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Essential Medicines List (EML) 2019 Application for the inclusion of bedaquiline in the WHO Model List of Essential Medicines for Children, as a

reserve second‐line drug for the treatment of multidrug‐resistant tuberculosis (complementary lists of anti‐

tuberculosis drugs for use in adults)

General items

1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of the forthcoming WHO Model List of Essential Medicines for Children

(EMLc) to include bedaquiline in the complementary list of anti‐tuberculosis medicines for children aged 6

years and older. It makes reference to amendments recommended to section 6.2.4 Antituberculosis

medicines of the latest edition of the 6th EMLc released in 2017 (1).

In 2014 the Global TB Programme of WHO applied for the inclusion of bedaquiline ‐ a diarylquinoline with a

novel mode of action that inhibits mycobacterial ATP synthase ‐ in the main WHO Model List of Essential

Medicines (19th EML)1. The application was favourably considered by the Expert Committee on the Selection and Use of Essential Medicines and in 2015 bedaquiline was added to the complementary list of anti‐

tuberculosis medicines for use in adults (2). The Global TB Programme now considers that bedaquiline should also be viewed as an essential medicine in children aged 6 years and older following the update by WHO of its treatment recommendations for adults and children with multidrug‐ or rifampicin-resistant (MDR/RR‐TB) in December 2018 (3). On the strength of recent data from trials, programmatic cohorts and observational

studies (Annexes 1 and 2), the 2018 guidelines have updated the first interim policy on the use of bedaquiline to treat M/XDR‐TB issued by WHO in 2013 and include an evidence-based recommendation for the use of bedaquiline in patients under 18 years of age.

Several thousand MDR‐TB and extensively drug‐resistant tuberculosis (XDR‐TB) patients have been started on bedaquiline-containing regimens in South Africa, the Russian Federation, India and elsewhere in the last few years (4). However, in many low resource settings, adults and children with M/XDR‐TB are still inadequately

treated and often die because of inadequate treatment regimens. Second‐line medicines to treat M/XDR‐TB

are frequently unavailable or unaffordable. In recent years, significant efforts have been made to increase access to bedaquiline, including the launch of a bedaquiline donation scheme and a substantial lowering of price for eligible countries purchasing bedaquiline and companion medicines from the Global Drug Facility2,3.

Bedaquiline is thus expected to become more widely available to patients worldwide.

This request to the EML is thus very timely and in line with the position of WHO, its expert advisers and its technical partners. If approved it would help build confidence by national drug regulatory authorities and TB

treatment programmes to use bedaquiline more widely. It would also synergize with global concerted efforts

to improve outcomes and reduce avoidable mortality for close to 600,000 TB patients estimated to develop MDR/RR‐TB in the world every year.

2. Name of the focal point in WHO submitting or supporting the application (where relevant) The focal point is the Unit of Laboratories, Diagnostics and Drug‐resistance of the Global TB Programme of

WHO Headquarters (WHO/HTM/GTB/LDR). The technical personnel directly concerned are Dennis FALZON and Ernesto JARAMILLO.

3. Name of the organization(s) consulted and/or supporting the application Not applicable.

1 See - https://www.who.int/selection_medicines/committees/expert/20/applications/Bedaquiline_WHO_8-May-15.pdf

2 See https://www.usaid.gov/what-we-do/global-health/tuberculosis/technical-areas/bedaquiline-donation-program

3 See http://www.stoptb.org/news/stories/2018/ns18_053.asp

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4. International Nonproprietary Name (INN, generic name) of the medicine The WHO INN (common name) of the medicine concerned is bedaquiline and ATC code J04AK054.

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) The proposed formulation is 100 mg tablet. Revised dosage schedules have been published in the 2018

updated guidelines, with a weight-based dosage for patients aged 6 -17 years (see also Annex 6 of (3)) :

16–30 kg - 2 tablets once daily for two weeks; then 1 tablet once daily on Mon/Wed/Fri for 22 weeks

>30 kg - 4 tablets once daily for 2 weeks; then 2 tablets once daily Mon/Wed/Fri for 22 weeks (i.e. adult dose)

6. International availability ‐ sources, of possible manufacturers and trade names Bedaquiline has been marketed by its manufacturer Janssen Therapeutics for use in adults with pulmonary MDR-TB under the proprietary name Sirturo(5). The US FDA awarded accelerated approval for bedaquiline on 28 December 2012 (6) and on 5 March 2014 the European Commission granted conditional approval to

Janssen‐Cilag International N.V. for Sirturo valid throughout the European Union(7). By May 2018, bedaquiline

had also been approved several low- or middle-income countries – including 11 of the 30 high MDR-TB burden countries – and was undergoing regulatory submissions in another 12 countries5.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

This request is for the inclusion of bedaquiline as an individual medicine, not as an example of its therapeutic

group, and therefore without a square box symbol.

