Introducing New TB Drugs & Regimens: the WHO Global TB Programme Approach. CPTR Workshop October 1-3, Washington DC

Introducing New TB Drugs & Regimens:

the WHO Global TB Programme Approach

Christian Lienhardt GTB/WHO Geneva, Switzerland

CPTR Workshop

October 1-3, 2013

---

Washington DC

 Background: the need for new TB drugs and the TB drug pipeline

 The WHO strategic plan for rational introduction of new TB drugs and regimens in countries

 Approaches for the introduction and delivery of new drugs and new drug regimens

 The WHO Policy Implementation Package

Overview of the presentation

GLOBAL TB

 Background: the need for new TB drugs and the TB drug pipeline

 The WHO strategic plan for rational introduction of new TB drugs and regimens in countries

 Approaches for the introduction and delivery of new drugs and new drug regimens

 The WHO Policy Implementation Package

Overview of the presentation

GLOBAL TB

Current TB Therapy and Unmet Needs

* Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E)

Patient Population Current Therapy Unmet Needs

Drug-Susceptible

DS-TB 4 drugs; 6 month therapy (2RHZE + 4RH) Shorter, simpler therapy Drug-Resistant

M(X)DR-TB

At least 4 drugs (including injectable); ≥20 months; poorly tolerated

Fully oral, shorter and safer therapy

TB/HIV

co-Infection Drug-drug interactions (DDI) with ARVs No or low DDI, co-administration with ARVs Latent TB

Infection 6-9 months H Shorter, safer therapy

► For all indications and treatment, issues in delivery and access ► Need shorter and simpler therapies against both DS and DR-TB

Lead Optimization _Development Preclinical GLP _Tox. Phase I Phase II Phase III Delamanid (OPC-67683) Gatifloxacin Moxifloxacin Rifapentine AZD5847 Bedaquiline (TMC-207) Linezolid Novel Regimens2 PA-824 Rifapentine SQ-109 Sutezolid (PNU-100480) CPZEN-45 DC-159a Q201 SQ609 SQ641 Preclinical Development

Discovery1 _{Clinical Development}

Diarylquinoline DprE Inhibitors GyrB inhibitors InhA Inhibitors LeuRS Inhibitors MGyrX1 inhibitors Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Riminophenazines

Ruthenium (II) complexes Spectinamides

Translocase-1 Inhibitors

Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone 1 _{Ongoing projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.} 2 _{Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,}

moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The second clinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitive and multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and clofazimine in combinations and is scheduled to begin September 2012.

Global TB Drug Pipeline

Updated: June 18, 2012 BTZ043 TBA-354 www.newtbdrugs.org 4 Repurposed Drugs 6 New Drugs 3 New Classes

Drugs currently in the regulatory review process

Implications for TB control programmes:

• Main issue is to determine optimal regimens for use of these newly developed and/or re-purposed drugs for treatment of DS- and DR-TB under programmatic conditions;

• evaluate requirements for patients’ eligibility; • assess programmatic feasibility;

• evaluate cost-effectiveness;

• ensure proper surveillance and pharmacovigilance – especially if accelerated approval;

• ensure responsible use (appropriate indication, doses, drug combination(s), and treatment duration)

• prevent off-label use and emergence of resistance;

Public health challenges of introduction of

new TB drugs in countries

GLOBAL TB

 Background: the need for new TB drugs and the TB drug pipeline

 The WHO strategic plan for rational introduction of new TB drugs and regimens in countries

 Approaches for the introduction and delivery of new drugs and new drug regimens

 The WHO Policy Implementation Package

Overview of the presentation

GLOBAL TB

Key Principles:

• Need for combination regimen(s),

• Adaptation to largely variable country settings (health and NTP infrastructure, geography, demography, TB epidemiology, level of preparedness, etc.),

• Ensure equitable access to safe and quality-assured new drugs for all patients in needs,

• Link with measures to prevent misuse of the drugs,

• Multistage and pluri-partner process.

