Application for the inclusion of CLOFAZIMINE in the WHO Model List of Essential Medicines (“EML”), as a reserve second-line drug for the treatment of multidrug-resistant tuberculosis (complementary lists of anti-tuberculosis drugs for use in adults and children)

General items

1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section 6.2.4 Antituberculosis medicines in the 2015 editions of both the 19th Model List of Essential Medicines of the World Health Organization (WHO) and the 5th WHO Model List of Essential Medicines for Children(1),(2). The proposal is to add clofazimine - a medicine which is already included on both lists for use in leprosy (6.2.3 Antileprosy medicines) - to the Complementary Lists of antituberculosis medicines in adults and children at the next revision of the Essential Medicines Lists (EMLs) in April 2017. The applicant considers that under the current circumstances clofazimine should be considered an essential medicine for national programmes to have as part of the treatment they offer to patients with rifampicin-resistant (RR-TB), multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) disease. In many low resource settings, patients with these forms of tuberculosis often die or are only partially treated as a result of the limited options in the medicines available to compose an adequate regimen(3). Agents like clofazimine are therefore needed more widely for health care providers to treat M/XDR-TB patients adequately. Unfortunately, access continues to be challenged by several factors, including the limited availability of quality-assured suppliers of the medicine as well as the fact that clofazimine is used either off-label (in countries where the manufacturer registered it with an indication for leprosy) or through other mechanism (when in place) to access non registered drugs. Its listing could encourage more pharmaceutical manufacturers to invest in its production, help counter the unfavourable conditions of the global market for such drugs as numbers of TB cases diminish in the world. The 2011 WHO guidelines on M/XDR-TB treatment included clofazimine in the Group 5 of second-line drugs and recommends its use when other treatment options are not possible(4). This reflects a WHO policy dating since at least 2006 to consider this drug as a reserve anti-tuberculosis agent for drug- resistant strains(5),(6). The role of clofazimine in MDR-TB regimen design has been reviewed by a WHO Guidelines Development Group in November 2015(7). The 2016 update of the WHO policy for the treatment of MDR-TB now conditionally recommends the use of a shorter MDR-TB regimen in which clofazimine is a mainstay second-line drug used throughout its 9 month duration(7). Clofazimine is a mainstay component of shorter regimens which have shown promise to reduce drastically the length of treatment for MDR-TB patients(8),(9),(10),(11); these novel regimens are currently being used in various treatment programmes and their effectiveness and safety are also being studied under randomized controlled (RCT) conditions(12),(13). Moreover, the 2016 update of the WHO treatment guidelines for MDR-TB includes clofazimine as one of the four medicines in “Group C”, making it a core-drug option even for conventional regimens for M/XDR-TB (Table 1). Clofazimine currently the only core second‐line medicine for the treatment of MDR-TB which does not yet feature in the EML as an antituberculosis agent1(7). A major multi-partner initiative to develop the treatment of TB and MDR-TB patients, supported by UNITAID funding up to USD60 million, is now being implemented: it aims to create new regimens using

1 Gatifloxacin is not yet listed either, but moxifloxacin - an alternative later generation fluoroquinolone - is included. A separate application for the inclusion of gatifloxacin in the 20th EML is being submitted concurrently

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combinations of both new medicines and old ones such as clofazimine(14). This request to the EML is thus very timely and well aligned the position of WHO and the consensus achieved with technical partners and experts on the subject. If approved, it would synergise with their concerted efforts to improve patient access to treatment, ensure more favourable outcomes and reduce avoidable mortality for the 580,000 patients estimated to develop rifampicin-resistant or MDR-TB in the world every year and who would need second-line TB treatment regimens to increase their likelihood of a successful outcome(3). Table 1. Medicines recommended for the treatment of rifampicin-resistant and multidrug-resistant TB as per the 2016 update of WHO policy for the treatment of drug-resistant TB(7)1