8. Information supporting the public health relevance (epidemiological information on disease burden,

assessment of current use, target population)

In 2017 alone it was estimated that about 558,000 new MDR/RR-TB cases emerged and about 230,000 MDR/RR‐TB patients died (4). Many MDR‐TB cases go undetected and are not placed on appropriate treatment, increasing the risk that they die and/or transmit drug‐resistant strains to others. In 2017, countries reported that about 139,000 patients started MDR‐TB treatment worldwide. The effectiveness of these efforts varies considerably and outcome reports from countries in recent years showed that only about half the MDR‐TB patients complete their treatment successfully worldwide. The rest of the patients die, sustain a treatment failure, interrupt treatment, or are otherwise lost to follow up. The complexity, duration, toxicity, cost and unavailability of the treatment regimens for MDR‐TB impedes a global scale‐up of curative services. Given the low success of M/XDR‐TB treatment interventions, every effort must be made to ensure that all possible medications used to treat MDR and XDR‐TB are widely available. Facilitating the creation of regimens which are more amenable for patients and providers is therefore a priority.

The contribution of bedaquiline to MDR‐TB regimens is crucial to compose regimens, particularly in frequent situations in which other effective and safe medicines are not available. In a substantial proportion of MDR/RR‐TB patients the susceptibility to fluoroquinolones is lost and other TB medicines cannot be given because of safety concerns. Reports of sporadic cases and outbreaks of MDR-TB and XDR-TB among patients not previously treated for TB treatment attests to the transmissibility of such strains, an additional public health concern, making the provision of effective treatment for all M/XDR‐TB patients very important. The likelihood of treatment success in MDR‐TB patients diminishes with the acquisition of additional drug resistance. Bedaquiline can increase the prospects of lasting cure in these patients.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical

guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

Bedaquiline is indicated as one of the three medicines of first choice for inclusion in longer MDR‐TB regimens in patients aged 6 years and older (Group A)(3). In addition to bedaquiline, the regimen would also include a 4 See https://www.whocc.no/atc_ddd_index/?code=J04AK05

5 See http://www.tbonline.info/media/uploads/documents/2018_05_31_sirturo_regulatory_status_janssen_(1).pdf

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fluoroquinolone, linezolid plus clofazimine or cycloserine/terizidone, to start with at least 4 agents likely to be effective. If it cannot be composed with these medicines, then one or more Group C agents is added (Table 1).

Table 1. Grouping of medicines recommended for use in longer MDR-TB regimens, WHO, 2018

GROUPS MEDICINE

Group A Levofloxacin OR Moxifloxacin Lfx / Mfx

Bedaquiline Bdq

Linezolid Lzd

Group B Clofazimine Cfz

Cycloserine OR Terizidone Cs / Trd

Group C Ethambutol E

Delamanid Dlm

Pyrazinamide Z

Imipenem-cilastatin OR Meropenem1 Ipm-Cln / Mpm

Amikacin (OR Streptomycin) Am / (S)

Ethionamide OR Prothionamide Eto / Pto

p-aminosalicylic acid PAS

Programmes need to adhere to key principles when using the agent. The medicine should not be used in a regimen that is too weak (e.g. too few effective agents or use for very short periods). The dosing regimens in

children aged 6 and more are detailed in Section 5 above and in Annex 3. Close monitoring with ECG may be recommended during treatment, particularly if the patient is on another QT-interval prolonging medication,

has a history of torsade de pointes, congenital long QT syndrome, hypothyroidism and bradyarrhythmias, or uncompensated heart failure; or a serum potassium, calcium or magnesium level below the lower limits of

normal. Active TB drug safety monitoring and management (aDSM) is advised for all patients on MDR-TB treatment(3),(8).

