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The use ofbedaquiline in

the treatment ofmultidrug-resistanttuberculosisInterim policy guidance


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Tis guidance was developed in compliance with the process for evidence gathering, assessment andformulation of recommendations, as outlined in the WHO Handbook for Guideline Development on,

2012 available at http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pdf.WHO Library Cataloguing-in-Publication Data

Te use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policyguidance.

1.Bedaquiline. 2.Antitubercular agents administration and dosage. 3.uberculosis, Multidrug-Resistant drug therapy. 4.reatment outcome. 5.Guideline. I.World Health Organization.

ISBN 978 92 4 150548 2 (NLM classification: WF 360)

World Health Organization 2013

All rights reserved. Publications of the World Health Organization are available on the WHOweb site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail:[email protected]).

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Te designations employed and the presentation of the material in this publication do not

imply the expression of any opinion whatsoever on the part of the World Health Organizationconcerning the legal status of any country, territory, city or area or of its authorities, or concerningthe delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate borderlines for which there may not yet be full agreement.

Te mention of specific companies or of certain manufacturers products does not imply thatthey are endorsed or recommended by the World Health Organization in preference to others ofa similar nature that are not mentioned. Errors and omissions excepted, the names of proprietaryproducts are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify theinformation contained in this publication. However, the published material is being distributed

without warranty of any kind, either expressed or implied. Te responsibility for the interpretationand use of the material lies with the reader. In no event shall the World Health Organization beliable for damages arising from its use.

Printed by the WHO Document Production Services, Geneva, Switzerland

WHO/HTM/TB/2013.6

Editing and design by Ins Communication www.iniscommunication.com


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Contents

Supporting internet materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Executive summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

List of abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. Guidance purpose and target audience . . . . . . . . . . . . . . . . . . . . . . . 15

3. Guidance development process. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4. Evidence base for policy formulation . . . . . . . . . . . . . . . . . . . . . . . . 20

5. Expert Group recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

6. WHO Interim policy recommendations . . . . . . . . . . . . . . . . . . . . . . 29

7. Dissemination and implementation . . . . . . . . . . . . . . . . . . . . . . . . . 33

Annexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Annex 1: WHO Guideline Steering Group members . . . . . . . . . . . . . . . . . . . . . . 42

Annex 2: Expert Group members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Annex 3: Expert Group meeting objectives and agenda . . . . . . . . . . . . . . . . . . . . . 4 6

Annex 4: Declarations o Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Annex 5: Glossary o GRADE terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Annex 6: External Review Panel members . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

List of Tables

able 1. Summary o evidence or the efficacy o bedaquiline in the treatment o MDR-B 22

able 2. Summary o adverse events o interest . . . . . . . . . . . . . . . . . . . . . . . . . . 23

able 3. Q prolongation during treatment as reflected by worst QcF . . . . . . . . . . . . 24

able 4. Investigator-reported hepatic events . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

able 5. rial C208 Stage 2: Causes o death. . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

able 6. Anti-tuberculosis agents or treatment o drug-susceptible and drug-resistanttuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

able 7. Te GRADE evidence profile summary . . . . . . . . . . . . . . . . . . . . . . . . . 34

able 8. Te GRADE Evidence to Recommendation. . . . . . . . . . . . . . . . . . . . . . . 36


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Supportinginternetmaterials

AcknowledgementsTis document was prepared by Christian Lienhardt, Karin Weyer, Dennis Falzon, FraserWares, Ernesto Jaramillo, Diana Weil and Mario Raviglione (World Health Organization(WHO), Stop B Department) on the basis o consensus at an international Expert Groupmeeting convened by WHO in Geneva, Switzerland on 2930 January 2013.

WHO grateully acknowledges the contributions o the Chair o the Expert Group(Holger Schnemann), and its members (Elie Akl, Adekunle V. Babawele, MauricioBaretto, Martien W. Borgdorff, Erlina Borhan, Richard E. Chaisson, Lucy Chesire,Erica Lessem, Norbert Ndjeka, Viet Nhung Nguyen, Joshua Obasanya, Michael L.Rich, Simon Schaa, Francis Varaine, Andrew Vernon, Susanne van Den Ho and Piret

Viiklepp) who jointly developed the recommendations, and the contributions rom thetechnical resource consultants (Bernard Fourie, Ekaterina Kurbatova, Charles Peloquinand Anna Vassall).

WHO also acknowledges the contributions o the members o the External ReviewPanel (Jose A. Caminero, Gavin Churchyard, Anna Marie Celina Garfin, GiovanniBattista Migliori, Ashok Kumar, Helen McIlleron, Richard Menzies, Rohit Sarin, AlenaSkrahina, Maarten van Cleeff). In addition, WHO acknowledges the specialized inputrom HIV experts Kelly Dooley, Diane Havlir and Gary Maartens, on concomitant useo bedaquiline and antiretroviral drugs.

Tis document was finalized ollowing consideration o all comments and suggestionsrom the participants o the Expert Group and the External Review Panel. echnicalediting was completed by im France, Inis Communication.

Te United States Agency or International Development (USAID) is acknowledgedor its support to the development o these guidelines through a USAID-WHOConsolidated Grant (project number: US 2012 0392). Te US Centers or DiseaseControl and Prevention is acknowledged or its contributive work on the use o sputumculture conversion as a surrogate marker o multidrug-resistant tuberculosis (MDR-B) treatment outcome (carried out by Ekaterina Kurbatova and colleagues).

Declarations of interest

All Expert Group (EG) members, technical resource consultants and members o theExternal Review Panel completed Declaration o Interest (DOI) orms. Tese werereviewed by the WHO Legal Department prior to the EG meeting and preparation othe current Interim Policy Guidance.

wo EG members (Erica Lessem and Andrew Vernon) declared receiving supportrom pharmaceutical companies or work not related to the present guidance. Tesedeclarations were deemed to be insignificant. Te other members o the EG, as well

as the technical resource consultants and the members o the External Review Panel,declared no interest.


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Executive summary

Background

Te emergence o drug resistance is a major threat to global tuberculosis (B) care andcontrol. Te World Health Organization (WHO) estimates that up to hal a millionnew cases o multidrug-resistant tuberculosis (MDR-B) cases (i.e. resistant to, at least,riampicin and isoniazid) occur each year globally. Current treatment regimens orMDR-B are ar rom satisactory: the overall duration is 20 months or more, requiring

daily administration o drugs that are more toxic and less effective than those used totreat drug-susceptible B, and have a high cost. Among MDR-B patients started ontreatment globally in 2009, only 48% were treated successully, largely as a result o ahigh requency o patient deaths (15%) and loss to ollow-up (28%), which is commonlyassociated with adverse drug reactions, among other actors. In a subset o 200extensively drug-resistant tuberculosis (XDR-B) patients in 14 countries, treatmentsuccess reached only 33% overall and 26% o the patients died. New drugs that wouldhelp build a better, saer, less toxic, shorter and cheaper regimen are thereore urgentlyneeded to reduce patient suffering and mortality.

Te landscape o B drug development has evolved dramatically over the past ten

years, and novel drugs are entering Phase III trials or the treatment o MDR-B.Among these, a new drug, bedaquiline, has recently (December 2012) been grantedaccelerated approval by the United States Food and Drug Administration (US-FDA)based on Phase IIb data. Similar submissions are currently being made to othernational regulatory authorities worldwide. WHO Member States have requested theorganization to provide interim policy guidance on the use o bedaquiline as part othe treatment o MDR-B.

It is acknowledged that developing interim guidance on the use o a new B drug onthe basis o Phase IIb trial data is a novel step or WHO. Issuing interim guidance

carries with it the responsibility o ensuring that it provides specific recommendationson the conditions or the use o the drug that reflect the limited data currently available.It will also be necessary or WHO to review, revise and/or update the interim guidanceas additional substantive data on efficacy and saety become available. Acceleration oPhase III trials and completion at the earliest opportunity is imperative, as is timelyanalysis o emerging operational data on the use o the drug. It should also be notedthat, in the absence o interim guidance rom WHO, uncontrolled and potentiallyirresponsible use o the drug may adversely affect B care and control efforts overall potentially prompting the emergence o bedaquiline resistance and the possible loss othe first new B chemotherapeutic drug in over 40 years.


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Objectives, rationale and methods used to develop the guidance

Tis document provides interim guidance or the use o bedaquiline in conjunctionwith other WHO-recommended MDR-B treatments. It also specifies the essentialtreatment and management conditions or the use o this drug. Te main audiences arenational B control programmes (NP), other public health agencies, and other publicand private partners involved in planning, implementing and monitoring MDR-Bcontrol activities. Te principles and recommendations are also relevant or specialistclinicians, technical advisors, laboratory technicians, drug procurement managers,other service providers, other relevant government officials, and implementing partnersinvolved in country-level MDR-B service strengthening. Individuals responsible orprogramme planning, budgeting, resource mobilization, and training activities orMDR-B diagnostic services may also benefit rom this guidance.