The WHO Strategic Plan for rational introduction

of new TB drugs and regimens in countries

GLOBAL TB

Describes key elements of a process aimed at

- producing policy

recommendations for the treatment of TB (all forms), according to progress made in the development of new drugs or combinations of drugs,

and

- assisting countries in the implementation of these recommendations

The WHO Strategic Plan

GLOBAL TB

5 steps:

1. Determination of the type of evidence and data to be required by WHO to recommend the use of new drug(s)/ regimen(s) for the treatment of TB, and production of technical information notes,

2. Development of a "Policy Development Framework” to establish recommendation for the introduction of new TB drugs/regimens in countries

3. Series of Expert consultations to evaluate new TB

drugs/regimens coming out of the pipeline and revise/update treatment guidelines as appropriate,

4. Recommendations and TA for introduction in countries 5. Market introduction

• Aimed at facilitating the evaluation of new

drugs/regimens and the production of ad-hoc policy recommendations for the treatment of TB (all forms)

• Information notes:

– to countries

– to drug/regimen developers

– to regulators

• Posted on New TB Drug Policy

Development dedicated website

1. Production of information notes

GLOBAL TB

Development of a "Policy Development Framework” for the introduction of new TB drugs/regimens in countries:

• describes the process for development of policies for treatment of TB including the new drugs/regimens

• used to guide the development or update of policy recommendations (guidelines) as data on specific drugs/regimens become available

2. Policy Development Framework

GLOBAL TB

Development of new TB drugs or new regimens

Reviewing the evidence

Convening an Expert Group

Assessing policy proposal and recommendations

Formulating and disseminating policy

WHO new TB drugs policy formulation process

• Partners (industry, researchers, consortia,…) • Body of evidence available (publications, SRA approval)

• Collection of data on pre-clinical and clinical development phases

• cost-effectiveness analysis

• Experts, methodologists, end-users • Guidelines Review Committee

• GRADE process for evidence synthesis • Peer-review by ERC

• Strategic and Technical Advisory Group • Endorsement/revision/addition

• Advise to WHO to proceed/not with policy • Guidelines Review Committee

• Dissemination to Member States

• Promotion with stakeholders & funders • Phased implementation & scale-up plan

Series of Expert consultations to evaluate new TB drugs/regimens coming out of the pipeline and revise/update treatment guidelines as appropriate Indicative: • Bedaquiline (Jan 2013) • Delamanid • Fluoroquinolone-containing regimens for DS-TB • New/shortened MDR-TB treatment • Treatment of LTBI • Others….

3. Expert consultations

Specifies the needs to ensure rational introduction of new TB drugs:

o Country preparedness:

• need for background information:

• Health system infrastructure

• NTP infrastructure

• Epidemiological data ("know your epidemics")

4. Introduction in countries (1)

GLOBAL TB

o Country support to enable access to new drugs

• Strengthened capacity for diagnosis (incl. drug resistance) and

treatment monitoring (surveillance, outcomes, pharmacovigilance)

• Sustained system in place for supply of QA drugs and management

• Discuss control mechanisms/regulations to protect new drugs from

irrational use, particularly in the private sector (e.g., accreditation)

• Develop "Pilot projects" for initial deployment of new drugs with

harmonised methods and surveillance

• Community/patients' representatives contribution

• Related training/capacity building

• Strong collaboration between key stakeholders (MoH, regulatory

authorities, NTPs, drug developers, TA/donors, WHO)

4. Introduction in countries (2)

GLOBAL TB

• map-out the detailed expertise needed (drug market

introduction, pricing, funding, public vs. private issues) and identify appropriate stakeholders (incl. GF; UNITAID; GDF; BMGF; CHAI, etc.)

• evaluate market shortcomings and commodity access issues • identify potential obstacles related to introduction and work

with stakeholders to optimize market introduction.

5. Market introduction

GLOBAL TB

 Background: the need for new TB drugs and the TB drug pipeline

 The WHO strategic plan for rational introduction of new TB drugs and regimens in countries

 Approaches for the introduction and delivery of new drugs and new drug regimens

 Key Messages

Overview of the presentation

GLOBAL TB

• Variable approaches according to:

– the type of drug/regimen to be introduced

– the population to be considered for treatment

– the public health needs/implications

– the national context

• So, evaluate potential scenarios for introduction of new TB

drug/regimens to assist rational decision-making

Approaches for introduction of new TB

drugs/regimens (1)

GLOBAL TB

• Main issues to address:

– delivery of - and access to treatment (by whom ? how ?)