10. Summary of comparative effectiveness in a variety of clinical settings: See Annexes 1 and 2

11. Summary of comparative evidence on safety: see Annexes 1 and 2

12. Summary of available data on comparative cost and cost‐effectiveness within the pharmacological class or therapeutic group: The cost-effectiveness of bedaquiline use in adults has been reported in both low and high prevalence settings (e.g.(9),(10),(11),(12),(13),(14),(15)). However, assumptions on costs, other input parameters and the role of the medicine in regimens are likely to have changed substantially in recent years, limiting the generalisability of the findings to patients aged 6-17 years in MDR-TB regimens conforming to current WHO guidelines.

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There is a marked differential in the price of bedaquiline between high income countries and countries eligible for concessional pricing through the Global Drug Facility. A range of published costs for a 6-month adult course (188 tablets of 100mg bedaquiline) is summarized below.

Source Price Comments (accessed 5 December 2018)

Global Drug Facility US$ 0-400 Bedaquiline is available via GDF, at a price of 400 USD for a 6-month course of adult treatment (16). The medicine has also been accessible to eligible countries through a donation project coordinated between the manufacturer and USAID, which is due to last till March 2019.

MSH International Drug Price Indicator Guide

- Available GDF price relates to 2015 and is outdated http://mshpriceguide.org/en/single-drug-information/?DMFId=1685&searchYear=2015

UNICEF/WHO - Not found on https://supply.unicef.org/

United Kingdom GB£ 18,700 As in July 2014 (https://www.engage.england.nhs.uk/consultation/specialised-services-consultation/user_uploads/bedaquiline-delamanid-policy-upd.pdf )

Italy EUR 26,481 As in 2017 (10)

Rep of Korea ~US$ 26,500 As in 2016 (14)

Regulatory information

13. Summary of regulatory status of the medicine (in various countries) Bedaquiline has now been granted approval in several countries, including some with stringent drug regulatory authorities (see below and at http://www.tbonline.info/media/uploads/documents/2018_05_31_sirturo_regulatory_status_janssen_(1).pdf).

Authority Regulatory status and indications US Food and Drug Administration (US FDA)

Janssen Therapeutics was granted accelerated approval for Sirturo on 28 December 2012 (https://www.accessdata.fda.gov/scripts/cder/daf/)

European Medicines Agency (EMA) Janssen‐Cilag International N.V. was granted conditional approval for Sirturo on 5 March 2014 (https://www.ema.europa.eu/en/medicines/human/EPAR/sirturo)

Japan Approved in January 2018 as on https://www.pmda.go.jp/

Australian Therapeutic Goods Administration

Not found at http://tga-search.clients.funnelback.com/s/search.html?query=&collection=tga-artg

Health Canada Not found at https://health-products.canada.ca/dpd-bdpp/

WHO List of Prequalified Medicinal Products

Not found under Medicines/Finished Pharmaceutical Products or Active Pharmaceutical Ingredients at https://extranet.who.int/prequal/content/prequalified-lists

Regulatory approval is for the use of bedaquiline in adults and the WHO recommendation for treatment with

this medicine in patients aged 6-17 years is considered “off-label use”. This is justified by the seriousness of

M/XDR-TB as a disease and reduced options to treat these forms of TB. The rationale for “off-label use” of

medicines such as bedaquiline in MDR-TB regimens has been discussed extensively in a WHO report(17).

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7. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United

States Pharmacopoeia, European Pharmacopeia)

There is no reference to bedaquiline in the several of the major pharmacopoeias:

Standard Reference (accessed 5 December 2018) International Pharmacopoeia not found on http://apps.who.int/phint/en/p/docf/ United States Pharmacopeia not found on http://www.usp.org/ European Pharmacopeia not found on https://crs.edqm.eu/db/ Korean Pharmacopoeia Specified as an orphan drug at

http://www.mfds.go.kr/eng/brd/m_18/view.do?seq=70115

15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary If this request is approved, it is proposed that a modification is made to the tabulations of the 2019 edition of

the WHO Model List of Essential Medicines for Children (7th list) to accommodate the new addition. Taking the

current children’s EML as a reference(1), it suggested that the following row be inserted under section 6.2.4 in

page 15 :

Complementary List Reserve second‐line drugs for the treatment of multidrug‐resistant tuberculosis (MDR‐TB) should be used in specialized centres adhering to WHO standards for TB control

Bedaquiline a Tablet: 100 mg

a > 5 years

References 1. WHO Model List of Essential Medicines for Children. 6th List [Internet]. Geneva, World Health Organization; 2017.

