1. Cross-Sector Perspectives: Global Health Christian Lienhardt Stop TB Department CPTR Workshop October 2-4, 2012

2. Overview of the presentation Background – Global TB burden Challenges in introducing new TB drugs/regimens Developing Guidance to countries A pluri-partners model

3. Overview of the presentation Background – Global TB burden Challenges in introducing new TB drugs/regimens Developing Guidance to countries A pluri-partners model

4. Estimated number of cases Estimated number of deaths 1.4 million (range: 1.2–1.6 million) 8.8 million (range: 8.5–9.2 million) 440,000 (range: 390,000–510,000) All forms of TB Multidrug-resistant TB (MDR-TB) HIV-associated TB 1.1 million (13%) (range: 1.0–1.2 million) 350,000 (range: 320,000–390,000) The Global Burden of TB -2010 about 150,000

5. TB Incidence Rates - 2010 Eastern Mediterranean 7% South-East Asia 40% Western Pacific 19% Africa 26% Americas 5% Europe 5% Highest burden in Asia (59% of 8.8 million cases) Highest rates in Africa, due to high HIV infection rate ~80% of HIV+ TB cases in Africa

6. Impact of HIV on TB in Africa Notified cases per 100,000 pop. 1980-2008 80% of all TB/HIV cases world-wide are in Africa 50% of all TB/HIV cases world-wide in 9 African countries 23% of the estimated 2 million HIV deaths due to TB

7. % MDR-TB among new TB cases, 1994-2009 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2010. All rights reserved

8. Estimated absolute numbers of reported cases with MDR-TB* *among reported pulmonary TB patients <100 100–999 1000–9999 >10,000

9. 13 top settings with highest % of MDR-TB among new cases, 2001-2010 35.3 Minsk, Belarus (2010) Preliminary results

10. Countries that had reported at least one XDR-TB case by late 2011 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2011. All rights reserved

11. 2015: Goal 6: Combat HIV/AIDS, malaria and other diseases Target 6c: to have halted by 2015 and begun to reverse the incidence… *Indicator 6.9: incidence, prevalence and mortality associated with TB *Indicator 6.10: proportion of TB cases detected and cured under DOTS 2015: 50% reduction in TB prevalence and deaths by 2015 2050: elimination (<1 case per million population) The Global TB Control Targets

12. Incidence, prevalence and mortality rates: global estimates Peak in 2002 Target PrevalenceMortality 150 100 50 0 Rate per 100,000 population 250 200 150 100 50 0 Incidence 25 20 15 10 5 0 199020101990201519902015 40% decline since 1990 Falling 1.4% per year

13. 7.6 8.8 3.7 5.8 Global notifications (black) in context of estimated incidence (green) TB cases (millions) Estimated Global Case Detection 65% (63–68%) Detection gap: 1/3

14. Treatment success 87% globally …but Europe lagging behind Global, new sm+WHO Regions, new sm+ 93 88 81 76 67Europe Americas Africa EMR SE Asia 89 W. Pacific

15. Notifications of MDR-TB increasing BUT only ~ 1 in 5 (19%) of estimated cases of MDR-TB among reported TB patients diagnosed and treated in 2011 Notified cases of MDR-TB 19,000 53,000 Global Plan target ~270,000 in 2015 MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, 2010 290,000

16. Time trends in TB and MDR-TB: reverting, controlling, and alarming… Botswana Tomsk Oblast, Russia Estonia

17. Overview of the presentation Background – Global TB burden Challenges in introducing new TB drugs/regimens Developing Guidance to countries A pluri-partners model

18. Current TB Therapy and Unmet Needs * Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E) Patient PopulationCurrent TherapyUnmet 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); ≥18 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 HShorter, safer therapy ► 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

19. Lead Optimization Preclinical Development GLP Tox. Phase IPhase IIPhase III Gatifloxacin Moxifloxacin Rifapentine Delamanid (OPC67683) Bedaquiline (TMC- 207) PA-824 Linezolid SQ-109 Rifapentine Novel Regimens 2 PNU-100480 AZD5847CPZEN-45 SQ641 SQ609 DC-159a Q201 Preclinical Development Discovery 1 Clinical Development Nitroimidazoles Mycobacterial Gyrase Inhibitors Riminophenazines Diarylquinoline Translocase-1 Inhibitor MGyrX1 inhibitor InhA Inhibitor GyrB inhibitor LeuRS Inhibitor Pyrazinamide Analogs Spectinamides 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 completed August 2011. Global TB Drug Pipeline 2012 BTZ043 www.newtbdrugs.org

20. Novel drugs and shortened treatment regimens with new and/or re-purposed drugs are proceeding along the clinical development pathway; New drugs submitted for regulatory approval for treatment of drug-resistant MDR-TB; Implications for TB control programmes: – determine optimal regimens for use of newly developed and/or repurposed drugs for treatment of DS- and DR-TB under programmatic conditions; – evaluate requirements for patients’ eligibility; – assess programmatic feasibility; – evaluate cost-effectiveness of newly-developed treatments; – ensure proper surveillance and pharmacovigilance; – ensure responsible use (appropriate indication, doses, drug combination(s), and treatment duration) – prevent off-label use and amplification of resistance; Public health challenges of introduction of new TB drugs in countries

21. Overview of the presentation B ackground – Global TB burden Challenges in introducing new TB drugs/regimens Developing guidance to countries A pluri-partners model

22. STAG-TB recommendations for guidance on new drugs for TB (Sept 2010) STAG-TB recommends that: -WHO issues clear policies to guide countries on the introduction of new regimens for treatment of DS and DR-TB […] upon availability of evidence in support of use of such regimens; -WHO issues specific requirements on what evidence and information would be needed to develop policy recommendations related to new drugs/regimens for treatment of DS and DR-TB; -WHO promotes collaboration and action by partners [...], so that appropriate drug regimens are utilized by programmes for the treatment of DS- and DR-TB, inclusive of the new drugs, and avoid irrational use of new tools; -WHO organizes expert consultation(s) to review the evidence for use of new drugs and regimens to inform timely development of treatment policy guidance to national health authorities.

