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Christopher Gilpin

Laboratories, Diagnostics and Drug Resistance Unit

Review of WHO TB diagnostics policy development

GLI Meeting: Les Pensières, Annecy, France : 15-18th April 2013

Outline

• Evidence required for WHO review of diagnostics

• Current WHO-endorsed TB diagnostics/approaches

• Requirements for implementing WHO policy guidance

• Diagnostic tools NOT recommended

• Policy and diagnostic pipeline

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 1: Research and Development • Upstream research and development to

define and validate a prototype • Laboratory validation under

international standards that culminate in a design-locked product.

• WHO interacts with developers if requested to discuss end-user requirements such as biosafety, assay robustness, intended settings of use.

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 2: Evaluation and Demonstration •The performance of the new diagnostic product should be evaluated in controlled trials at 3-5 trial sites in high-burden TB and HIV countries. •Product registration with global and/or national regulatory authorities such as FDA and/or CE marking. •Product specifications and performance should subsequently be validated in uncontrolled trials under field conditions in 5-10 trial sites in high-burden TB and HIV countries, and include cost-effectiveness studies.

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 3: Evidence Assessment NEW TECHNOLOGIES Submission of dossier with Phase 1 and 2 data to WHO FAST-FOLLOWER Manufactured under ISO 13:485 standards; Equivalent performance demonstrated – SRL comparison Structured evidence assessment using GRADE. WHO does not recommend technologies for individual country use.

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Systematic review

Guideline development

P I C O

Outcome

Outcome

Outcome

Outcome

Critical

Important

Critical

Not Summary of findings & estimate of effect for each outcome

Grade overall quality of evidence

across outcomes based on lowest quality

of critical outcomes

Randomization increases initial

quality

1. Risk of bias 2. Inconsistency 3. Indirectness 4. Imprecision 5. Publication

bias

Gra

de

d

ow

n

Gra

de

u

p

1. Large effect 2. Dose

response 3. Opposing bias

& Confounders

Very low

Low

Moderate

High

Grade recommendations •For or against (direction) •Strong or conditional/weak (strength) By considering balance of:

Quality of evidence Balance benefits/harms Values and preferences

Revise if necessary by considering: Resource use (cost)

Formulate Recommendations ( | …) •“The panel recommends that ….should...” ( | …) •“The panel suggests that ….should...” (? | …) •“The panel suggests to not ...” (? | …) •“The panel recommends to not...” ( | …)

Guideline

OOO

O

OO

GRADE - PICO Question *Grades of Recommendation Assessment, Development and Evaluation

P Population Who is targeted by the action being recommended?

I Intervention What action is being considered?

C Comparator What is the alternative choices of action?

O Outcome What is the purpose of the recommendation?

GRADE evaluation

Clear separation: • Recommendation strong or conditional/optional/weak (for or against an intervention)

– Benefits and downsides, values and preferences, impact, resource use balanced with

• Quality of evidence (High), (Moderate), (Low), (Very low)

– Methodological quality of evidence – Likelihood of bias – By outcome and across outcomes

• GRC review cycle 3 to 5 years

*Grades of Recommendation Assessment, Development and Evaluation

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 4: Phased uptake and collection of evidence for scale-up New diagnostic successfully implemented in routine diagnostic services by early implementers in high/burden TB and HIV countries Systematic assessment of proposed algorithms, laboratory workload, operational constraints, country cost-effectiveness. Lessons learnt by early implementers used for country adaptation

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and collection of evidence for

scale-up

Phase 5 Scale-up and policy

refinement

Evidence required for WHO review of diagnostics

Phase 5: Scale-up and Policy refinement Scale-up of the new diagnostic, with subsequent data used to inform and refine WHO policy guidance in a dynamic and on-going process.

WHO recommended diagnostics for use at

different levels of laboratory sophistication

*Available at: http://www.who.int/tb/dots/laboratory/policy/en

Considerations for implementing WHO Diagnostic Policies

• Diagnostic algorithms should start with appropriate screening policies to identify persons at risk.

• New, rapid WHO-recommended tests (e.g. Xpert MTB/RIF) should be prioritised in persons with risk factors for drug resistance and/or persons with HIV co-infection.

• Drug susceptibility testing (DST) is accurate and reproducible for detection of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR) TB. For other drugs, DST is problematic and the clinical relevance of results are unclear.

• Conventional laboratory capacity (microscopy, culture and DST) must be maintained for monitoring patient response to treatment and detecting resistance to drugs other than rifampicin.

• Scale-up of diagnostic capacity must be matched with access to appropriate treatment and care.

*

Laboratory requirements for implementing

WHO Diagnostic Policies •Sufficient funding

•Adequate human resources and training

•Country-specific diagnostic algorithms

•Appropriate infrastructure and biosafety

•Specimen transport and referral mechanisms

•Equipment validation and maintenance

•Management of laboratory commodities

•Laboratory information management systems.

•Laboratory quality management systems

Not recommended due to current insufficient evidence

•Sputum concentration and decontamination methods. •Phage-plaque technology •Thin-layer agar methods •Interferon-gamma release assays as replacement for the tuberculin skin test for detection of latent TB in low- and middle-income (typically high TB and/or HIV) settings •Molecular line probe assays for 2nd-line anti-TB drugs. •Loop-mediated isothermal amplification (LAMP) test kit for TB

Molecular line probe assays for 2nd-line anti-TB drugs

Expert Group Recommendations The Expert Group recommended that the Genotype MTBDRsl assay cannot be used as a replacement test for conventional phenotypic DST

Strong recommendation - Very Low Quality of Evidence Remarks: 1. The Genotype MTBDRsl may be used as a rule-in test for XDR-TB but cannot be used to

define XDR-TB for surveillance purposes; 2. As cross-resistance between the second-line injectables is incomplete, the Genotype

MTBDRsl cannot be used to identify individual drugs to be used for treatment; 3. The Genotype MTBDRsl may be used to guide infection control precautions while awaiting

confirmatory results from conventional phenotypic testing.

Loop-mediated isothermal amplification (LAMP) test kit for TB. Expert Group Recommendations LAMP technology has potential as a rapid TB diagnostic tool but that the body of evidence presented on the TB-LAMP assay was insufficient to make a recommendation either in favour of, or against the use of TB-LAMP as a replacement test for sputum smear microscopy.

– The specificity of the TB-LAMP assay remains a major concern especially when the TB prevalence falls below 10%

– Further studies in different geographical regions are needed, especially in high HIV prevalence settings where the sensitivity of sputum smear microscopy is reduced;

– Head-to-head comparison studies with TB-LAMP and LED microscopy – Further research is recommended to simplify the technology – The anticipated cost of the TB-LAMP perceived as a major barrier to

implementation and scale-up; – Evaluation of the TB-LAMP assay by more investigators is encouraged to enable

further independent assessment.

Recommended NOT to use

•Commercial TB serodiagnostic tests.

•Interferon-gamma release assays for detection of active TB (all settings).

Policy guidance 2013-2014 • Laboratory biosafety

– Procedure (risk)-based, minimum requirements published Q1 2013

• DST guidance update

– Update on 2008 interim guidance Q3 2013

• Xpert MTB/RIF update

– Update on 2010 guidance Q3 2013

• LPA update

– Update of 2008 guidance planned for Q2 2014

Pipeline for new TB diagnostics growing

Acknowledgements

• WHO/STB/LDR staff

K Weyer, F Mirzayev, W van Gemert, J Iragena

• GRADE Working Group Chair: Holger Schünemann

• Expert Group members

• WHO STAG members

• Funding: USAID, WHO,

• FIND: Evaluation studies and reports