Available from: http://www.who.int/medicines/publications/essentialmedicines/6th_EMLc2017.pdf

2. Annex 1. 19th WHO Model List of Essential Medicines (April 2015) [Internet]. 19th list. Geneva, World Health Organization; 2015. Available from: http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf

3. WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update (WHO/CDS/TB/2018.15) [Internet]. Geneva, World Health Organization. 2018. Available from: https://www.who.int/tb/publications/2018/WHO.2018.MDR-TB.Rx.Guidelines.prefinal.text.pdf

4. Global tuberculosis report 2018 (WHO/CDS/TB/2018.20) [Internet]. Geneva, World Health Organization; 2018. Available from: http://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf

5. SIRTURO® product information for healthcare providers (Sirturo® bedaquiline 100mg tablets) [Internet]. Titusville, NJ 08560, USA: Janssen Therapeutics, Division of Janssen Products, LP; 2016. Available from: https://www.sirturo.com/sites/default/files/pdf/SIRTURO-product-guide.pdf

6. BRIEFING PACKAGE Division of Anti-Infective Products Office of Antimicrobial Products CDER, FDA. SirturoTM

(bedaquiline 100 mg tablets) For the treatment of adults (≥ 18 years) as part of combination therapy of pulmonary multi-drug resistant tuberculosis (MDRTB). Applicant: Janssen Research and Development, L.L.C FDA Anti-Infective Drugs Advisory Committee Meeting Silver Spring, MD Date: November 28, 2012 [Internet]. [cited 2013 Feb 21]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329258.pdf

7. Sirturo (bedaquiline) [Internet]. European Medicines Agency; Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002614/human_med_001730.jsp&mid=WC0b01ac058001d124

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8. Active tuberculosis drug-safety monitoring and management (aDSM). Framework for implementation (WHO/HTM/TB/2015.28) [Internet]. Geneva, World Health Organization; 2015. Available from: http://apps.who.int/iris/bitstream/10665/204465/1/WHO_HTM_TB_2015.28_eng.pdf

9. Wolfson LJ, Walker A, Hettle R, Lu X, Kambili C, Murungi A, et al. Cost-Effectiveness of Adding Bedaquiline to Drug Regimens for the Treatment of Multidrug-Resistant Tuberculosis in the UK. Diel R, editor. PLOS ONE. 2015 Mar 20;10(3):e0120763.

10. Codecasa LR, Toumi M, D’Ausilio A, Aiello A, Damele F, Termini R, et al. Cost-effectiveness of bedaquiline in MDR and XDR tuberculosis in Italy. J Mark Access Health Policy. 2017 Jan;5(1):1283105.

11. Wirth D, Dass R, Hettle R. Cost-effectiveness of adding novel or group 5 interventions to a background regimen for the treatment of multidrug-resistant tuberculosis in Germany. BMC Health Serv Res [Internet]. 2017 Dec [cited 2019 Jan 7];17(1). Available from: http://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-017-2118-2

12. Schnippel K, Firnhaber C, Conradie F, Ndjeka N, Sinanovic E. Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis. Appl Health Econ Health Policy. 2018 Feb;16(1):43–54.

13. Fan Q, Ming W, Yip W, You JHS. Cost-effectiveness of bedaquiline or delamanid plus background regimen for multidrug-resistant tuberculosis in a high-income intermediate burden city of China. Int J Infect Dis. 2019 Jan;78:44–9.

14. Park H-Y, Ku H, Sohn H-S, Seo H-S, Yung Lee H, Hwa Lim K, et al. Cost-effectiveness of Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the Republic of Korea. Clin Ther. 2016 Mar;38(3):655-667.e2.

15. Lu X, Smare C, Kambili C, El Khoury AC, Wolfson LJ. Health outcomes of bedaquiline in the treatment of multidrug-resistant tuberculosis in selected high burden countries. BMC Health Serv Res [Internet]. 2017 Dec [cited 2019 Jan 9];17(1). Available from: http://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-016-1931-3

16. Stop TB Partnership | Global Drug Facility (GDF) - GDF Products List [Internet]. [cited 2016 Apr 26]. Available from: http://www.stoptb.org/gdf/drugsupply/drugs_available.asp

17. WHO best-practice statement on the off-label use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis (WHO/HTM/TB/2017.20) [Internet]. Geneva, World Health Organization; 2017. Available from: http://apps.who.int/iris/bitstream/10665/258941/1/WHO-HTM-TB-2017.20-eng.pdf

18. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (WHO/HTM/TB/2014.11) [Internet]. Geneva, World Health Organization; 2015. Available from: http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf

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Annex 1 – GRADE Table for bedaquiline (from (4) see https://www.who.int/tb/publications/2018/Annexes_8-10.pdf)

Question: In patients with rifampicin-resistant or multidrug-resistant TB (MDR/RR-TB), which individual agents are more likely to improve outcomes when forming part of a longer regimen conforming to WHO guidelines?