An Expert Group (EG) was convened by the WHO/Stop B Department in Geneva,Switzerland rom 29th to 30th January 2013 to assess all available data on bedaquiline,and with a view to issuing interim policy recommendations on its use, as appropriate.Since efficacy and saety data available or this drug, used or the treatment o MDR-B,are results rom Phase IIb studies only (i.e. not Phase III trials), the potential guidancecould only be provisional, until urther clinical trial and saety data are available.

Te overall objective o the EG meeting was to evaluate the added benefit o bedaquilineor the treatment o MDR-B and, i appropriate, to provide recommendations toWHO or interim guidance to countries on its use in conjunction with other second-line drugs used in MDR-B treatment.

Te specific objectives were:

(1) o evaluate the efficacy and saety o bedaquiline in addition to currently WHO-recommended MDR-B treatments.

(2) o evaluate the balance between harms and benefits o the drug, its potential cost-effectiveness, patient and provider preerences and concerns, and the easibility ointroducing the drug into MDR-B programmes.

(3) o provide, as appropriate, recommendations on the use o the drug as part o

WHO-recommended MDR-B treatment regimens, including attention toconcerns/constraints relevant to the potential use o a new drug or which Phase IIIclinical trial data are not yet available.

Te EG consisted o researchers, epidemiologists, end-users (clinicians and NPofficers), community representatives and experts in evidence synthesis. Declarations oInterest were managed according to WHO rules.

Publicly available data on the pre-clinical and clinical development o the drug werereviewed to assess efficacy, saety and tolerability o the drug, and complementedby modelling work to assess the potential cost-effectiveness o programmaticimplementation. Issues to be addressed in uture research were also discussed. In


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addition, data on final outcomes o the pivotal proo-o-concept Phase II trial (that hadnot been evaluated by the US-FDA in their accelerated regulatory assessment) were

provided to WHO by the manuacturer, allowing more comprehensive review by theEG. o comply with current standards or evidence assessment in ormulation o policyrecommendations, the GRADE system1adopted by WHO or policy and guidelinesdevelopment was used.

A PICO question2 was pre-defined in consultation with the EG: In MDR-Bpatients, does the addition of bedaquiline to a background regimen based on WHO-recommendations safely improve patient outcomes?

Te ollowing outcomes were selected by the EG or evaluation:

1. Cure by end o study 120 weeks.2. Serious adverse events during investigational 24 weeks treatment phase.

3. Mortality.

4. ime to culture conversion over 24 weeks.

5. Culture conversion at 24 weeks.

6. Acquired resistance to second-line drugs (fluoroquinolones, amino-glycosides andcapreomycin) at 72 weeks.

Summary of available data

Data were available rom a series o studies and trials made public by the manuacturer,and supplemented with final outcome results made available to WHO. Main findingson efficacy and saety originated rom two Phase IIb trials: (1) C208, a two-stage trialo which Stage 1 was an exploratory study, and Stage 2 was a multi-centre, stratified,randomized, double-blind placebo-controlled trial serving as a pivotal proo-o-efficacystudy; and (2) C209, a single-arm, open label trial.

1. Evidence for the efficacy of bedaquiline in the treatment of MDR-TB

Subjects aged 18 to 65 years with newly diagnosed pulmonary MDR-B were enrolled in

the C208 Stage 2 efficacy trial rom 15 sites in Brazil, India, Latvia, Peru, the Philippines,the Russian Federation, South Arica and Tailand; 160 subjects were randomized toreceive bedaquiline or placebo as well as a five-drug MDR-B background regimen(BR), which consisted o various combinations o fluoroquinolones, aminoglycosides,pyrazinamide, ethionamide, ethambutol, and/or cycloserine/terizidone. Bedaquilinewas given at 400 mg daily or the first 2 weeks, ollowed by 200 mg three times perweek or the remaining 22 weeks. Aer 24 weeks, subjects continued the BR o MDR-B therapy until a treatment duration o 96 weeks was achieved. Te total duration othe study was 120 weeks. An interim analysis was done at 72 weeks.

1 GRADE: Grading o Recommendation Assessment, Development and Evaluation.2 PICO: Population, Intervention, Comparator, Outcome.


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Te primary efficacy endpoint or the C208 Stage 2 trial was time to sputum cultureconversion in commercial liquid culture (MGI 960 Mycobacterial Detection System,

Becton Dickinson Diagnostic systems, USA) during the 24-week investigationaltreatment period (subjects who discontinued beore week 24 were considered as nothaving culture converted). Te analysis was conducted on a modified intention totreat population (mI) o 132 subjects (66 in each o the bedaquiline and placebogroups).3

Te median time to culture conversion was 83 days (95%CI: 56, 97) in the bedaquilinegroup versus 125 days (95%CI: 98, 168) in the placebo group. Using Cox proportionalhazards model (adjusted or lung cavitation and pooled centre) there was a higher chanceo aster culture conversion in the bedaquiline arm compared with the placebo arm(HR=2.44 [1.57, 3.80], p20.0% o subjects) were nausea (35.3%), arthralgia (29.4%),headache (23.5%), hyperuricaemia (22.5%), and vomiting (20.6%). Te incidence o

these AEs was generally similar in the Any bedaquiline and the Any placebo groups,except or headache (in 23.5% and 11.4% o subjects, respectively), nausea (35.3% and25.7%, respectively), and arthralgia (29.4% and 20.0%, respectively). Additional AEswere, in order o requency: dizziness, increased transaminases, myalgia, diarrhoea andQ prolongation on electrocardiogram (ECG). Tere was a higher incidence o eventsrelated to hepatic disorders (mostly increases in transaminases) in the Any bedaquilinegroup compared to the Any placebo group. Q prolongations were observed in boththe bedaquiline and placebo groups, but were more pronounced in the bedaquiline

3 Te mI-excluded subjects who had drug-susceptible B, XDR- or unconfirmed MDR-B

(based on susceptibility tests taken prior to randomization), or had missing or negative baselinecultures, or who were positive at baseline, but had no post-baseline culture results.


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group: more patients had QcF4values above 450 ms (26.6% versus 8.6%) and morepatients had QcF increases >60 ms rom reerence values (9.1 % versus 2.5%). Te use

o bedaquiline with other potential Q prolonging medications (e.g. cloazimine) wasound to increase the risk o prolonged Q interval.

welve deaths were reported rom the C208 Stage 2 trial in total (i.e. irrespective owhen deaths occurred). O these, 10/79 (12.7%) came rom the bedaquiline groupand 2/81 (2.5%) rom the placebo group (p=0.017) (intention to treat analysis). Inthe bedaquiline group, 8 o the 10 deaths occurred in culture converters. B wasreported to be the cause o death in the two placebo-arm deaths and in 5 o the 10bedaquiline-arm deaths (all occurred off bedaquiline treatment). Counting deathsstrictly at the 120 weeks cut-off point revealed nine in the bedaquiline and one inthe placebo group. Tere were no discernible associations between death and cultureconversion, relapse, microbiological response, susceptibility to drugs used in the BR,human immunodeficiency virus (HIV) status, or severity o B-related disease. Despitedetailed descriptive line listings o all deaths, the reasons or the imbalance in deathsbetween the two arms were not identified.

Expert Group findings

Te EG concluded that the randomized, double-blind, design o the pivotal study waso high quality, although inormation on the desired sample size and on the actual

randomization process was not available. Te EG was, however, concerned about the useo mI analysis (and subsequent assumptions made), as well as the representativenesso the study population. Experts were also concerned about the low cure rate at 120weeks observed in the placebo group, when compared to those reported rom recentpublished reviews. Tis could indicate that the patients included in the trial were notrepresentative o the MDR-B population at large and that the effects observed in thebedaquiline arm may not be reproducible under programme conditions.

Concern was also expressed that, in the absence o patient data on drug susceptibilitytest status in the different arms, the BR used in various sites o the trial may not havebeen compliant with WHO recommendations. Tere was urther concern on the

generalizability o the data to the target patient group (e.g. a greater proportion o HIVco-inected B cases occurred in the placebo arm; XDR-B patients were excluded).Lastly, there was concern on the generalizability o study findings to all populationsand to all regions in the world. Te overall quality o evidence or efficacy was thereoregraded as Low, i.e. the EG had low confidence in the estimate o effect (or efficacy) obedaquiline.

Te EG expressed concern on the risk o Q prolongation and the additive effect incombination with other MDR-B drugs reported to prolong Q. Te EG also expressedconcerns regarding co-morbidities (notably HIV inection and liver diseases), and the

4 QcF: Q interval corrected or heart rate according to the Fridericia method.


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effects o alcohol or substance use on the risk o severe adverse events. Te evidence orsaety as reflected by AEs was thereore graded as Very low.

Te EG was highly concerned with the observed difference in mortality between thebedaquiline and placebo arms in the C208 stage 2 trial. No clear pattern could beobserved, and reason(s) or the imbalance were unclear. Te quality o evidence ormortality as a measure o saety was thereore graded as Very low.