– risks to individuals (ADRs, DDIs) and implications

– risk of irrational use (off-label, inadequate combinations, inadequate doses or duration, etc.)

– risk for resistance development

– feasibility and potential public health impact,

– cost-effectiveness.

– great variability of national contexts (TB epidemics,

infrastructure, logistics, finances) !

Approaches for introduction of new TB

drugs/regimens (2)

GLOBAL TB

Depend on the type of new drug/regimen to be introduced:

• New MDR-TB drug: add-on to existing regimen (e.g. bedaquiline, delamanid)

• New MDR-TB regimen

(e.g. "Bangladesh regimen")

• New DS-TB regimen

(e.g. substitution of one drug with either repurposed - FQ - or new TB drug)

• Full new DS/DR-TB regimen – no R/H (e.g. PaMZ, others)

Potential models

GLOBAL TB

1. What population would benefit most of the new drugs/regimens?

• Depends on the product characteristics and indications :

- MDR-TB treatment: all MDR-TB patients ? those failing MDR-TB treatment only ? "pre-XDR" ? XDR-TB patients ?

- DS-TB treatment: all DS-TB patients ? only those with proven

susceptibility ? practical implications (e.g. diagnostics of FQ resistance) ? - “all-TB treatment” for both DS and DR-TB patients: practical implications

(e.g. availability of appropriate DST for all TB drugs) ?

• Consider high-risk groups:

- HIV infected population: high vs. low HIV prevalence in TB cases - Respective proportions of new vs. re-treatment in MDR-TB cases

• High variability of situation according to countries

Key questions (1)

GLOBAL TB

2. What would be best impact considering characteristics of the new drug/regimen and the variability of national contexts?

• Variable scenarios according to the local/national context in terms of : - case-detection - diagnostics capacity - enrolment on treatment - treatment performance - etc.

Key questions (2)

MDR−TB cases detected in 2011 compared to estimated

% of estimated MDR−TB cases enrolled on treatment, 2011

Outcomes for MDR−TB cases starting treatment in 2009

% of MDR cases notified in 2009 monitored for outcome % trea tm en t succe ss, 20 09 coh ort

Relationship between the % of MDR cases notified in 2009 monitored for outcome* and % success in 2009 MDR−TB cohorts - target countries reporting outcomes

Variable scenarios according to the type of tests available and their location – e.g.:

- only conventional H+R DST at central/reference level,

- the above + Xpert in main health centres (district),

- decentralized conventional H+R and/or liquid culture (MGIT) and/or LPA (Hain),

- Collection of samples for new drug DST

Key questions (3)

3. Availability of diagnostics of drug resistance at country level ?

GLOBAL TB

4. What will be best timing of introduction ?

• Phased introduction in relation with country’s health

infrastructure

• Phased introduction in relation with geography, especially for vast countries (India, China, Brazil)

• Possibility to pilot introduction and then step-wedge approach – allow for comparison

Key questions (4)

GLOBAL TB

5. How to ensure optimal deployment of new drug(s)/regimens in countries?

• What procedures are needed to prevent misuse of new agents, either in unapproved combinations, or off-label ?

• Selection of specific health facilities for the management of TB/MDR-TB based on demonstrating full capacity to guarantee appropriate use ?

• Restriction of new agents be restricted to a limited group of health care providers (e.g. Brazil: limited to certified PH

sector)?

Key questions (5)

GLOBAL TB

 Background: the need for new TB drugs and the TB drug pipeline

 The WHO strategic plan for rational introduction of new TB drugs and regimens in countries

 Approaches for the introduction and delivery of new drugs and new drug regimens

 The WHO Policy Implementation Package

Overview of the presentation

GLOBAL TB

Objective:

To assist countries (particularly high-TB and MDR-TB burden countries) for rational introduction and use of new TB

drugs/regimens.