Setting: Treatment of MDR/RR-TB patients with or without additional resistance using longer regimens in hospital or ambulatory models of care in low-, middle- and high-income countries, using an individual patient data meta-analysis with 13,104 records from 53 studies in 40 countries.

Certainty assessment № of patients Effect

Certainty Importance № of

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations bedaquiline no bedaquiline

Relative (95% CI)

Absolute (95% CI)

Treatment failure/relapse vs treatment success - Strain susceptible to Bedaquiline

53 observational studies

not serious not serious not serious not serious strong association 133/1391 (9.6%) 419/3237 (12.9%) aOR 0.3 (0.2 to 0.4)

17 fewer per 100

(from 23 fewer to 11 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

Death vs treatment success - Strain susceptible to Bedaquiline

53 observational studies

not serious not serious not serious not serious strong association 222/1480 (15.0%) 831/3649 (22.8%) aOR 0.2 (0.2 to 0.3)

30 fewer per 100

(from 34 fewer to 26 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

RCT, TMC207-C208 - Treatment failure/relapse vs treatment success

1 randomised trials

not serious not serious not serious serious b none 5/43 (11.6%) 20/41 (48.8%) aOR 0.1 (0.0 to 0.4)

37 fewer per 100

(from 55 fewer to 19 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

RCT, TMC207-C208 - Death vs treatment success

1 randomised trials

not serious not serious not serious serious b none 8/46 (17.4%) 2/23 (8.7%) aOR 5.0 (0.6 to 42.0)

15 more per 100

(from 0 fewer to 29 more) a

⨁⨁⨁◯

MODERATE

CRITICAL

Sensitivity Analysis - Case-control study using South Africa data only - Treatment failure/relapse vs treatment success - Restricted to strains susceptible to Bedaquiline

53 observational studies

not serious not serious not serious not serious strong association 69/869 (7.9%) 276/1188 (23.2%) aOR 0.3 (0.2 to 0.4)

15 fewer per 100

(from 18 fewer to 12 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

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Sensitivity Analysis - Case-control study using South Africa data only - Death vs treatment success - Restricted to strains susceptible to Bedaquiline

53 observational studies

not serious not serious not serious not serious strong association 176/976 (18.0%) 694/1606 (43.2%) aOR 0.3 (0.2 to 0.4)

25 fewer per 100

(from 29 fewer to 22 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

Sensitivity Analysis - Patients with XDR (No restriction on number of effective drugs) - Treatment failure/relapse vs treatment success

53 observational studies

not serious not serious not serious serious b strong association 59/512 (11.5%) 191/539 (35.4%) aOR 0.2 (0.1 to 0.3)

26 fewer per 100

(from 36 fewer to 16 fewer) a

⨁⨁◯◯

LOW

CRITICAL

Sensitivity Analysis - Patients with XDR (No restriction on number of effective drugs) - Death vs treatment success

53 observational studies

not serious not serious not serious serious b strong association 98/551 (17.8%) 469/817 (57.4%) aOR 0.1 (0.1 to 0.2)

45 fewer per 100

(from 52 fewer to 39 fewer) a

⨁⨁◯◯

LOW

CRITICAL

Sensitivity Analysis - Excluding patients who received other new drugs (Lzd, CFZ or Carbapenems), no restriction on number of effective drugs - Treatment failure/relapse vs treatment success

53 observational studies

not serious not serious not serious not serious strong association 40/415 (9.6%) 621/4219 (14.7%) aOR 0.3 (0.2 to 0.5)

16 fewer per 100

(from 24 fewer to 8 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

Sensitivity Analysis - Excluding patients who received other new drugs (Lzd, CFZ or Carbapenems), no restriction on number of effective drugs - Death vs treatment success

53 observational studies

not serious not serious not serious not serious strong association 67/442 (15.2%) 1127/4725 (23.9%) aOR 0.3 (0.2 to 0.4)