Lastly, the EG had concerns about the available data on emergence o resistance, due toa high risk o bias, as serial drug susceptibility data on patient strains were not provided(i.e. at enrolment and during ollow-up). Te quality o evidence or acquisition oresistance to fluoroquinolones, aminoglycosides or capreomycin was, thereore, gradedas Very low.

Modelling o the incremental cost-effectiveness o adding bedaquiline to WHO-recommended MDR-B regimens was conducted by an independent consultantcontracted by WHO or review by the EG. Te model assumed that bedaquiline wouldbe added to treatments or all patients starting MDR-B treatment. Data rom WHOwere available on current MDR-B treatment costs (excluding programme costs)and effectiveness in several high B burden settings. Several scenarios were exploredto appraise the cost-effectiveness o bedaquiline in these settings. Under the modelassumptions, the bedaquiline-containing regimens were assessed as relatively cost-effective in most settings, but results were ambiguous in low-income settings and

highly dependent on the assumptions made about the generalizability o trial resultsto routine settings. Te EG noted that urther analysis would be needed to test therobustness o the assumptions in various settings and to separately assess affordability.As the recommendation o the EG was to use bedaquiline only or selected sub-groupso the ull MDR-B patient population, as opposed to all patients with MDR-B thatwere considered in the cost-effectiveness analysis, the cost-effectiveness model needsto be urther refined such that results are available or these sub-groups specifically.

Te final grading o evidence or the use o bedaquiline in MDR-B treatment wasVery low. Tere was modest agreement among the EG that the quality o evidence orpossible benefits was Low due to imprecision and indirectness, and high agreement

that the quality o evidence or possible harms was Very low due to imprecision,indirectness and risk o bias. Te EG could not reach consensus, however, on theoverall balance o harms and benefits and proceeded to a vote (observers and technicalresources consultants were excluded). Te results were as ollows: 10 votes that benefitsoutweighed harms; 4 votes that harms outweighed benefits; and 2 abstentions (includingthe chair).

Expert Group recommendations

Te EG suggested that, as an interim recommendation, bedaquiline may be added

to a WHO-recommended regimen in adult MDR-B patients under the ollowing


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implementation, ideally through observational cohorts, where the ollowing measuresare in place. Te WHO recommendation or the inclusion o bedaquiline in the adult

treatment regimen o MDR-B is subject to the ollowing five conditions being met:1. Treatment is administered under closely monitored conditions,adhering to best

practices in treatment delivery, to enable optimal drug effectiveness and saety. Giventhat the results o the Phase IIb trial showed an excess mortality in the bedaquilinearm versus placebo arm, and that results o Phase III trials are only expected a ewyears rom now, it is particularly important that the introduction o bedaquilineis careully monitored or saety. It is thereore recommended that the ollowingmeasures are in place:

a. Sound treatment and management protocols, including clear patient eligibilitycriteria, procedures or inormed consent and defined roles and responsibilities

o all proessionals involved. Te treatment protocols should allow or theprospective capture o data on key variables or both effectiveness andsaety. Saety concerns are best addressed using the cohort event monitoringmethodology employed or active pharmacovigilance. Electronic systems willacilitate efficient data management and generation o key indicators.

b. reatment protocols are preerably submitted to and approved by the relevantnational ethics authority in the country, prior to patient enrolment on treatment.

c. Preerably, oversight o treatment and management programmes is providedby an independent group o experts in clinical management and public health or instance, such as a national MDR-B advisory group.

2. Proper patient inclusion.Te current recommendation or the use o bedaquilineapplies to adults (18yrs) with pulmonary disease. Special caution is neededwhen bedaquiline is used in persons aged 65 years and older, and in adults livingwith HIV, as data on efficacy and saety are extremely limited. Use o the drug inpregnant women and children is not advised due to a lack o evidence on saety andefficacy. While patients with exclusive extrapulmonary disease were not includedin the bedaquiline trial, the use o the drug in extrapulmonary B patients may beconsidered, extrapolating rom the data in patients with pulmonary B.

3. Patient informed consent obtained.Health-care providers should ensure that thepatient is: (i) aware o the novel nature o bedaquiline; (ii) appreciates the reasonwhy the drug is being proposed to be included in the regimen; and (iii) recognizesthe benefits and potential harms. In addition, health-care workers should obtainthe patients agreement on the inclusion o bedaquiline in the prescribed treatmentregimen. Tis inormed consent process must be documented and signed by thepatient, and applies to all situations where bedaquiline is employed, including undercompassionate use programmes.

4. Adherence to principles of designing a WHO-recommended MDR-TB regimen.As uncertainties remain about the relative benefits and harms when using

bedaquiline, caution is advised when other options to compose an effective MDR-B


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regimen using conventional second-line medication still exist. In addition, theshortcomings o conventional drug-susceptibility testing (DS) o second line anti-

B drugs must be taken into account: DS o second-line drugs is only consideredto be accurate and reproducible or fluoroquinolones, aminoglycosides (kanamycin,amikacin) and capreomycin (a polypeptide).

a. Te WHO-recommended MDR-B treatment regimen is typically composedo at least pyrazinamide and our second-line drugs considered to be effective(based on drug susceptibility testing (DS) and/or previous use and/or drugresistance surveillance data): a fluoroquinolone (preerably later-generation),a second-line injectable agent, and two bacteriostatic drugs, preerablyprothionamide or ethionamide plus cycloserine or p-aminosalicylic acid.Bedaquiline may be indicated i such a regimen is not easible because o:

i) in vitro resistance to a drug (see b. and c. below );ii) known adverse drug reactions, poor tolerance, or contraindication to any

component o the combination regimen; or

iii) unavailability or lack o a guaranteed supply o a drug(s).

b. MDR-B patients with strains resistant to fluoroquinolones or the second-lineinjectable drugs (kanamycin, amikacin, capreomycin) represent a particularconcern given that these are the two most effective classes o second-linedrugs. In such cases, bedaquiline may have a crucial role to play to strengthena regimen, bringing the number o drugs likely to be effective to a minimumo our, and averting the acquisition o additional resistance and progression

towards XDR-B.

c. While experience in the use o bedaquiline in the management o XDR-Bis limited, it may have an indication in such patients given the limitations indesigning an effective regimen based on existing recommendations in manysituations. In patients resistant to both classes o injectable drugs and also tofluoroquinolones (i.e. XDR-B), bedaquiline may lower the need to includedrugs belonging to Group 5, some o which have unproven anti-B activity,high cost, and/or high toxicity.5Bedaquiline may thus be used with or insteado a Group 5 drug. In these cases, special caution is advised on the potentialincrease o adverse drug reactions due to potential drugdrug interactions,

particularly the synergistic cardiotoxic effect on Q prolongation, necessitatingclose ECG monitoring.

d. In line with general principles o B therapeutics, bedaquiline should not beintroduced into a regimen in which the other companion drugs are known orbelieved to be ineffective or are ailing to show effectiveness. Tis implies thatbedaquiline should not be added alone to a ailing regimen, and should beintroduced well beore the regimen ails completely.

e. Bedaquiline should be used strictly at the dose recommended by the manuacturer,i.e. 400mg daily or the first two weeks, ollowed by 200mg three times per week

5 Group 5 drugs belong to different classes o medicines and are not recommended by WHO orroutine use in DR-B patients.


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at least 48 hours apart, or a total maximum duration o 24 weeks. Available datasuggest better uptake o bedaquiline when administered with ood.

5. Pharmacovigilance and proper management of adverse drug reactions andprevention of drugdrug interactions.

a. Special measures need to be put in place to ensure the early detection and timelyreporting o adverse events using active pharmacovigilance methods, such ascohort event monitoring. Any adverse drug reaction attributed to bedaquilineshould also be reported to the national pharmacovigilance centre as part o thespontaneous reporting mechanism in the country. As or any other drug in theMDR-B regimen the patient should be encouraged to report to the attendinghealth worker any adverse event that occurs during the time the drug is being

taken. Such occurrences should also trigger a rapid response to manage theseuntoward effects in the patient.

b. When introducing bedaquiline into a regimen, there is also the potentialor its interaction with other medications administered concurrently, withadditive or synergic adverse effects. Other second-line drugs that are likely tobe administered with bedaquiline, particularly cloazimine and moxifloxacin,may increase the risk o cardiotoxicity. Tus, i the drug is introduced into theMDR-B treatment regimen, monitoring o patients or cardiac dysrhythmiasor Q prolongation (i.e. using ECG), liver dysunction, renal impairment, andother effects as denoted in the product briefing package is mandatory.

c. Caution should be exercised when giving bedaquiline together withaccompanying drugs that may inhibit liver unction (e.g. the effect oketoconazole or lopinavir/ritonavir on the enzyme CYP3A4), as these couldincrease bedaquiline concentrations, resulting in toxicity, or with accompanyingdrugs that may induce liver unction (e.g. the effect o riampicin on the enzymeCYP3A4), as these could result in sub-therapeutic bedaquiline concentrations,resulting in reduced efficacy. O note, very limited data are available on drugdrug interactions with antiretroviral medicines, and these are based on singledose studies conducted in healthy normal volunteers. Tereore, people livingwith HIV who will be receiving bedaquiline as part o MDR-B treatmentshould have their antiretroviral therapy (AR) regimens designed in close

consultation with HIV clinicians and AR specialists.

d. Lastly, caution is advised in patients with pre-existing health conditions thatmay be exacerbated or worsened by bedaquiline. Currently there are no dataon the efficacy and saety o bedaquiline in patients with co-morbid conditionssuch as diabetes, liver and/or renal dysunction, malignancies, alcohol andsubstance use, and thereore careul screening or these conditions prior totreatment initiation is required.