A. Fluoroquinolones2 Levofloxacin Lfx Moxifloxacin Mfx Gatifloxacin Gfx B. Second-line injectable agents Amikacin Am Capreomycin Cm Kanamycin Km (Streptomycin)3 (S) C. Other core second-line agents2 Ethionamide / Prothionamide Eto / Pto Cycloserine / Terizidone Cs / Trd Linezolid Lzd Clofazimine Cfz D. Add-on agents Pyrazinamide Z (not part of the core MDR-TB regimen) D1 Ethambutol E High-dose isoniazid Hh Bedaquiline Bdq D2 Delamanid Dlm p-aminosalicylic acid PAS Imipenem-cilastatin4 Ipm D3 Meropenem4 Mpm Amoxicillin-clavulanate4 Amx-Clv (Thioacetazone)5 (T)

Notes for Table 1 1. This regrouping is intended to guide the design of conventional regimens; for shorter regimens lasting 9-12 months the composition is usually standardised 2. Medicines in Group A and Group C are shown by decreasing order of usual preference for use (subject to other considerations; see Guidelines text) 3. Refer to the Guidelines text for the conditions under which streptomycin may substitute other injectable agents. Resistance to streptomycin alone does not qualify for the definition of extensively drug-resistant TB (XDR-TB) 4. Carbapenems (Imipenem-cilastatin or Meropenem) and clavulanate are meant to be used together; clavulanate is only available in formulations combined with amoxicillin 5. HIV-status must be tested and confirmed to be negative before thioacetazone is started

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, Tiziana MASINI and Ernesto JARAMILLO.

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3. Name of the organization(s) consulted and/or supporting the application Dr Kaspars Lunte of Global Drug Facility (GDF)

4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine. The WHO INN (generic name) of the medicine concerned is clofazimine (15). The Anatomical Therapeutic Chemical (ATC) code of the medicine concerned is J04BA012.

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) The formulations proposed, for both adults and children, are the same as those listed in the EML for use in leprosy, namely soft gelatin capsules in dosages of 50 mg and 100 mg. A drug information sheet for clofazimine is at Annex 1. The product package insert is available online(16). Clofazimine has been marketed by its original producer Novartis under the proprietary name Lampren and Lamprene®(16). Other manufacturers produce the product under different trade names: Clofozine, Hansepran, and Lapren. Novartis has stopped the production of the active pharmaceutical ingredient (API) of clofazimine, but other manufacturers have been producing clofazimine API3. Clofazimine is one of three drugs making up the multidrug therapy (MDT) regimen recommended by WHO for the treatment of adults and children with multibacillary leprosy4. The drug is also useful in the management of erythema nodosum leprosum and reversal immunity reactions(17). Clofazimine is still available today for leprosy, its registered indication. As several other medicines under the The drug is also used outside of this indication for the treatment of M/XDR-TB (see above). In early 2012, in the wake of a much-publicized report from India of TB patients with broad patterns of resistance, WHO convened an technical consultation(18),(19). The experts at this meeting recommended that two “Group 5” drugs - clofazimine and linezolid - be made available by the Global Drug Facility (GDF) to countries as a matter of priority. Following this, the 50mg and 100mg formulation of clofazimine can now be purchased through GDF5. The gel capsules do not require extraordinary storage conditions.

6. Whether listing is requested as an individual medicine or as a representative of a pharmacological class This request is for the inclusion of clofazimine as an individual medicine without a square box symbol. Clofazimine is the only riminophenazine with a market authorization for use in the treatment of leprosy in several countries with stringent drug regulatory authorities: Australia, France, Netherlands, Spain, Switzerland, and USA. It is also the only member of this pharmacological class for which there is experience and published information on effectiveness and safety when used in the treatment of drug- resistant TB patients, although other candidates from the same family of medicines may become available in future(20),(21).