24 fewer per 100

(from 31 fewer to 17 fewer) a

⨁⨁⨁◯

MODERATE

CRITICAL

Adverse events (drug stopped permanently)

12 observational studies

not serious not serious not serious not serious none 8/447 (1.8%) not estimable 2 more per 100 (from 1 more to

4 more) c

⨁⨁◯◯

LOW

IMPORTANT

CI: Confidence interval

Footnotes a. Risk differences and confidence interval from propensity score matched regression meta-analysis of individual patient records b. Small numbers c. Pooled incidence of adverse events of random effect in meta-analysis

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Annex 2 – Assessment of paediatric PK & safety data from paediatric trials of bedaquiline (Author : Dr S Abdel Rahman, 2018; reported as part of reviews for (4) see https://www.who.int/tb/publications/2018/Annexes_8-10.pdf)

Source Data Paediatric data for bedaquiline were reviewed to explore the extent to which adult data can be extrapolated to children. The focus of this review was on safety and pharmacologic exposure data available from 2 ongoing paediatric studies: 1. TMC207‐C211: A Phase 2, Open‐label, Multicenter, Single‐arm Study to Evaluate the Pharmacokinetics, Safety,

Tolerability and Anti‐mycobacterial Activity of TMC207 in Combination With a Background Regimen (BR) of Multidrug

Resistant Tuberculosis (MDR‐TB) Medications for the Treatment of Children and Adolescents 0 Months to <18 Years of

Age Who Have Confirmed or Probable Pulmonary MDR‐TB. 2. IMPAACT P1108: A Phase I/II, Open‐Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and

Tolerability, of Bedaquiline (BDQ) in Combination with optimized Individualized Multidrug‐Resistant Tuberculosis (MDR‐

TB) on in HIV‐Infected and HIV‐Uninfected Infants, Children and Adolescents with MDR‐TB Disease.

The data available from TMC207‐C211 included a sponsor generated summary document for patients from cohort 1

along with suppressed raw data files for all enrolled participants in the 12‐18 year cohort. From IMPAACT P1108,

summary data were provided for participants enrolled to date with selected raw data provided on follow‐up request. For

the purposes of comparison, adult reference data were extracted from the publicly accessible FDA review of application

#204384. With respect to limitations, it was noted that both trials are still ongoing and not all of the data provided were

verifiable. However, where possible, sponsor summary presentations were examined against the sponsor raw data and

sponsor derived pharmacokinetic exposure parameters were examined against independently calculated

pharmacokinetics.

Patient Characteristics

Enrolled Participants TMC207‐C211 IMPAACT P1108

Count 15 a 10

b

Nationality/Race Philippines (2): Russia (5): South Africa (8) Black, non‐Hispanic (10)

Comorbid HIV excluded included c

Age (yr) 14 ‐ 17 6 ‐ 17

Sex (M:F) 3:12 6:4

Height (cm) 150 – 175 121 ‐ 162

Weight (kg) 38.4 – 75 15 ‐ 65

BMI z‐score ‐2.8 to 1.7 N/A

Dose d

: cohort 1 : ≥ 30 kg 400 mg QD 2wk; 200 mg TIW 22 wk 400 mg QD 2wk; 200 mg TIW 22 wk

N/A : ≥ 15 to <30 kg 200 mg QD 2wk; 100 mg TIW 22 wk

a only 6 participants with 2 week PK data

b only 9 participants with safety data and 7 participants with week 24 PK data

c no HIV positive participants enrolled to date

d IMPAACT P1108 used a body weight of <30 kg as the threshold to adjust the paediatric dose to half the adult dose whereas TMC207-C211 used age <12 years to make the same dose adjustment.

Safety

Physical exam/Laboratory based safety. As of the meeting date, 14 children from cohort 1 experienced adverse events

(AE) in TMC207‐C211. Those occurring at a rate of greater than 10% included hypoacusis, tinnitus, eye pain, blurred

vision, nausea, URI, vulvovaginal candidiasis, prolonged prothrombin time (PT), arthralgia, acne, and rash. Among these,

the only AE for which a safety signal had net been previously reported in adults was elevated PT. There were 5 grade 3 or

4 AE: 1 episode of elevated ALT/AST/Bili which did not recur upon de/rechallenge; 1 episode of elevated CPK which

resolved after 1 day; and 3 episodes of elevated PT two of which were preceded by an elevated PT at baseline or

screening, none of which appeared to be the result of an underlying coagulation disorder, and all of which resolved at

next scheduled visit (4wk). The investigators of IMPAACT P1108 reported no grade 3 or 4 physical exam or laboratory

based safety endpoints.

