantly more effective than plain soap– average of 2.8 log*

• Hand rub (leave-on)– not be significantly less effective than 60% IPA– average of 4.6 log*

* Kampf and Ostermeyer, J Hosp Infect (2002) 52: 219-224.

European Performance Criteria


Summary of Testing Methodology

• We measure bacterial log reduction on the testing methodology for healthcare personnel handwash, surgical hand scrub, and patient preop. These log reductions are used as surrogate endpoints to evaluate effectiveness. How should we analyze this data?

• The relationship of these outcomes and a corresponding reduction in the incidence of nosocomial infections in the healthcare setting where the products are used remains undefined.


Concluding Remarks

• Aware of limitations of test methods

• Assume incidence of infection:– related to current use of existing products– lowering these standards may increase

infection rates

• Need research to validate these surrogates

• Need to have products on the market and the use of actionable criteria in the meantime

1 Nonprescription Drugs AC Meeting March 23, 2005 Testing of Healthcare Antiseptic Drug Products...

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