WHO strongly recommends the acceleration o Phase III trials in order to generate amore comprehensive evidence base to inorm uture policy guidance on bedaquiline.

WHO strongly urges the development o accurate and reproducible DS methods orbedaquiline and other second-line drugs.


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Listofabbreviations

List of abbreviations

AE adverse events

ART antiretroviral therapy

BR background regimen

DDI drugdrug interaction

DOI declaration o interest

DST drug-susceptibility testing

ECG electrocardiogram

EG Expert Group

ERP External Review Panel

GRADE Grading o Recommendations Assessment Development and Evaluation

GRC Guidelines Review Committee

HIV human immunodeficiency virus

ITT intention to treat

MDR-TB multidrug-resistant tuberculosis

MIC minimal inhibitory concentration

mITT modified intention to treat

NTP national tuberculosis control programme

PLHIV people living with HIV

PMDT programmatic management o drug-resistant tuberculosis

STAG-TB Strategic and echnical Advisory Group or B

TB tuberculosis

USAID United States Agency or International Development

US-FDA United States Food and Drug AdministrationXDR-TB extensively drug-resistant tuberculosis

WHO World Health Organization


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Interim policy guidance

The use of bedaquiline in the treatment of multidrug-

resistant tuberculosis

1. Background

Te emergence o drug resistance is a major threat to global tuberculosis (B) careand control. Te World Health Organization (WHO) estimates that up to hal amillion cases o multidrug-resistant tuberculosis (MDR-B) cases (i.e. resistant to,at least, riampicin and isoniazid) occur each year globally.6O these, less than 20%were reported to WHO, largely as a result o critical gaps in diagnostic and treatmentcapacity in most countries. Furthermore, 84 countries have now reported at least onecase o extensively drug-resistant tuberculosis (XDR-B), a orm o B that is resistantto at least our o the core anti-B drugs (riampicin, isoniazid, fluoroquinolones andsecond-line injectable agents), and associated with high mortality, particularly amongpeople living with human immunodeficiency virus (PLHIV).

Te global deployment o new, rapid diagnostic tests or drug resistance, such as theXpert MB/RIF assay, is increasing the demand or treatment o MDR-B patients.Current treatment regimens or drug-resistant B are ar rom satisactory. Whereasmost drug-susceptible B patients can usually be treated successully with a 6-monthcourse o treatment, in most MDR-B cases a treatment duration o 20 months ormore is used, requiring the daily administration o drugs that are more toxic and lesseffective than those used to treat drug-susceptible B. Among MDR-B patients startedon treatment globally in 2009, only 48% were treated successully, as a result o highrequency o mortality (15%) and loss to ollow-up (28%), commonly associated withadverse drug reactions, among other actors.7In a subset o 200 XDR-B patients in 14

countries, treatment success only reached 33% overall and 26% o cases died. Effectivenew drugs and treatment regimens are thereore urgently needed to improve sae andeffective treatment to reduce patient suffering and deaths.

6 Global tuberculosis control: WHO report 2010(WHO/HM/B/2010.7). Geneva, World HealthOrganization, 2010.

7 Global tuberculosis control: WHO report 2012(WHO/HM/B/2012.6). Geneva, World HealthOrganization, 2012.


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Te landscape o B drug development has evolved dramatically over the past tenyears, and novel drugs are presently, or will soon be, entering Phase III trials or the

treatment o MDR-B. Among these, the bedaquiline compound, proposed or use inthe treatment o MDR-B, has been granted license by the United States Food and DrugAdministration (US-FDA) in December 2012. Files have been submitted to a numbero other national regulatory authorities, which are currently being evaluated underprocedures o accelerated or conditional approval based on early (Phase IIb) clinicaldata. Several WHO Member States have requested the organization to provide interimadvice on the use o bedaquiline in MDR-B treatment. For these reasons, WHOconvened an Expert Group (EG) meeting rom 29th to 30th January 2013 in Geneva,Switzerland to review the available evidence on the efficacy, saety and effectiveness othis new drug or the treatment o MDR-B, and to recommend whether WHO interim

guidance on the use o this drug as part o the treatment o MDR-B is warranted.

It is acknowledged that developing interim guidance on the use o a new B drug onthe basis o Phase IIb data only is a novel step by WHO, and one made in response torequests rom WHO Member States or specific guidance. Issuing interim guidancecarries with it the responsibility o ensuring that it provides specific recommendationson the conditions or the use o the drug, which reflect the limited data that is currentlyavailable. It will also be necessary or WHO to review, revise or update the interimguidance as additional substantive data on efficacy and saety o bedaquiline becomeavailable. Acceleration o Phase III trials and completion at the earliest opportunity isimperative, as is timely analysis o emerging operational data on the use o the drug. It

should also be noted that, in the absence o interim guidance rom WHO, uncontrolledand potentially irresponsible use o the drug may adversely affect B care and controlefforts overall potentially prompting the emergence o bedaquiline resistance and thepossible loss o the first new B drug in over 40 years.

2. Guidance purpose and target audience

2.1. Purpose

Te overall objective o this guidance is to provide the interim principles that shouldguide the use o bedaquiline a newly available drug or the treatment o MDR-B, alie-threatening orm o tuberculosis in conjunction with other WHO-recommendedMDR-B treatment regimens. It also specifies the essential treatment and managementconditions or use o this drug, in particular patient eligibility criteria and saetyconditions, and presents the necessary caveats relevant to the use o a new drug orwhich Phase III clinical trial data are not yet available.


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WHO guidelines are already available or the programmatic management o drug-resistant tuberculosis (PMD), and the current document should be read in conjunction

with those guidelines.8, 9

Tis document should be read in conjunction with the detailed findings included inthe EG meeting report. Te interim guidance positions bedaquiline in the context oexisting guidelines on MDR-B treatment, as the drug cannot be used on its own andshould be added to MDR-B regimens designed according to WHO-recommendedprinciples.

Manuals and tools to operationalize the interim guidance and introduce bedaquilinewithin a programmatic context will be provided in subsequent WHO publications.

Te planned date o review o this interim guidance is 2015, or earlier in case osignificant developments. It is expected that data emerging rom planned Phase IIIclinical trial(s) and early implementing countries will inorm uture review and possiblerefinement o the interim policy guidance.

2.2 Target audience

Te main target audiences are national B control programmes (NP), otherpublic health agencies, and other public and private partners involved in planning,implementing and monitoring tuberculosis control activities. Te principles and

recommendations are also relevant or specialist clinicians, technical advisors,laboratory technicians, drug procurement managers, other service providers, otherrelevant government officials, and implementing partners involved in country-levelMDR-B service strengthening. Individuals responsible or programme planning,budgeting, resource mobilization, and training activities or B diagnostic servicesmay also benefit rom this guidance.

3. Guidance development process

Te process developed by the Guideline Review Committee (GRC) o WHO was

strictly ollowed. A WHO Guideline Steering Group was ormed (see Annex 1), whichidentified, together with the chair o the EG (see below), the areas requiring evidencesynthesis.

8 Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008.(WHO/HM/B/2008.402). Geneva, World Health Organization, 2008.

9 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update . Geneva:World Health Organization, 2011.


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3.1 Expert Group meeting

An EG meeting was convened by the WHO Stop B Department rom 29th to 30thJanuary 2013 to assess all available data on bedaquiline, and with a view to developinginterim policy recommendations on its use, as appropriate. Te EG (Annex 2) comprisedresearchers, epidemiologists, end-users (clinicians and national B programmeofficers), community representatives and evidence synthesis experts. Te EG meetingollowed a structured agenda (Annex 3) and was chaired by a clinical epidemiologist/methodologist with expertise and extensive experience in evidence synthesis andguideline development.

Te overall objective o the EG meeting was to evaluate the added benefit o bedaquilineor the treatment o MDR-B and, i appropriate, to provide recommendations to

WHO or interim guidance to countries on its use in conjunction with other second-line drugs used in MDR-B treatment.

Te specific objectives were:

1. o evaluate the efficacy and saety o bedaquiline in addition to currently WHOrecommended MDR-B treatment regimens.

2. o evaluate the balance between harms and benefits o the drug, its potential cost-effectiveness, patient and provider preerences and concerns, and the easibility ointroducing the drug into MDR-B programmes.

3. o provide, as appropriate, recommendations on the use o the drug as part o WHO-recommended MDR-B treatment regimens, including attention to concerns/constraints relevant to the use o a new drug or which Phase III clinical trial dataare not yet available.

