National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Introduction to Tuberculosis Trials Consortium: Role of TB labs in clinical research

Anne Purfield, PhDCDR, United States Public Health Service

Director of Laboratory Operations, Tuberculosis Trials Consortium

11th National Conference on Laboratory Aspects of TuberculosisApril 24, 2019

Division name here

Clinical Trial Primer

Evaluate behavioral or medical/device interventions, including drug products– Evaluate efficacy and safety

Regulated – All trials are registered– Protocols reviewed by FDA for drug products/devices without prior

approved indication– FDA reviews all patient-level data

• Every culture result, adverse event, dose missed

TB Clinical Trials are THE Most Complex

Mtb is challenging to culture Drug resistance Treatment is long and arduous Population affected is often marginalized and stigmatized Co-infection with HIV Very difficult to be confident of “cure”

Not a lot of money in TB…

Phases of Clinical Trials

Phase 0/Pre-clinical Phase 1 (pharmacokinetics) Phase 2 (efficacy) Phase 3 (safety and efficacy) Phase 4 (pharmacovigilence)

Phase 0/Pre-clinical

Phase 1 PK (n=20)

Phase 2Efficacy (n>100)

Phase 3Safety & Efficacy

(n>1000)

Phase 4 Pharmacovi

gilance

FDA Review of New Drug Application (NDA)

Who Does TB Clinical Trials?

Pharmaceutical Companies

Trial Consortiums (public-private partnerships)– Tuberculosis Trials Consortium (TBTC)– TB Alliance– AIDS Clinical Trials Group

Tuberculosis Trials Consortium (TBTC)

Members– CDC – Domestic and international public health departments and labs– Academic medical centers– Veterans Administration medical centers

Trial sites include clinical, research and public health Mycobacteriology labs

TBTC--Current Sites

Role of Mycobacteriology Laboratories

Screening specimens to determine patient is eligible for trial– Smear, NAAT, culture, definitive identification of Mtb? Latent TB?

Is the patient appropriate for the treatment regimen?– Drug susceptibility testing? Co-infections with NTM?

Is the participant getting better?– Smear and culture over time

All questions Myco labs can easily tackle…. but

Challenge to ensure each laboratory is evaluating each specimen with the same sensitivity and specificity

These are all apples, but can we compare them to each other?

Mycobacteriology Laboratory Impacts on Trial Endpoints

Primary Endpoint Critical Mycobacteriology TestTB disease-free survival at 12 months after study treatment assignment

Liquid and/or solid culture, sequencing of baseline and follow-up isolates

Secondary EndpointsTB disease-free survival at 18 months after study treatment assignment

Liquid and/or solid culture, sequencing of baseline and follow-up isolates

Time to stable sputum culture conversion (solid and liquid media considered separately)

Liquid and solid culture

Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection

Liquid culture

Proportion of participants who are culture negative at completion of 8 weeks of treatment (solid and liquid media considered separately)

Liquid and solid culture at baseline and 8 week follow-up

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Mycobacteriology testing used to determine study outcomes

Time to culture conversion

Culture conversion = 2 consecutive negative sputum specimens, taken >28 days apart

Time to culture conversion = # days of treatment until the first of 2 consecutive negative specimens

Lab reporting for each specimen: – Date inoculated– Date Mtb growth observed (yes/no/contaminated)

Base Week 2 Week 4 Week 8 Week 12 Week 17 Week 22

Pt. 1 7 10 16 21 Negative Negative Negative

Pt. 2 12 16 18 Negative Negative Negative Negative

Pt. 3 5 7 14 Negative 18 Negative Negative

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84 days

56 days

119 days

Rate of change for time to detection Time to Detection (TTD) = number of days between inoculation and

detection of growth on MGIT With treatment, bacillary load is reduced and TTD increases Lab reporting for each specimen: Date of positive culture

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05

10152025

0 2 4 8 12 17 22 26

Day

s to

Posi

tive

Cul

ture

Time on treatment (weeks)

Time to Positivity with Study Treatment12345678910

Participants

Proportion who are culture negative at 8 weeks

For all participants in each arm, the proportion that have a negative culture from sputa collected at the 8-week visit

Solid and liquid media analyzed separately Lab reporting for each specimen: Culture outcome for

specimen collected at 8 wk visit

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0%20%40%60%80%

100%

0 2 4 8 12 17 22 26Parti

cipa

nts

Time (weeks)

NegativePositive30% Negative

A tale of identical specimens at BASELINE

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Lab A Lab BTransport Time 1 hour 3 daysTransport Temp 4oC 21oCDecontamination 1.5% NaOH 2% NaOHCentrifuge 3000 x g at 4oC for 20 min. 3000 x g, ambient temp. for

15 min. with cold PBSResuspension vol. 1.5 mL 2.5 mLMGIT inoculum 0.5 mL 0.5 mLBaseline TTD 7 days 12 days

Controlling what we can control

Every Myco Lab perfected their system for local diagnostic mycobacteriology– Lab A = 7 days report “positive culture” to physician– Lab B = 12 days report “positive culture” to physician

For diagnostic purposes, Labs A and B do the same thingpatient has TB, needs treatment

For a clinical trial, comparing results from Labs A and B could affect the trial outcome

Aim to control factors that introduce variability between labs and study participants

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A tale of identical specimens after 8 weeks of study treatment

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Lab A Lab BTransport Time 1 hour 3 daysTransport Temp 4oC 21oCDecontamination 1.5% NaOH 2% NaOHCentrifuge 3000 x g at 4oC for 20 min. 3000 x g, ambient temp. for

15 min. with cold PBSResuspension vol. 1.5 mL 2.5 mLMGIT inoculum 0.5 mL 0.5 mLBaseline TTD 7 days 12 days8 week TTD 21 days Negative Culture

A tale of identical specimens after 8 weeks of study treatment

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Lab A Lab BTransport Time 1 hour 3 days 1 hourTransport Temp 4oC 21oC 4oCDecontamination 1.5% NaOH 2% 1.5% NaOHCentrifuge 3000 x g at 4oC for 20 min. 3000 x g, ambient temp. for

15 min. with cold PBS at 4oC for 20 min.

Resuspension vol. 1.5 mL 2.5 mL 1.5 mLMGIT inoculum 0.5 mL 0.5 mLBaseline TTD 7 days ~7 days8 week TTD 21 days ~21 days

Study 31 endpoints rely on Mycobacteriology Lab data

Assessment of study endpoints depends heavily on laboratory data– Rate of reduction in bacillary load– Time to culture conversion– Proportion culture-negative at 8 weeks

TB studies may require smear, liquid culture, solid culture, and definitive MTB ID for all sputum specimens at baseline and beyond to assess these endpoints

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Lab Time and Events Schedule

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Myco Lab test and source Screen Base

Week MonthEarly term. visit

Unscheduled visit2 4 8 12

EOT17 22

EOT

26 9 12 15 18Sputum specimenXpert MTB/RIMolecular DSTSmear microscopyCulture– solid mediaCulture-- MGITIsolate from cultureMTB confirmationLocal storage of isolateDrug susceptibility testingShip isolate to CDC

Patient likely to produce specimen

Applicable, only if specimen is collected

Role of Your Myco Lab in TBTC Studies

Quality Mycobacteriology Testing– Mycobacteriology Lab data is crucial for assessing study endpoints

Accurately reporting Mycobacteriology test results– Complete case report form for each participant sputum specimen

Shipping isolates Retaining accurate and auditable source documents

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For more information, contact CDC1-800-CDC-INFO (232-4636)TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.