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Cardiac safety. In TMC207‐C211, 6 participants experienced an increase in QTcF of 30‐60 msec. In IMPAACT P1108, 1

participant experienced an increase in QTcF of 93.7 msec. Concurrent QTc prolonging medications included levofloxacin

in both studies and clofazimine on the IMPAACT trial.

Exposure

Observed PK data. Observed 2‐ and 12‐week Cmax, Cmin and AUC0‐24hr data in the TMC207‐C211 pediatric cohort were

available for comparison with the corresponding 2‐ and 24‐week exposure data from adults (Figure 1). The expected

markers of internal consistency (i.e. dose‐exposure and exposure‐exposure relationships were present) were observed in

the TMC207‐C211 data set. In addition, the reported covariate relationship in adults, specifically the race effect,

appeared to be reproducible in the adolescent cohort.

Population PK data. AUC0‐168hr data predicted using a popPK approach were available from both pediatric studies along

with the reference adult trial (Figure 2). The age subgroups represented were selected to parallel the actual age range of

children enrolled in TMC207‐C211, the intended age range for cohort 1 in TMC207‐C211, and the children expected in

cohort 2 of TMC207‐ C211.

It should be highlighted that the popPK models used by the Janssen and IMPAACT study teams are not identical and the

extent to which they differ is unclear. Visual predictive checks for both models were available for GDG review.

Considerations by the 2018 Guideline Development Group (GDG) in their recommendation

Will the administration of BDQ harm adolescents to whom it is administered? The GDG preliminarily concluded that the

safety risk in children down to 6 years of age and constituted by the population enrolled in these trials (e.g. HIV negative,

limited exposure to concomitant medications with the potential to prolong QTc, etc.) does not appear to exceed that of

adults.

Will the administration of BDQ provide benefit for adolescents to whom it is administered? Operating under the

assumption that exposure‐response (efficacy) profiles can be extrapolated from adults to children, the GDG preliminarily

concluded that the doses evaluated do not appear to produce exposures that would put children at increased risk for

therapeutic failure. Note that the variability present in the limited sample size precluded a comment on exposure‐

response (safety).

Can the risk : benefit balance be shifted in favour of benefit? The GDG preliminarily concluded that risk‐benefit

considerations for the use of bedaquiline are similar to those considered for adults. The GDG also endorsed the need to

amass additional data in children before the strength of any recommendation can be modified.

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Annex 3 – Drug information sheet (draft for the update of (18); including information from

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf, accessed 5 December 2018)

Bedaquiline (Bdq)

DRUG CLASS: DIARYLQUINOLONE

WHO GROUPING FOR LONGER MDR-TB REGIMENS: GROUP A

Activity against TB, mechanism of action and metabolism

Bactericidal: Inhibits ATP synthesis; novel method of action. The drug has a 5.5-month half-life. CYP3A4 is the major CYP isoenzyme involved in the metabolism of bedaquiline. The metabolism leads to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23–31%) in humans and lower antimycobacterial activity (4- to 6-fold lower) compared to the parent compound. M2 concentrations appeared to correlate with QT prolongation. Bedaquiline is mainly eliminated in faeces. The renal clearance of unchanged drug is insignificant.

Cross-resistance Cross-resistance with clofazimine has been demonstrated in both directions through efflux-based resistance.

Dose Adults: 400 mg once daily for 2 weeks, followed by 200 mg once daily, 3 times per week for 22 weeks, administered with food. The maximum daily dose is 400 mg. After the first two weeks of treatment, the dose changes to 200 mg three times per week, even if doses were missed during the first two weeks. Patients should not make up for missed doses during the first 2 weeks of treatment. From week 3 onwards, if a 200 mg dose is missed, patients should take the missed dose as soon as possible, and then resume the 3 times a week regimen. Concomitant medications: Bedaquiline is metabolized by CYP3A4 and co-administration of rifamycins (e.g., rifampicin, rifapentine and rifabutin) or other strong CYP3A4 inducers may require dose adjustment. See Section 7 in http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf.