3.2 Management of conflicts of interest

WHO policies on conflicts o interest were developed and applied in consultationwith the WHO Legal Department. Every member o the EG was asked to completethe WHO Declaration o Interest (DOI) orm beore their invitation was confirmedand data shared with them under non-disclosure agreements. All completed ormswere reviewed by the WHO Guideline Steering Group in conjunction with theWHO Legal Department prior to the EG meeting. Particular attention was given topotential conflicts o interest related to the appraisal o evidence, the ormulation orecommendations and the external peer review process. Particular attention was alsogiven to assessment o financial as well as intellectual interests. In addition, individualswho were involved in clinical trials conducted by the bedaquiline manuacturer, or inany entity or committee related to the conduct o any trial conducted by the company(e.g. trial steering committee, data monitoring committee, scientific advisory board),even i not remunerated, as well as individuals who had been involved in developmentand testing o the new drug or other, potentially competing, drugs were not considered

or inclusion in the EG.


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DOI statements were summarized by the WHO/Stop B Department (SB) secretariatat the start o the meeting. A summary is attached in Annex 4.

echnical resource consultants participated in the meeting and provided specificinormation on selected technical issues but were not involved in the decision-making process, or in the preparation o the actual recommendations. Observersparticipated only at the request o the Chair and did not contribute to the preparationo the recommendations. All participants signed a confidentiality agreement and werereminded o the need or confidentiality until the ull WHO process had been concluded.

3.3 Review of evidence

Publicly available data on the pre-clinical and clinical development o the drug wereassembled and reviewed to assess efficacy, saety and tolerability o the drug,10 andcomplemented by modelling work to assess the cost-effectiveness o implementation othe drug in MDR-B programmes. Issues to be addressed in uture research were alsodiscussed. In addition, data on final outcomes o the pivotal proo-o-efficacy Phase IItrial (that were not available at the time o US-FDA review) were provided to WHO bythe manuacturer.

An independent consultant was contracted to review and synthesize all available datainto a comprehensive document that was made available to all members o the EG, andprepare the dra GRADE11evidence tables that were reviewed by the EG.

o comply with current standards or evidence assessment in ormulation o policyrecommendations, the GRADE system, adopted by WHO or all policy and guidelinesdevelopment,12was used. Te GRADE approach, assessing both the quality o evidenceand strength o recommendations, aims to provide a comprehensive and transparentapproach or developing policy guidance. Te GRADE process assesses the impact oa particular intervention on patient-important outcomes and the generalizability oresults to the target population, taking into consideration the comparator used andwhether comparison was direct or indirect.

A PICO (Population, Intervention, Comparator, Outcome) question was pre-defined inconsultation with the WHO EG: In MDR-B patients, does the addition of bedaquilineto a background regimen based on WHO-recommendations safely improve patientoutcomes?

10 All available at: http://www.da.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InectiveDrugsAdvisoryCommittee/ucm293600.htm

11 GRADE: Grades o Recommendation Assessment, Development and Evaluation(www.gradeworkinggroup.org).

12 WHO Handbook for Guideline Development, 2012. Geneva, World Health Organization, 2012.Available at: http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pd


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Te ollowing outcomes were selected by the EG or evaluation:

1. Cure by end o study 120 weeks.

2. Serious adverse events during investigational 24 weeks treatment phase.

3. Mortality.

4. ime to culture conversion over 24 weeks.

5. Culture conversion at 24 weeks.

6. Acquired resistance to second-line drugs (fluoroquinolones, amino-glycosides andcapreomycin) at 72 weeks.

In a first stage, experts evaluated the quality of evidenceor each o the above outcomesaccording to the ollowing criteria:

Study design: randomized trial(s), or consecutive selection o patients (observational),or selection o patients according to given reerence standard (case-control).

Risk o bias or limitations in study design and execution.

Inconsistency: unexplained inconsistency in study endpoints or estimates.

Indirectness: absence o direct evidence o impact on patient-important outcomesand generalizability.

Imprecision: wide confidence intervals or treatment outcome estimates.

Other considerations: possibility o publication bias, etc.

A glossary o the GRADE terms used can be ound in Annex 5.

In the second stage, as called or by GRADE, and based on the PICO question, the EGdeveloped a recommendation and considered the strength o the recommendation(strong or conditional), based on a balance o effects (benefits weighed against harms),patient values and preerences, resources and equity. Te system used to establish thestrength and ranking o the recommendations involved assessing each interventionon the basis o: (1) desirable and undesirable effects; (2) quality o available evidence;(3) values and preerences related to interventions in different settings; and (4) costoptions or different epidemiological settings.

3.4 Decision-making during the Expert Group meeting

Te EG meeting was chaired by a recognized methodologist/evidence synthesis expert.Decisions were based on consensus (preerred option). Only exceptionally, when aconsensus could not be achieved among members, did the EG proceed to a vote (withsimple majority rule) this was resorted to in only one instance (see page 27). Concernsand opinions o EG members were noted and included in the final meeting report. Tedetailed meeting report was prepared by the WHO Secretariat Steering Group and wasrevised based on input and sign-off by all EG members.


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3.5 External peer review

An External Review Panel (ERP) independently reviewed the dra interim guidanceprepared by the WHO Guideline Steering Group on the basis o the recommendationsby the EG. Te ERP was composed o 10 reviewers external to the EG, including contentexperts, end-users rom high B and HIV burden countries, and representatives romthe WHO Strategic and echnical Advisory Group or B (SAG-B). Te list omembers o the ERP can be ound in Annex 6. Comments made by the members o theERP were reflected in the final version o the guidance document.

3.6 Financial support

Financial support or the EG meeting and related analyses were provided under the

USAID consolidated grant to the WHO Stop B Department (project number: US2012 0392). Te US Centers or Disease Control (CDC) completed the evaluationo sputum culture conversion as a surrogate marker o MDR-B treatment outcome(work carried out by Ekaterina Kurbatova and colleagues).

4. Evidence base for policy formulation

Publicly available data on the pre-clinical and clinical development o bedaquiline werereviewed. Tese included toxicity, dosing and pharmacokinetic studies, drugdruginteraction (DDI) studies, an early bactericidal activity study, saety studies, a pivotalPhase IIb clinical trial and an (ongoing) single arm open-label trial.13,14

A total o 265 subjects participated in 11 Phase I trials with bedaquiline (208 subjectswere enrolled in eight single-dose trials evaluating bedaquiline doses up to 800 mg;and 57 subjects were enrolled in three multiple-dose trials evaluating bedaquilinedoses up to 400 mg daily with a maximum treatment duration o 15 days). Te Phase Itrials provided a basic understanding o bedaquilines pharmacokinetic characteristics,DDI potential, and short-term saety/tolerability in healthy subjects and in a specialpopulation o moderately hepatic-impaired subjects. A double-blind, single-dose trialwas conducted to evaluate the effect o a single supra-therapeutic (800 mg) dose o

bedaquiline on the Q corrected (Qc) interval.

A Phase IIa, 7-day extended early bactericidal activity trial in 75 patients with drug-susceptible B (evaluating doses up to 400 mg bedaquiline daily) was conducted toevaluate clinical antimycobacterial activity o bedaquiline.

13 Janssen Pharmaceutical Companies, 2012. MC207 (bedaquiline) treatment of patients with MDR-B (NDA 204384). Briefing document to the Anti-Inective Drugs Advisory Committee Meeting,28 November 2012. All documents available at: http://www.da.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InectiveDrugsAdvisoryCommittee/ucm293600.htm

14 Reerences or all documents available on bedaquiline can be ound at the website indicated inpage 1 o this document.
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm293600.htmhttp://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm293600.htmhttp://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm293600.htmhttp://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm293600.htm


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Te bedaquiline Phase II programme encompassed 2 Phase IIb clinical trials: C208and C209. rial C208 consisted o two stages, o which Stage 1 was an exploratory

study and Stage 2 was a multi-centre, stratified, randomized, double-blind placebo-controlled trial, serving as a pivotal proo-o-efficacy study. Study C209 is a single-arm,open label trial (ongoing).

4.1 Evidence for the efficacy of bedaquiline in the treatment of MDR-TB

Evidence or efficacy derives rom the C208 Stage 2 trial, in which subjects aged 18to 65 years with newly diagnosed MDR-B enrolled rom 15 sites in Brazil, India,Latvia, Peru, the Philippines, the Russian Federation, South Arica and Tailand wererandomized in a 1:1 ratio to receive bedaquiline 400 mg, or placebo, daily or the first

two weeks, ollowed by 200 mg bedaquiline, or placebo, three times per week or theremaining 22 weeks.15In both the bedaquiline and placebo arms, patients received a five-drug MDR-B background medication regimen (BR) consisting o fluoroquinolones(mainly ofloxacin), aminoglycosides (mainly kanamycin), pyrazinamide, ethionamide,ethambutol, and cycloserine/terizidone in various combinations. Aer 24 weeks,subjects continued the BR o MDR-B therapy until a total treatment duration o96 weeks was achieved. Te total duration o the study was 120 weeks. All subjectspresented in the data sets completed Week 72 (the pre-determined study data cut-offpoint) and also Week 120 (end o study).

