Cross-Sector Perspectives: Global Health

Christian LienhardtStop TB Department

CPTR WorkshopOctober 2-4, 2012

Overview of the presentation

• Background – Global TB burden

• Challenges in introducing new TB drugs/regimens

• Developing Guidance to countries

• A pluri-partners model

Overview of the presentation

• Background – Global TB burden

• Challenges in introducing new TB drugs/regimens

• Developing Guidance to countries

• A pluri-partners model

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

Estimated TB incidence rates, by country, 2010

TB cases per 100 000

0–24

25–49

50–99

100–299

>=300

No estimate

Estimated TB incidence rates, by country, 2010

TB cases per 100 000

0–24

25–49

50–99

100–299

>=300

No estimate

TB Incidence Rates - 2010

Estimated TB incidence rates, by country, 2010

TB cases per 100 000

0–24

25–49

50–99

100–299

>=300

No estimate

Eastern Mediterranean7%

South-East Asia40%

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

Impact of HIV on TB in Africa

Notified cases per 100,000 pop. 1980-2008

Percentage of global estimated HIV-positive TB cases

EMR

Cameroon

Thailand

Brazil

Democratic Republic of the Congo

China

Myanmar

EUR

Côte d'Ivoire

Malawi

United Republic of Tanzania

AMR

Zambia

WPR

Ethiopia

Mozambique

Kenya

Uganda

Zimbabwe

Nigeria

India

SEA

South Africa

AFR

1% 5% 10% 20% 50% 90% 0

100

200

300

400

500

600

700

1980 1984 1988 1992 1996 2000 2004 2008

Botswana

Côte d'Ivoire

DR Congo

Gabon

Guinea

Kenya

Malawi

Mozambique

South Africa

UR Tanzania

Zimbabwe

• 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

% 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

Australia, Democratic Republic of the Congo, Fiji, Guam, New Caledonia, Solomon Islands and Qatar reported data on combined new and previously treated cases.

0-<3

3-<6

6-<12

12-<18

>=18

No data available

Subnational data only

Notified cases of MDR-TB

Cases of MDR-TB

0–99

100–999

1000–9999

≥10 000

NA

Estimated absolute numbers of reported cases with MDR-TB*

Notified cases of MDR-TB

Cases of MDR-TB

0–99

100–999

1000–9999

≥10 000

NA*among reported pulmonary TB patients

<100100–999

1000–9999>10,000

13 top settings with highest % of MDR-TB among new cases, 2001-2010

16.5

19.2

19.3

19.4

20.0

22.3

23.8

27.3

28.3

15.4

14.8

16.0

16.1

0 5 10 15 20 25 30

Tashkent, Uzbekistan (2005)

Estonia (2008)

Donetsk Oblast, Ukraine (2006)

Mary El Republic, Russian Federation (2008)

Dushanbe city and Rudaki district, Tajikistan (2009)

Belgorod Oblast, Russian Federation (2008)

Kaliningrad Oblast, Russian Federation (2008)

Republic of Moldova (2006)

Ivanovo Oblast, Russian Federation (2008)

Baku city, Azerbaijan (2007)

Arkhangelsk Oblast, Russian Federation (2008)

Pskov Oblast, Russian Federation (2008)

Murmansk Oblast, Russian Federation (2008)

35.3Minsk, Belarus (2010)Preliminary results

Countries that had reported at least oneXDR-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

Argentina Bhutan France Japan Namibia Republic of Korea ThailandArmenia Cambodia Georgia Kazakhstan Nepal Republic of Moldova TogoAustralia Canada Germany Kenya Netherlands Romania TunisiaAustria Chile Greece Kyrgyzstan Norway Russian Federation UkraineAzerbaijan China India Latvia Pakistan Slovenia United Arab EmiratesBangladesh Colombia Indonesia Lesotho Peru South Africa United KingdomBelgium Czech Republic Iran (Islamic Rep. of) Lithuania Philippines Spain United States of AmericaBotswana Ecuador Ireland Mexico Poland Swaziland UzbekistanBrazil Egypt Israel Mozambique Portugal Sweden Viet NamBurkina Faso Estonia Italy Myanmar Qatar Tajikistan