23. Objectives: To advise and assist WHO Stop TB in the development and monitoring of a strategic plan to prepare WHO policy guidance for the rational introduction of new TB drugs/regimens in countries; To advise and assist in the development of a policy development framework for the introduction of new drugs/regimens for the treatment of TB in countries; To assist and facilitate the implementation and evaluation of activities listed in the strategic plan Established April 2012; 12 members + 2 observers Task Force for new TB drug policy development

24. Introduction of new anti-TB drugs in practice is a multistage process; Development of appropriate combination(s) of drugs needs efficient coordination and sharing of data between key partners; Introduction of new TB drugs should be adaptable to countries settings according to country's own health infrastructure and preparedness; Need for rapid approval of new TB drugs by regulatory authorities in high-TB burden countries so as to favor due access; Equitable access to new drugs to all patients in needs worldwide is essential and should be linked with measures to prevent misuse of the drugs; WHO has a key role to play for the development of policy recommendations for rational introduction and use of new drugs/regimens in programmatic settings, ensuring proper, equitable and cost-effective access to treatment. The Strategy Plan - Principles

25. I. Determination of the type of evidence and data that would be required by WHO to recommend the use of new drug(s)/ regimen(s) for the treatment of DS and/or MDR-TB Review of current drug/regimen development landscape Review of requirements for licensure by stringent regulatory authorities Determination of data according to indications (DS or DR-TB) and populations (children, PLHIV) Priority categories (fundamental -> nice to have) The Strategy Plan – Contents (1)

26. II. Production of information notes: aimed at facilitating the production of policy recommendations for the treatment of TB (all forms), according to progress made in the development of new drugs/combinations of drugs Information notes: – to countries – to drug/regimen developers – to regulators – on compassionate use The Strategy Plan – Contents (2)

27. III. 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. Will be used to guide development of policy recommendations for specific drugs/regimens as data become available – based on progress of new drugs/drug combinations along clinical development pathway (e.g. PK and drug-drug interaction studies, Phase II trials, Phase III pivotal trials), – approval by stringent regulatory authorities (FDA, EMA, …). Will be used by the expert committees that will be convened by WHO to update/revise policy recommendations as needed. The Strategy Plan – Contents (3)

28. IV. Plan for expert consultations on revision of treatment guidelines (depending upon drug pipeline development) Timing of meetings (through 2012-2014) Drugs/regimens to be assessed Preparation of key data Experts selection & planning Discuss with GRC - Rapid advice approach ? Include time for STAG submission/endorsement and finalization of policies The Strategy Plan – Contents (4)

29. V. 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; CHAI, etc) Evaluate market shortcomings and commodity access issues Identify potential obstacles related to introduction and work with stakeholders (countries, drug developers, economists, market specialists, NGOs, donors…) to optimize market introduction. The Strategy Plan – Contents (5)

30. VI. Introduction in countries Country preparedness – Background epidemiological data ("know your epidemics") – Health infrastructure – NTP structure Country support to enable access to new drugs – Strengthened capacity for diagnosis, drug resistance surveillance, pharmacovigilance – Standardized definitions of outcomes (harmonize data collection after drug introduction) – Drug supply and management – Discuss check/control mechanisms (accreditation) – Develop "Demonstration sites" for initial deployment of new drugs with harmonised methods and surveillance The Strategy Plan – Contents (6)

31. Overview of the presentation B ackground – Global TB burden Challenges in introducing new TB drugs/regimens Developing Guidance to countries A pluri-partners model

32. Ensure equitable access to new drugs to all patients in needs worldwide and avoid acquisition of new resistances Identify suitable drug combination(s) for treatment of DS and DRTB early Need to work on country preparedness and clarify conditions for controlled/accredited access to new drugs Encourage collaboration between drug developers, regulators, and programme managers Find the suitable balance for easy access to new therapies and guarantee patients protection with use of drugs that remain efficient and safe worldwide Key messages

33. Dialogue needed with drug/regimen developers, sponsors, regulators, National TB Programme Managers. Information Notes: –Drafts circulated to partners/stakeholders for comments and feed-back to ensure buy-in –To be finalised and disseminated in Oct-Dec 2012 Meetings with stakeholders: –Task Force –Satellite meeting at International Conference of Drug Regulatory Authorities (ICDRA), Tallinn (22 Oct 2012) –Meeting at International Conference on Lung Health, Kuala Lumpur (Nov 2012) A pluri-partners model

34. As unique forum grouping representatives from key drug development initiatives, CPTR has a critical role to play in the dialogue with key stakeholders. Contribute/promote interactions – e.g. through - Global Regulatory Pathway Working Group - Working Group on Access and Appropriate Use Contribute to works of the Task Force for New Drug Policy Development – technical resource Later stages ? A role for CPTR

35. Task Force members WHO staff, particularly Samvel Azatyan, Dennis Falzon, Christopher Fitzpatrick, Malgosia Grzemska, Ernesto Jaramillo, Shanthi Pal, Andrea Pantoja, Charles Penn, Lembit Rägo, Mario Raviglione, Diana Weil & Karin Weyer BMGF; USAID; DfID Acknowledgements

36. Thank you for your attention !