2 http://www.whocc.no/atc_ddd_index/?code=J04BA01; accessed 27.06.2016 3 For example : http://www.sangroselabs.com/home.html; accessed 27.06.2016 4 http://www.who.int/lep/mdt/regimens/en/; accessed 27.06.2016 5 http://www.stoptb.org/gdf/drugsupply/pc3.asp?PID=562; accessed 27.06.2016

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Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) WHO guidelines recommend clofazimine in the treatment of MDR-TB patients as part of two treatment approaches: 1) Longer (individualized) regimens : A typical MDR-TB regimen is composed of at least 4 second- line anti-TB drugs considered to be effective, including a later-generation fluoroquinolones, a second-line injectable, and two or more of ethionamide (or prothionamide), cycloserine (or terizidone), clofazimine or linezolid(7). When one or more of these drugs is considered ineffective, as a result of in vitro resistance, severe intolerance, or prolonged use in the same patient, the regimen can be bolstered by “group D” drugs, such as bedaquiline(4). One exemplar of a typical regimen for a patient with XDR-TB could be 6 Z-Cm-Mfx-Eto-Bdq-Lzd-Cfz / 6 Z-Cm-Mfx-Eto-Lzd-Cfz / 12 Z-Mfx-Eto-Cfz. In such a case clofazimine is used for 24 months. The standard adult dose is 200–300 mg/day for the first 2 months, then 100 mg/day. In children the experience is limited but 1 mg/kg body weight daily, with a maximal daily dose of 200 mg, is recommended(4). 2) Shorter MDR-TB regimen : Clofazimine is an important component of both the intensive and the continuation phase of the shorter regimens(12). The regimen is nowadays composed of pyrazinamide, ethambutol, isoniazid, moxifloxacin, capreomycin (kanamycin), prothionamide and clofazimine for 4 months (prolonged to 6 months if response is slow), followed by a continuation phase of pyrazinamide, ethambutol, moxifloxacin, and clofazimine for 5 months. Clofazimine is thus used for 9-11 months. The standard dose is 100 mg per day and 2-3 mg/kg for patients weighing less than 25 kg. Between August 2012 and May 2016, WHO advised countries to introduce such regimens under operational research conditions, subject to the approval of a national ethics review, and with an appropriate assessment of the effectiveness and safety of treatment(22). Since May 2016, WHO conditionally recommends the use of a shorter MDR-TB regimen under normal programmatic conditions in patients who fulfil the eligibility criteria for this treatment.

8. Information supporting the public health relevance. Each year it is estimated that 580,000 new rifampicin-resistant and multidrug-resistant TB (MDR/RR-TB) cases emerge in the world and 250,000 MDR/RR-TB patients die(3). About one half of MDR-TB cases globally have also lost susceptibility to key drugs in the MDR-TB regimen: fluoroquinolones, second-line injectable agents, or both (i.e. XDR-TB). XDR-TB represents about 10 % of MDR-TB cases and 122 countries and other settings have now detected at least one such case. In 2015, countries reported that about 125,000 MDR/RR-TB patients and over 7,000 XDR-TB patients started treatment worldwide. The effectiveness of these efforts vary considerably and data on outcome reporting in recent years showed that about half the MDR-TB patients complete their treatment successfully (23). The rest die, sustain a treatment failure, interrupt treatment, or are otherwise lost to follow up. While treatment programmes in some countries show encouraging results, the complexity, duration, toxicity, cost and unavailability of the drug regimens for MDR-TB treatment pose a substantial impediment to an appropriate global scale- up of curative services. Facilitating the creation of regimens which are more amenable for patients and providers is therefore a priority. The contribution of clofazimine to the shorter regimens thus also has strategic significance. The shorter MDR-TB regimen is less costly (about US$700 for drug costs alone under programmatic conditions6, being about 3-4 times less costly than the typical medicines needed for

6 http://www.stoptb.org/gdf/drugsupply/pc2.asp?CLevel=2&CParent=4; accessed 08.11.2016

