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

Transcription

1 Introducing New TB Drugs & Regimens: the WHO Global TB Programme Approach CPTR Workshop October 1-3, Washington DC Christian Lienhardt GTB/WHO Geneva, Switzerland

2 Overview of the presentation 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

3 Overview of the presentation 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

4 Current TB Therapy and Unmet Needs Patient Population Current Therapy Unmet Needs Drug-Susceptible DS-TB Drug-Resistant M(X)DR-TB TB/HIV co-infection 4 drugs; 6 month therapy (2RHZE + 4RH) At least 4 drugs (including injectable); 20 months; poorly tolerated Drug-drug interactions (DDI) with ARVs Shorter, simpler therapy Fully oral, shorter and safer therapy No or low DDI, coadministration with ARVs Latent TB Infection 6-9 months H Shorter, safer therapy * Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E) For all indications and treatment, issues in delivery and access Need shorter and simpler therapies against both DS and DR-TB Adapted from TB Alliance

5 Global TB Drug Pipeline Discovery 1 Preclinical Development Clinical Development Lead Optimization Preclinical Development GLP Tox. Phase I Phase II Phase III Diarylquinoline DprE Inhibitors GyrB inhibitors InhA Inhibitors LeuRS Inhibitors MGyrX1 inhibitors Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Riminophenazines Ruthenium (II) complexes Spectinamides Translocase-1 Inhibitors CPZEN-45 DC-159a Q201 SQ609 SQ641 BTZ043 TBA Repurposed Drugs 6 New Drugs 3 New Classes AZD5847 Bedaquiline (TMC-207) Linezolid Novel Regimens 2 PA-824 Rifapentine SQ-109 Sutezolid (PNU ) Delamanid (OPC-67683) Gatifloxacin Moxifloxacin Rifapentine Drugs currently in the regulatory review process Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone 1 Ongoing projects without a lead compound series can be viewed at 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 Updated: June 18, 2012

6 Public health challenges of introduction of new TB drugs in countries 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;

7 Overview of the presentation 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

8 The WHO Strategic Plan for rational introduction of new TB drugs and regimens in countries 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.

9 The WHO Strategic Plan 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

10 The Strategic Plan 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

11 1. Production of information notes 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

12 2. Policy Development Framework 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

13 WHO new TB drugs policy formulation process Development of new TB drugs or new regimens Reviewing the evidence Convening an Expert Group Assessing policy proposal and recommendations Formulating and disseminating policy 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

14 3. Expert consultations 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.

15 4. Introduction in countries (1) 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")

16 4. Introduction in countries (2) 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)

17 5. Market introduction 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.

18 Overview of the presentation 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

19 Approaches for introduction of new TB drugs/regimens (1) 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

20 Approaches for introduction of new TB drugs/regimens (2) 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)!

21 Potential models 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)

22 Key questions (1) 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

23 Key questions (2) 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.

24 MDR TB cases detected in 2011 compared to estimated % MDR TB detected in 2011 out of total estimated that year

25 % of estimated MDR TB cases enrolled on treatment, 2011 enrolled / total MDR TB estimated among notified (%)

26 Outcomes for MDR TB cases starting treatment in 2009 Cohort size next to country names, % success Falzon et al, Lancet ID 2013

27 % treatment success, 2009 cohort % of MDR cases notified in 2009 monitored for outcome Relationship between the % of MDR cases notified in 2009 monitored for outcome* and % success in 2009 MDR TB cohorts - target countries reporting outcomes *excluding unevaluated cases

28 Key questions (3) 3. Availability of diagnostics of drug resistance at country level? 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

29 Key questions (4) 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

30 Key questions (5) 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)?

31 Overview of the presentation 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

32 WHO Policy Implementation Package for Rational Introduction of New TB Drugs/Regimens in Countries Objective: To assist countries (particularly high-tb and MDR-TB burden countries) for rational introduction and use of new TB drugs/regimens.

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

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35 MDR-TB drug add-on to New MDR-TB regimen New DS-TB regimen New DS/DR regimen existing regimen Small Medium Large Large Expected No of patients Setting Specialized centers +/- decentralization, or all existing MDR-TB sites (if use is uncomplicated) Means of introduction Monitoring options: a) if conditional regulatory approval Initially in specialized sites only a) Patient registry; clinical/operational research; compassionate use or expanded access programme Existing MDR-TB sites; additional sites if new regimen is simpler than existing regimen Initially in specialized sites or by certified MDR-TB treatment providers a) Patient registry clinical/operational research; Existing DS-TB treatment level Physician prescription or provision by certified TB treatment provider a) NA Existing DS-TB treatment level or subset of these sites Physician prescription or provision by certified TB treatment provider a) NA b) if fully approved Phased introduction Laboratory implications b) Routine pharmacovigilance Depending on context: begin at tertiary/referral level or trial sites High Need to align with appropriate DST availability b) Routine pharmacovigilance Depending on context: begin at tertiary/ referral level, or at certified MDR-TB treatment sites, then roll out High Need to align with appropriate DST availability b) Routine pharmacovigilance Begin as pilot, then scale up Moderate Need to align with appropriate DST availability b) Routine pharmacovigilance Begin as pilot, then scale up Unknown Need to align with appropriate DST availability

36 Elements of introduction of new TB drugs / regimens in countries 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.

37 Pharmacovigilance 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

38 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.

39 Acknowledgements 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.

40 Thank you for your attention!