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 20152050: elimination (<1 case per million population)

The Global TB Control Targets

Incidence, prevalence and mortality rates: global estimates

Peak in 2002

TargetTarget

Prevalence Mortality

150

100

50

0

Rat

e p

er 1

00,0

00 p

op

ula

tio

n

250

200

150

100

50

0

Incidence

25

20

15

10

5

0

1990 2010 1990 2015 1990 2015

40% decline since 1990Falling 1.4% per year

7.68.8

3.7

5.8

Global notifications (black) in context of estimated incidence (green)

TB

cas

es (

mil

lio

ns)

Estimated Global Case Detection

65% (63–68%)

Detection gap: 1/3

Treatment success 87% globally…but Europe lagging behind

Global, new sm+ WHO Regions, new sm+93

88

81

76

67

87

8584

86 86

83

80

76

78

80

82

84

86

88

Tre

atm

ent

succ

ess

rate

(%

)

65

70

75

80

85

90

95

Europe

Americas

Africa

EMR

SE Asia 89

W. Pacific

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

0

10

20

30

40

50

60

2005 2006 2007 2008 2009 2010

Nu

mb

er

of

pa

tie

nts

(th

ou

sa

nd

s)

19,000

53,000

Global Plan target ~270,000 in 2015

0

50

100

150

200

250

300

SE Asi

a

W. P

acifi

c

Europe

Africa

EMR

Americ

as

World

Not on treatment

Treated

MDR-TB cases treated and estimated numbers not

treated for MDR-TB, among notified TB patients, 2010

290,000

Time trends in TB and MDR-TB: reverting, controlling, and alarming…

1

10

100

1000

1996 1998 2000 2002 2004 2006 2008

0.3% per year

19.4% per year

____ TB ____ MDR-TB

1

10

100

1999 2001 2003 2005 2007 2009

2.4% per year

-2.4% per year

____ TB ____ MDR-TB

1

10

100

1998 2000 2002 2004 2006 2008

-6.7% per year

-5.1% per year

____ TB ____ MDR-TB

Botswana

Tomsk Oblast, Russia

Estonia

Overview of the presentation

• Background – Global TB burden

• Challenges in introducing new TB drugs/regimens

• Developing Guidance to countries

• A pluri-partners model

Current TB Therapy and Unmet Needs

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

Patient Population Current Therapy Unmet Needs

Drug-SusceptibleDS-TB

4 drugs; 6 month therapy (2RHZE + 4RH) Shorter, simpler therapy

Drug-ResistantM(X)DR-TB

At least 4 drugs (including injectable); ≥18 months;poorly tolerated

Fully oral, shorter and safer therapy

TB/HIVco-Infection

Drug-drug interactions (DDI) with ARVs

No or low DDI, co-administration with ARVs

Latent TBInfection 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-TBAdapted from TB Alliance

Lead Optimization Preclinical Development

GLP Tox. Phase I Phase II Phase III

GatifloxacinMoxifloxacinRifapentineDelamanid (OPC67683)

Bedaquiline (TMC-207)PA-824LinezolidSQ-109RifapentineNovel Regimens2

PNU-100480

AZD5847CPZEN-45SQ641SQ609DC-159aQ201

Preclinical DevelopmentDiscovery1 Clinical Development

NitroimidazolesMycobacterial Gyrase InhibitorsRiminophenazinesDiarylquinolineTranslocase-1 InhibitorMGyrX1 inhibitorInhA InhibitorGyrB inhibitorLeuRS InhibitorPyrazinamide AnalogsSpectinamidesChemical 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.php2 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

• 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

Overview of the presentation

• Background – Global TB burden

• Challenges in introducing new TB drugs/regimens

• Developing guidance to countries

• A pluri-partners model

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.

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

• 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

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)

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)

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)

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)

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)

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)

Overview of the presentation

• Background – Global TB burden

• Challenges in introducing new TB drugs/regimens

• Developing Guidance to countries

• A pluri-partners model

• 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

• 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

• 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

• 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

Thank you for your attention !