WHO Policy Implementation Package for Rational Introduction of New TB Drugs/Regimens in Countries

GLOBAL TB

1. Technical recommendations on the rational introduction and management of new drugs & regimens for the treatment of TB

- new/updated guidelines for TB treatment

- checklist for Country preparedness and planning

2. A set of best practice regulations to provide rational access and

rational protection of new drugs

- criteria to license/accredit public and private providers - well-established pharmacovigilance system,

3. A routine DRS system (pheno- and genotypic) for current and new

drugs

4. A generic best-practice database to collect relevant information to

measure feasibility, acceptability and impact, and an operational research platform for evaluation,

5. A system for rational procurement and delivery of high-quality

affordable drugs.

WHO Policy Implementation Package for Rational Introduction of New TB Drugs/Regimens in Countries

GLOBAL TB

MDR-TB drug – add-on to existing regimen

New MDR-TB regimen New DS-TB regimen New DS/DR regimen

Expected No of patients

Small Medium Large Large

Setting Specialized centers +/- decentralization, or all existing MDR-TB sites (if use is uncomplicated)

Existing MDR-TB sites; additional sites if new regimen is simpler than existing regimen

Existing DS-TB treatment level

Existing DS-TB treatment level or subset of these sites

Means of introduction

Initially in specialized sites only Initially in specialized sites or by certified MDR-TB treatment providers Physician prescription or provision by certified TB treatment provider Physician prescription or provision by certified TB treatment provider Monitoring options: a) if conditional regulatory approval b) if fully approved a) Patient registry; clinical/operational research; compassionate use or expanded access programme b) Routine pharmacovigilance a) Patient registry clinical/operational research; b) Routine pharmacovigilance a) NA b) Routine pharmacovigilance a) NA b) Routine pharmacovigilance Phased introduction Depending on context: begin at tertiary/referral level or trial sites

Depending on context: begin at tertiary/ referral level, or at certified MDR-TB treatment sites, then roll out

Begin as pilot, then scale up

Begin as pilot, then scale up

Laboratory implications

High

Need to align with appropriate DST availability

High

Need to align with appropriate DST availability

Moderate

Need to align with appropriate DST availability

Unknown

Need to align with appropriate DST availability

Develop "Pilot sites" for initial deployment of new drugs.

• Assessment of background requirements

• Capacity building/training in place

• Ensure capacity to use standardised methods for

• diagnostics - microbiological laboratory capacities

• treatment

• monitoring

• management

• surveillance (correct definitions; criteria; standard record keeping;

defined endpoints)

• access to TB drugs

• access to special and at-risk populations

• Implementation/operational research context: protocol,

database, lines of responsibilities, regular feed-back, analysis.

Elements of introduction of new TB drugs / regimens in countries

GLOBAL TB

• National Pharmacovigilance Centre responsible to develop mechanisms for reporting and receive reports

• Adverse events considered serious to be reported: death, life-threatening events;

hospitalization or prolonging hospitalization; persistent disability; etc…

• Active reporting system in place

Pharmacovigilance

GLOBAL TB

Key Messages

WHO/GTB considers of most importance to:

• engage/support national authorities and all stakeholders early in the preparation of policies for introduction of new TB

drugs/regimens at programmatic level (including drug quality, drug procurement, etc.);

• ensure that new TB drugs/regimens are introduced in an optimal way to protect patients from misuse and prevent emergence of resistance;

• ensure that introduction of new drugs follows recommendations and that appropriate plans are prepared at an early stage to ensure feasibility and inform policy-making.

GLOBAL TB

• Members of the WHO Task Force for New Drug Policy

Development: Gavin Churchyard, Margareth Dalcolmo, Gerry Davies, Viet Nhung Nguyen, Christophe Perrin, Michael Rich, Giorgio Roscigno, Holger Schunemann, Alena Skrahina, Soumya Swaminathan, Tido von Schon-Angerer, Andrew Vernon.

• Observers: Martha Brumfield, Richard Hafner, Andrew Jones,

Michael Kimerling, Ya-Diul Mukadi.

• WHO staff: Dennis Falzon, Ernesto Jaramillo, Lembit Rägo, Mario

Raviglione, Mukund Uplekar, Fraser Wares, Diana Weil & Karin Weyer.

• Support from B&MGF; USAID.

Acknowledgements

GLOBAL TB

Thank you for

your attention !

GLOBAL TB