Teprimary efficacy endpoint for C208 Stage 2 was time to sputum culture conversion16

in commercial liquid culture (MGI 960 Mycobacterial Detection System, BectonDickinson Diagnostic systems, USA) during the 24-week investigational treatmentperiod, evaluated aer all subjects had completed the 24-week investigationaltreatment period, or discontinued earlier. In the primary efficacy analysis, subjects whodiscontinued beore week 24 were considered as not having culture converted (censoredat the last culture visit, i.e. missing = ailure). Primary efficacy analysis was based on amodified intention to treat (mI) population, which excluded subjects who had drug-susceptible B, XDR-B or unconfirmed MDR-B (based on susceptibility tests takenprior to randomization), or had missing or negative baseline cultures, or who werepositive at baseline, but had no post-baseline culture results. Te mI population

was composed o 132 subjects (66 in each o the bedaquiline and placebo groups).Te median time to culture conversion was 83 days (95%CI: 56, 97) in the bedaquilinegroup compared to 125 days (95%CI: 98, 168) in the placebo group. Primary analysisat Week 24 using the Cox proportional hazards model (adjusted or lung cavitation andpooled centre) showed a statistically significant difference in time to culture conversion

15 Tis dose regimen was selected based on non-clinical saety and microbiology data as well assaety and pharmacokinetic results rom several Phase I clinical trials with bedaquiline, and earlybactericidal activity results rom the earlier Phase IIa trial C202.

16 Defined as: two consecutive negative cultures rom sputa collected at least 25 days apart (as wellas all intermediate cultures), and this culture negativity was not ollowed by a confirmed positive

MGI culture (or a single positive sputum result aer the subject completed the trial), and thesubject did not discontinue up to the time point being analyzed.


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between the two treatment groups in avour o bedaquiline: HR=2.44 [1.57, 3.80](p


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Similar numbers o patients in the bedaquiline group and placebo group reportedadverse events (AEs) (able 2). Te most requently reported AEs in the bedaquiline

group (rom both controlled and uncontrolled trials) were nausea, arthralgia, headacheand vomiting. Additional AEs identified were, in order o requency: dizziness, increasedtransaminases, myalgia, diarrhoea and Q prolongation on electrocardiogram (ECG).AEs o at least grade 3 were similar in both groups: 28/102 (27.5) in the bedaquilinegroup and 24/105 (22.9) in the placebo group. Main saety concerns included Qprolongation and cardiac events, hepatic events, and deaths.

Table 2. Summary of adverse events of interest

Bedaquiline/BR

N=79 (%)

Placebo/BR

N=81 (%)

Musculoskeletal and connective tissue 39 (49.4) 40 (49.4)

Myalgia 6 (7.6) 7 (8.6)

Musculoskeletal pain 4 (5.1) 4 (4.9)

Rhabdomyolysis/Myopathy 0 0

Gastrointestinal disorders 53 (67.1) 53 (65.4)

Pancreatitis 1 (1.3) 0

Increased amylase 2 (2.5) 1 (1.2)

Nausea 32 (40.5) 30 (37.0)

Vomiting 23 (29.1) 22 (27.2)

Upper abdominal pain 10 (12.7) 7 (8.6)

Gastritis 7 (8.9) 16 (19.8)

Cardiovascular safety (rial C208: pooled experience Stage 1 and Stage 2)

Mean QcF17increases were observed in both the pooled bedaquiline (Any bedaquiline)and pooled placebo (Any placebo) groups, but they were more pronounced in the Anybedaquiline group: more patients had QcF values above 450 ms (26.6% versus 8.6%)and more patients had QcF increases >60 ms rom reerence values (9.1 % versus2.5%). Tere were no reports o orsade de Pointes events, and no reported atalitiesrom sudden death. Bedaquiline, in multiple dosing, can prolong the Q interval andthe risk is highest during the treatment phase, but could extend beyond the treatmentperiod. Te use o bedaquiline with Q-prolonging medications increases the risk oprolonged Q interval, i.e. QcF prolongation rom multiple QcF prolonging drugscould be additive (e.g. cloazimine).

17 QcF: Q interval corrected or heart rate according to the Fridericia method.


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Table 3. QT prolongation during treatment as reflected by worst QTcF

ECG parameter,

abnormality

Investigational treatment phase: pooled controlled trials

Bedaquiline (Any)

N (%)

Placebo (Any)

N (%)

QcF calc (ms)

450 ms 480 ms

480 ms 500 ms

More than 500 ms

102

23 (22.5)

3 (2.9)

1 (1.0)

105

7 (6.7)

1 (1.0)

0

QcF calc (ms)

Increase by 3060 ms

Increase by >60 ms

99

52 (52.5)

10 (10.1)

101

33 (32.7)

4 (4.0)

N = number of ITT subjects with data; QTcF: QT interval corrected for heart rate to the Fridericia method.

Hepatic events (rial C208: pooled experience Stage 1 and Stage 2)

Tere was a higher incidence o events related to hepatic disorders in the Anybedaquiline group (9 subjects, 8.8%) compared to the Any placebo group (2 subjects,1.9 %). Increases in transaminases accounted or the majority o these reported events.An analysis to identiy cases o severe liver toxicity revealed 1 case o a patient whoexperienced concurrent >3-old elevation o aspartate aminotranserase (AS) and>2-old elevation in total bilirubin, but was conounded by reported alcoholic hepatitisand concurrent intake o hepatotoxic background medications.

Table 4. Investigator-reported hepatic events

Investigator-reported events Bedaquiline 24 weeks (N=79) Placebo 24 weeks (N=81)

Liver-related signs/symptoms 8 (10%) 3 (3.7%)

Hepatic disorders 10 (12.5%) 5 (6.7%)

Possible hepatic-related disorders 10 (12.5%) 5 (6.7%)

Hepatitis (non-inectious) 2 (2.5%) 1 (1.23%)

Hepatic ailure, fibrosis, cirrhosis, liver

damage-related conditions

1 (1.25%) 0

Mortality

Four deaths were reported rom the C208 Stage 1 trial: 2 out o 23 subjects (8.7%)in the bedaquiline arm and 2 out o 24 subjects (8.3 %) in the placebo arm. In theC208 Stage 2 trial, twelve deaths were reported in total (irrespective o when deathsoccurred). O these, 10/79 (12.7%) came rom the bedaquiline group and 2/81 (2.5%)rom the placebo group (p=0.017) (I analysis). In the bedaquiline group, 8 o the 10deaths occurred in culture converters. B was the cause o death in the two placebo-

arm deaths and in 5 o the 10 bedaquiline-arm deaths (all occurred off bedaquilinetreatment). Counting deaths strictly at the 120 weeks cut-off point reveal nine deaths in


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the bedaquiline and one death in the placebo group. Tere was no discernible patternbetween death and culture conversion, relapse, microbiological response, susceptibility

to drugs used in the BR, HIV status, or severity o disease. Despite detailed descriptiveline listings o all deaths, the reason(s) or the imbalance were not clear.

Table 5. Trial C208 Stage 2: Causes of death

Subject Treatment arm Category Cause of death

Deaths while followed during trial

2084041 BDQ Non-responder; converted; discontinued Alcohol poisoning

2084153 BDQ Non-responder; relapse B-related illness


2085069 BDQ Non-responder; converted; discontinued Cirrhosis, hepatitis, anaemia

2084399 BDQ Responder; converted Cerebrovascular accident

2085067 BDQ Responder; converted Peritonitis and septic shock

2084120 Placebo Non-responder; ailure to convert Haemoptysis (B)

Deaths during long-term survival follow-up of prematurely withdrawn subjects

2084127 BDQ Non-responder; ailure to convert B-related illness


2084378 BDQ Non-responder; relapse Motor vehicle accident

2084464 BDQ Non-responder; ailure to convert B-related illness

2084155 Placebo Non-responder; ailure to convert B-related illness

4.3. Cost effectiveness

Modelling o the incremental cost-effectiveness o adding bedaquiline to WHO-recommended MDR-B regimens was conducted by an independent consultantcontracted by WHO or review by the EG. Te model assumed that bedaquiline wouldbe added to treatment or all patients starting MDR-B treatment. Data rom WHOwere available on current MDR-B treatment costs (excluding programme costs)and effectiveness in several high B burden settings. Several scenarios were exploredto appraise the cost-effectiveness o bedaquiline in these settings. Under the modelassumptions, the bedaquiline-containing regimens were assessed as relatively cost-effective in most settings, but results were ambiguous in low-income settings, andhighly dependent on the assumptions made about the generalizability o trial resultsto routine settings. Te EG noted that urther analysis would be needed to test therobustness o the assumptions in various settings and to separately assess affordability.As the recommendation o the EG is to use bedaquiline or only selected sub-groupso the ull MDR-B patient population (as opposed to all patients with MDR-B thatwere considered in the cost-effectiveness analysis), the cost-effectiveness model needs

to be urther refined such that results are available or these sub-groups specifically.