Children aged > 5 years: Has not been studied extensively in children (see Annex 2 above). For children who weigh 16-30 kg, 200 mg once daily for 2 weeks, followed by 100 mg once daily three times per week for 22 weeks, administered with food. For children who weigh 31 to >34 kg 400 mg once daily for two weeks, followed by 200 mg once daily three times per week for 22 weeks, administered with food.

Renal failure/dialysis: No dose adjustment needed for mild to moderate renal insufficiency. It should be used with caution in patients requiring renal dialysis.

Route of administration Oral

Preparation 100 mg tablets.

Storage Store tablet at room temperature (15–25 °C). Tablets removed from the original packaging should be stored in a tight, light-resistant container and labelled with an expiration date not to exceed 3 months.

Oral absorption Better absorption is obtained if taken with food.

CSF penetration Insufficient knowledge about CSF penetration and treatment of TB of the central nervous system with bedaquiline

Special circumstances Use in pregnancy/breastfeeding: Pregnancy category B. No foetal harm found in animal studies. The drug is concentrated in breast milk and it may be necessary to avoid breastfeeding. Use in renal disease: No dosage adjustment is required in patients with mild to moderate renal impairment, but it should be used in caution in patients requiring peritoneal or haemodialysis. Therapeutic drug monitoring may be useful if available. Use in hepatic disease: No dosage adjustment is required in patients with mild to moderate hepatic impairment. Bedaquiline has not been studied in patients with severe hepatic impairment and should be used in caution in these patients only when the benefits outweigh the risks. Clinical monitoring for bedaquiline related adverse reactions is recommended.

Adverse reactions QTc prolongation, hepatitis, nausea, joint pain (arthralgia), headache, elevated

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amylase, coughing up blood, chest pain, loss of appetite and/ or rash. Less common: hyperuricaemia, phospholipidosis (the accumulation of phospholipids in the body tissues), elevated aminotransferases. Possible early signal for increased risk of pancreatitis.

Contraindications Do not use or discontinue bedaquiline in the presence of: • Clinically significant ventricular arrhythmia. • A QTcF interval of >500 ms (confirmed by repeat ECG). • Severe liver disease. • Abnormal electrolytes. Use with caution in the following situations (with more frequent ECG monitoring and evaluation of risk versus benefit): • Use with other QT prolonging drugs (see drug interactions) • A history of torsade de pointes • A history of congenital long QT syndrome • A history of hypothyroidism and bradyarrhythmias • A history of uncompensated heart failure • Serum calcium, magnesium or potassium levels below the lower limits of normal. • Concomitant use of other medicines that may prolong the QT-interval (see below)

Drug interactions Bedaquiline is metabolized by CYP3A4. Rifampicin (a CYP3A4 inducer) reduces bedaquiline in blood by half. Efavirenz based on a single dose study appears to reduce the amount of bedaquiline by inducing CYP3A4. CYP3A4 inhibitors (e.g. azole anti-fungal drugs, some macrolides, protease inhibitors, and many others) can raise the level of bedaquiline but can be considered for use if the benefits outweigh the risk. Use with other medicines that prolong the QTc interval may cause additive QTc prolongation and monitoring precautions apply (e.g. clofazimine, fluoroquinolones, delamanid, azole anti-fungal drugs, and many others). Any syncopal event (fainting) should prompt an immediate medical evaluation and ECG.

Monitoring An ECG should be obtained before initiation of treatment, and at least 2, 12 and 24 weeks after starting treatment. Stop bedaquiline if QTc >500 and monitor ECGs frequently until QTc returns to normal. More frequent monitoring recommended if cardiac conditions, hypothyroidism or electrolyte disturbances are present. Baseline potassium, calcium and magnesium, repeat if QTc prolongation occurs and monthly if on an injectable drug. Liver function tests should be done at baseline, then monthly.

Warning In addition to above, an increased risk of death was seen in the bedaquiline treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. There was no pattern to the causes of death, and cause and effect could not be established. This effect was not observed in subsequent studies.

Patient instructions and alerting symptoms

Avoid alcohol. Take medication with food.

Instruct patients to inform their health care provider right away if any of the following occurs: • Serious heart rhythm changes (QTc prolongation). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint.

• Liver problems (hepatotoxicity). Call your healthcare provider right away if you have unexplained symptoms such as nausea or vomiting, stomach pain, fever, weakness, itching, unusual tiredness, loss of appetite, light-coloured bowel movements, dark-coloured urine, yellowing of your skin or the white of your eyes.