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a longer, individualised , 24-month MDR-TB regimen). If the shorter MDR-TB regimen can secure a relapse-free cure for at least 80% of eligible patients then the gains are clearly evident.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings: In addition to the observational studies of shorter-regimens containing clofazimine from Bangladesh (8), four recently-published papers summarize much of the experience in the use of this drug in the treatment of multidrug-resistant TB (17),(20),(24), (25). Additionally, a Chinese trial of 105 MDR-TB patients randomised to receive 21-month individualised regimens with and without clofazimine in 2010- 2011 has been published (26). The findings attest to higher success rates and earlier resolution of disease markers in patients receiving clofazimine.

Clofazimine is active against M tuberculosis and MDR-TB strains in vitro (27). However, its therapeutic efficacy in various animal models has given inconsistent results. The release of clofazimine on the market coincided in time with the emergence of very effective anti-TB regimens (based on R-H-Z-E) associated with less adverse effects. Interest in exploring the potential role of clofazimine in anti-TB regimens thus waned.

A systematic review of studies reporting on the efficacy and safety of clofazimine as part of combination therapy for drug-resistant TB examined six databases and six conference abstract sites up until April 2012(24). Twelve studies, comprising 3,489 patients situated in 10 countries, were included in this review. Treatment success ranged between countries from 16.5% (95% CI 2.7%–38.7%) to 87.8% (95% CI 76.8%–95.6%), with an overall pooled proportion of 61.96% (95% CI 52.79%–71.12%). The most commonly reported adverse events were gastrointestinal disturbances and skin pigmentation (see also next section). The authors inferred that clofazimine could function as an additional option in the treatment of drug-resistant TB. The optimal dose of clofazimine and duration of use however required further investigation.

Another review (up to February 2012) of PubMed, Embase and the Cochrane Library for publications on clofazimine used for M/XDR-TB treatment identified nine observational studies (6 MDR-TB and 3 XDR- TB) spanning 1985 to 2011(25). The geographical spread of the location of these studies was broad (Bangladesh, China, Netherlands, Peru, Spain, Sri Lanka and USA). The median number of drugs used in the regimens, including clofazimine, ranged from 4 to 7. Overall, 65% (95%CI 54–76%) of the patients were reported to have completed treatment successfully. Using random effects meta-analysis, 65% (95%CI 52–79%) of those with MDR-TB and 66% (95%CI 42–89%) of those with XDR-TB experienced favourable treatment outcomes.

The rates of successful outcome reported in these two reviews are higher than what is usually reported in M/XDR-TB patient series in whom clofazimine is rarely used (28),(29),(30). Nevertheless, the incremental success in the studies included in these reviews cannot be attributed solely to the effect of clofazimine, given that regimen composition is heterogeneous across studies and the individual effect of drugs cannot be easily teased out when these are administered simultaneously; moreover none of the studies were RCTs and therefore various types of bias may have been introduced and residual confounding unaccounted for.

10. Review of harms and toxicity: summary of evidence on safety: Clofazimine entered clinical use in 1962. The associated adverse drug reactions (ADRs) have been fairly well characterised over the last decades as among the many individuals (mostly leprosy patients) who have been exposed to it for many months at a time (17),(31)(see Annex 1(4)). Much less is known about

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the safety profile in children. Orange-red skin pigmentation occurs in 75% to 100% of patients within a few weeks and is usually reversible months to years after the cessation of treatment. This may be distressing to patients. It is usually also accompanied by discoloration of conjunctiva, cornea and body fluids. Other commonly associated ADRs include dry skin, pruritus, rash, ichthyosis, dry skin, and gastrointestinal intolerance. Less common ADRs include maculopathy, severe abdominal symptoms, photosensitivity bleeding, bowel obstruction and prolongation of the QT interval and ventricular tachyarrhythmias. QT prolongation is associated with higher doses of clofazimine. Another concern is that the joint administration of clofazimine with other medicines known to prolong the QT interval (e.g. bedaquiline, fluoroquinolones, delamanid, azole anti-fungal drugs, and many others) may cause additive adverse effects.