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5. Expert Group recommendations

5.1. Summary of evidence to recommendation

Based on the GRADE process, the EG had a low level o confidence in using the availabledata or global decision-making, given that the available evidence was limited. Terewere concerns about imprecision and indirectness due to the small sample size, the useo mI (i.e. not I) analysis, and the low quality o evidence or the backgroundMDR-B treatment regimens used in the trial. In particular, the EG was concernedabout the low cure rate at 120 weeks observed in the placebo group when comparedto those reported rom recent published reviews.18,19,20 Tis could indicate that thepatients included in the trial were not representative o the MDR-B population at

large and that the effects observed in the bedaquiline arm may not be reproducibleunder programme conditions.

Te EG also discussed the potential to draw conclusions or different sub-categorieso MDR-B patients, such as patients with strains resistant to either fluoroquinolonesor injectable drugs. No evidence or use o the drug in XDR-B patients was available,since these patients were excluded rom the mI analysis. No inormation, aside romMDR-B status, was available on drug susceptibility testing at diagnosis. Members othe EG did, however, eel that the use o bedaquiline in XDR-B patients or thosewith resistance or contraindication to fluoroquinolones or injectables may have addedbenefit, given that treatment options or these patients are severely curtailed.

Te EG also concluded that recommendations could only be made on the use obedaquiline in addition to current WHO-recommended regimens. Bedaquiline shouldnot replace drugs generally recommended or MDR-B treatment unless these areconsidered ineffective.21

Tere was modest agreement that the quality o evidence or benefits was low dueto imprecision and indirectness, and high agreement that the quality o evidence orharms was low or very low due to imprecision, indirectness and risk o bias. Te EGexpressed particular concern about mortality risk, with a high degree o uncertainty

about the evidence.

18 Ahuja SD et al. Multidrug resistant pulmonary tuberculosis treatment regimens andpatient outcomes: an individual patient data meta-analysis o 9,153 patients. PLoS Medicine2012;9(8):e1001300.

19 Orenstein EW et al. reatment outcomes among patients with multidrug-resistant tuberculosis:systematic review and meta-analysis. LancetInfectious Diseases2009 Mar;9(3):15361.

20 Johnston JC, Shahidi NC, Sadatsaavi M and Fitzgerald JM. reatment Outcomes o Multidrug-Resistant uberculosis: A Systematic Review and Meta-Analysis. PLoS ONE. 2009 Sep 9;4(9):e6914.

21 WHO. Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 Update.(WHO/HM/B/2011.6). Geneva, World Health Organization, 2011.


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Table 6. Anti-tuberculosis agents for treatment of drug-susceptible and drug-resistant tuberculosis

Group 1 First-line oral agents isoniazid (H); riampicin (R); ethambutol (E); pyrazinamide

(Z); riabutin (Rf) a

Group 2 Injectable agents kanamycin (Km); amikacin (Am); capreomycin (Cm);

viomycin (Vm); streptomycin (S)

Group 3 Fluoroquinolones moxifloxacin (Mx); levofloxacin (Lx); ofloxacin (Ox)

Group 4 Oral bacteriostatic second-line

agents

ethionamide (Eto); prothionamide (Pto); cycloserine (Cs);

terizidone (rd);p-aminosalicylic acid (PAS)

Group 5 Agents with unclear role in DR-B

treatment (not recommended by WHO or

routine use in DR-B patients)

cloazimine (Cz); linezolid (Lzd); amoxicillin/clavulanate

(Amx/Clv); thioacetazone (Tz); imipenem/cilastatin (Ipm/

Cln); high-dose isoniazid (high-dose H);b

clarithromycin (Clr)

aRiabutin is not on the WHO Essential Medicines List. It has been added here as it is used routinely inmany settings, among patients taking protease inhibitors.

bHigh-dose H is defined as 1620 mg/kg/day.

Te need or caution in prescribing bedaquiline was stressed, as well as the importanceo clear and understandable communication with patients prior to drug prescription.Mention was made o the need to support this by inormed consent, ideally in writing.

Te EG could not reach consensus on the overall balance o harms and benefits and

proceeded to a vote (observers and technical resources consultants were excluded).Te results were as ollows: 10 votes that benefits outweighed harms; 4 votes that harmsoutweighed the benefits; and 2 abstentions (including the chair).

Te EG elt that there were potentially large variations in patient values and preerencesor each outcome. Most members elt that patients would place high value on survivalbut that it was less clear that patients would value microbiological culture conversion inthe same way. EG members expressed the view that patient acceptance o bedaquilinewould depend on the severity o their disease and the likelihood o designing aneffective background regimen e.g. XDR-B patient groups might be more likely toaccept the risk o taking a new drug with apparent increased risk o death than patientswith uncomplicated MDR-B without additional drug resistance.

Te EG had difficulty reaching consensus on the resource requirements o the proposedrecommendation. While the cost-effectiveness modelling showed overall benefit,there were concerns about the simpliying assumptions used (e.g. no accounting orthe difference in serious adverse events, no accounting or effect on transmission,uncertainty about application o trial outcomes including deaths to routineprogrammatic conditions, etc.). Te EG also elt that cost effectiveness would notnecessarily translate into affordability or country readiness to pay given the potentiallyhigh cost o bedaquiline. Resource implications related to programme costs, training o

health care staff, and establishing active pharmacovigilance systems were not explicitly


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Te EG also recommended that these interim recommendations be re-assessed in 2015,or earlier i additional data o significance become available increasing the knowledge

on saety, toxicity and efficacy o bedaquiline (e.g. post-marketing studies, ongoingtrials and other studies).

5.3. Research implications

Te EG strongly supported the need or an acceleration o Phase III trials to expandknowledge on saety and efficacy o bedaquiline, with particular attention to mortality(including causes o death), in the treatment o MDR-B. Te EG identified urtherresearch gaps, including:

development o a reliable drug susceptibility test or bedaquiline;

pharmacokinetics, saety and efficacy studies in specific populations (inants andchildren, HIV patients especially those on antiretroviral therapy (AR), alcoholand substance users, elderly people, pregnant or nursing women, people withextrapulmonary B, people with diabetes);

saety studies, including type, requency and severity o adverse events (short andlong term), and mortality (including cause o death);

drugdrug interactions, including with other existing and newly developed Bdrugs and AR;

acquisition o resistance to bedaquiline and to other B drugs;

identification o optimal combination o drugs including bedaquiline anddetermination o optimal duration and dosing o treatment;

patient acceptability;

appropriate cost-effectiveness studies.


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6. WHO Interim policy recommendations

In view o the aorementioned evidence assessment and advice provided by the EG,WHO recommends that bedaquiline may be added to a WHO-recommended regimenin adult patients with pulmonary MDR-B (conditional recommendation, very lowconfidence in estimates of effects).

Given the limited data available on bedaquiline and its use under the various situationsthat may be encountered in different clinical settings, adequate provisions or sae andeffective use o the drug must be in place. Consequently, countries are advised to ollowa phased approach to bedaquiline implementation, ideally through observationalcohorts, where the ollowing measures are in place. Te WHO recommendation or

the inclusion o bedaquiline in the adult treatment regimen o MDR-B is subject tothe ollowing five conditions being met:

1. Treatment is administered under closely monitored conditions,adhering to bestpractices in treatment delivery to enable optimal drug effectiveness and saety. Giventhat the results o the Phase IIb trial showed an excess mortality in the bedaquilinearm versus placebo arm, and that results o Phase III trials are only expected a ewyears rom now, it is particularly important that the introduction o bedaquilineis careully monitored or saety. It is thereore recommended that the ollowingmeasures are in place:

a. Sound treatment and management protocols, including clear patient eligibility

criteria, procedures or inormed consent, and defined roles and responsibilitieso all proessionals involved. Te treatment protocols should allow or theprospective capture o data on key variables or both effectiveness andsaety. Saety concerns are best addressed using the cohort event monitoringmethodology employed or active pharmacovigilance.23Electronic systems willacilitate efficient data management and generation o key indicators.24

b. reatment protocols are preerably submitted to and approved by the relevantnational ethics authority in the country, prior to patient enrolment on treatment.

c. Preerably, oversight o treatment and management programmes is providedby an independent group o experts in clinical management and public health

or instance, a national MDR-B advisory group.2. Proper patient inclusion.Te current recommendation or the use o bedaquiline

applies to adults (18yrs) with pulmonary disease. Special caution is neededwhen bedaquiline is used in people aged 65 years and older, and in adults livingwith HIV, as data on efficacy and saety are extremely limited. Use o the drug inpregnant women and children is not advised due to a lack o evidence on saety and

23 A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis:enhancing the safety of the B patient. Geneva, World Health Organization, 2012. Available rom:http://www.who.int/medicines/publications/pharmacovigilance_tb/

24 Electronic recording and reporting for tuberculosis care and control(WHO/HM/B/2011.22).Geneva, World Health Organization, 2012.


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efficacy. While patients with exclusive extrapulmonary disease were not includedin the bedaquiline trial, the use o the drug in extrapulmonary B patients may be

considered, extrapolating rom the data in patients with pulmonary B.3. Patient informed consent obtained.Health-care providers should ensure that the

patient is: (i) aware o the novel nature o bedaquiline; (ii) appreciates the reasonwhy the drug is being proposed to be included in the regimen; and (iii) recognizesthe benefits and potential harms. In addition, health-care workers should obtainthe patients agreement on the inclusion o bedaquiline in the prescribed treatmentregimen. Tis inormed consent process must be documented and signed by thepatient, and applies to all situations where bedaquiline is employed, including undercompassionate use programmes.

4. Adherence to principles of designing a WHO-recommended MDR-TB regimen.

As uncertainties remain about the relative benefits and harms when usingbedaquiline, caution is advised when other options to compose an effective MDR-B regimen using conventional second-line medication still exist. In addition,the shortcomings o conventional drug-susceptibility testing (DS) o second-line anti-B drugs must be taken into account: DS o second-line drugs is onlyconsidered to be accurate and reproducible or fluoroquinolones, aminoglycosides(kanamycin, amikacin) and capreomycin (a polypeptide).25Evidence or accuracyand reproducibility o DS to other second-line drugs is very limited and valueor clinical decision-making is uncertain. DS or bedaquiline has not yet beenstandardized. Laboratory testing o the minimal inhibitory concentration (MIC)

o bedaquiline seems to suggest a breakpoint or susceptibility at


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ii) known adverse drug reactions, poor tolerance, or contraindication to anycomponent o the combination regimen; or

iii) unavailability or lack o a guaranteed supply o a drug.b. MDR-B patients with strains resistant to either fluoroquinolones or the

second-line injectable drugs (kanamycin, amikacin, capreomycin) representa particular concern given that these are the two most effective classes osecond-line drugs. In such cases, bedaquiline may have a crucial role to playto strengthen a regimen, bringing the number o drugs likely to be effective toa minimum o our, and averting the acquisition o additional resistance andprogression towards XDR-B.

c. While experience in the use o bedaquiline in the management o XDR-Bis limited, it may have an indication in such patients given the limitations in

designing an effective regimen based on existing recommendations in manysituations.27In patients resistant to both classes o injectable drugs and also tofluoroquinolones (i.e. XDR-B), bedaquiline may lower the need to includedrugs belonging to Group 5, some o which have unproven anti-tuberculosisactivity, high cost, or high toxicity. Bedaquiline may thus be used with or insteado a Group 5 drug. In these cases, special caution is advised on the potentialincrease o adverse drug reactions due to potential drugdrug interactions,particularly the synergistic cardiotoxic effect on Q prolongation, necessitatingclose ECG monitoring.

d. In line with general principles o B therapeutics, bedaquiline should not be

introduced into a regimen in which the other companion drugs are known orbelieved to be ineffective or are ailing to show effectiveness. Tis implies thatbedaquiline should not be added alone to a ailing regimen, and should beintroduced well beore the regimen ails completely.

e. Bedaquiline should be used strictly at the dose recommended by themanuacturer, i.e. 400mg daily or the first two weeks, ollowed by 200mg threetimes per week at least 48 hours apart, or a total maximum duration o 24weeks. Available data suggest better uptake o bedaquiline when administeredwith ood.

5. Pharmacovigilance and proper management of adverse drug reactions and

prevention of drugdrug interactions.

a. Special measures need to be put in place to ensure the early detection and timelyreporting o adverse events using active pharmacovigilance methods, such ascohort event monitoring. Any adverse drug reaction attributed to bedaquilineshould also be reported to the national pharmacovigilance centre as part o thespontaneous reporting mechanism in the country. As or any other drug in theMDR-B regimen the patient should be encouraged to report to the attendinghealth worker any adverse event that occurs during the time the drug is being

27 Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008.(WHO/HM/B/2008.402). Geneva, World Health Organization. 2008.


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taken. Such occurrences should also trigger a rapid response to manage theseuntoward effects in the patient.

b. When introducing bedaquiline into a regimen, there is also the potentialor its interaction with other medications administered concurrently, withadditive or synergic adverse effects. Other second-line drugs that are likely tobe administered with bedaquiline, particularly cloazimine and moxifloxacin,may increase the risk o cardiotoxicity. Tus, i the drug is introduced into theMDR-B treatment regimen, monitoring o patients or cardiac dysrhythmiasor Q prolongation (i.e. using ECG), liver dysunction, renal impairment, andother effects as denoted in the product briefing package is mandatory. 28

c. Caution should be exercised when giving bedaquiline together withaccompanying drugs that may inhibit liver unction (e.g. the effect o

ketoconazole or lopinavir/ritonavir on the enzyme CYP3A4), as these couldincrease bedaquiline concentrations, resulting in toxicity, or with accompanyingdrugs that may induce liver unction (e.g. the effect o riampicin on the enzymeCYP3A4), as these could result in sub-therapeutic bedaquiline concentrations,resulting in reduced efficacy. O note, very limited data are available on drugdrug interactions with antiretroviral medicines, and these are based on singledose studies conducted in healthy normal volunteers. Tereore, people livingwith HIV who will be receiving bedaquiline as part o MDR-B treatmentshould have their AR regimens designed in close consultation with HIVclinicians and AR specialists.

d. Lastly, caution is advised in patients with pre-existing health conditions thatmay be exacerbated or worsened by bedaquiline. Currently there are no dataon the efficacy and saety o bedaquiline in patients with co-morbid conditionssuch as diabetes, liver and/or renal dysunction, malignancies, alcohol andsubstance use, and thereore careul screening or these conditions prior totreatment initiation is required.

WHO strongly recommends the acceleration o Phase III trials in order to generate amore comprehensive evidence base to inorm uture policy on bedaquiline.

WHO strongly urges the development o accurate and reproducible DS methods or

bedaquiline and other second-line drugs.

7. Dissemination and implementation

WHO interim policy guidance, as well as the systematic review reports and the EGmeeting report, will be published online (www.who.int/tb/en) and disseminated

28 It should be noted that bedaquiline has a very large apparent volume o distributionand has a markedly prolonged terminal hal-lie (about 5.5 months), which reflects theslow release o the compound rom peripheral tissue compartments. See: http://www.

da.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InectiveDrugsAdvisoryCommittee/UCM329260.pd


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through WHO/SB listserves to all WHO Regional and Country Offices, MemberStates, the Stop B Partnership, donors, technical agencies and other stakeholders. As

stated above, this interim guidance will be re-assessed in 2015, or earlier i additionaldata o significance become available increasing the knowledge on saety, toxicity andefficacy o bedaquiline (e.g. post-marketing studies, ongoing trials and studies). In thisrespect, it is noted that the US-FDA made the ollowing requests to the company:

- A phase III trial in MDR-B cases, with assessment o long-term outcomes o ailureor relapse at least 6 months aer all MDR-B treatment is completed (to be submittedby March 2022).

- Establishment o a patient registry or all bedaquiline-treated patients to assess theincidence o saety concerns (with annual reporting until 2018).

- Studies to define MIC methods or bedaquiline (by 2014), and assessment o actualMICs in clinical use (by 2019).

- An in-vitro study to assess the potential o bedaquiline and its metabolite assubstrate, inducers or inhibitors o OAP1B1 and OAP1B3 drug transporters (byDecember 2013).

o acilitate the implementation o this guidance, a derivative product (i.e. operationalhow-to document) will be developed. WHO will provide guidance to programmes onmonitoring and evaluation aspects as well as on essential data to be collected.


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VALUESANDPREFERENCES

Whatarethepatientsvalues

andpreferenc

es?

Aretheassumedoridentified

relativevalues

similaracross

thetargetpopulation?

Tegreaterthesimilarity

invaluesandpreferences,

themorelikelyisastrong

recommendation.

Similarvalues

Somevariation

Largevariation

AgreeSomewhat

agree

UncertainSomewhat

disagree

Disagree

Valuesandpreferenceslikely

similar

reatmentsuccess,seriousadverseeventsand

mortalitywereconsideredimportanttopatients

whiletimetocon

versioncultureconversionand

resistancewerelessso.

Telikelihoodthatpatientswouldacceptan

effectivetreatmentregimenwoulddependon

subgroupsofthe

MDR-Bpopulatione.g.

patientswithMD

R-Bplusadditionalresistance

tofluoroquinoloneand/orinjectabledrugsmay

bemorelikelyto

accepttheriskoftakinganew

drugwithpotentialincreaseinmortalitythan

patientssufferingfromnewlydiagnosedand

provenMDR-B

.Tereisminimalvariationfor

death,largervariationforotheroutcomes

RESOURCES

Istheincrementalcost(or

resourceuse)

smallrelative

tothebenefits?

Aretheresourcesworth

theexpectednetbenefit

fromfollowin

gthe

recommendation?

Telowerthecostofan

interventioncomparedto

thealternative,andother

costsrelatedtothedecision

thatis,t

hefe

w

who review bedaquiline

Documents