A systematic review published in 2014 assessed the clinical and programmatic value of clofazimine as an anti-TB agent(20). A search of PubMed, MEDLINE, Embase and the Cochrane Library databases for studies published between 1950 and May 2013 included keywords to capture harms (‘outcomes’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequela’, ‘toxicity’, ‘tolerability’, or ‘safety’) associated with the use of clofazimine for the treatment of TB. In 5 observational studies traced, 602 out of 861 patients enrolled received clofazimine. The overall proportion (pooled) of patients with ADRs was 21.9% (95%CI: 0.0% to 46.1%), but only 0.1% (0.0 to 0.6%) required discontinuation of clofazimine. This risk is comparable to that observed in patients on first-line TB treatment, and could conceivably be managed under programmatic conditions.

In conclusion, despite the fact that clofazimine is associated with several ADRs, WHO and other authorities have since many years considered it to be an essential drug for the treatment of leprosy, a condition which is far less lethal than M/XDR-TB. Treatment of MDR-TB commonly leads to a whole constellation of adverse effects and the majority of patients exposed have at least one event, often requiring a modification of the regimen(32). If the addition of clofazimine to a regimen can increase the likelihood of success by 10%, at the expense of a slight increase in non-serious adverse effects, then the balance of risks to benefits may well tip in favour of the latter.

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: The range of (published) costs for clofazimine when used for the treatment of leprosy is summarized below: Source Price Comments (US$) accessed 27.06.2016 Global Drug 109.48/100 caps as per Product Information available online Facility (100 mg) (www.stoptb.org/gdf/drugsupply/pc3.asp?PID=562) MSH 126.72/100 caps As per 2014 price (Source : GDF) International (100 mg) (erc.msh.org/dmpguide/resultsdetail.cfm?language=english&c Drug Price ode=CLO100T&s_year=2013&year=2013&str=100%20mg&des Indicator Guide c=Clofazimine&pack=new&frm=TAB- CAP&rte=PO&class_code2=06.2.3.&supplement=&class_name =%2806.2.3.%29Antileprosy%20medicines%3Cbr%3E) Médecins sans 50 mg: 0.547-0.713 Price per capsule. Replicating the “GDF pooled procurement” Frontières (33) 100 mg: 1.095-1.267 price

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Regulatory information

12. Summary of regulatory status of the medicine The table below summarizes the regulatory status of clofazimine vis-à-vis the stringent regulatory authorities and WHO’s Prequalification Programme. Wherever clofazimine is currently registered, it is not indicated for tuberculosis. Clofazimine has a marketing authorization for the treatment of leprosy in Australia, France, the Netherlands, Spain, Switzerland, and the USA. Clofazimine used to be registered for the treatment of leprosy in several other countries but it has been de-registered because its demand was being met entirely through a Novartis-donation programme coordinated through WHO.

Only the product produced by Novartis is approved by the US Food and Drug Administration (FDA). While other manufacturers exist (e.g., in China and India), their conformity to recognised standards is unknown.

Authority Regulatory status and indications US Food and Drug The Novartis product (Lamprene®) approved since 15 Dec 1986 for the treatment of Administration (FDA) leprosy www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_ Current_Drug&ApplNo=019500&DrugName=LAMPRENE&ActiveIngred=CLOFAZIMINE &SponsorApplicant=NOVARTIS&ProductMktStatus=3&goto=Search.DrugDetails (accessed 08.11.2016) European Medicines Not found. Agency (EMA) However, the medicine is registered with an indication for leprosy in France (1997; see below in this Table), the Netherlands (1970), Spain (1970) and Switzerland (1969). Australian Therapeutic Lamprene 50mg capsules registered by Novartis Pharmaceuticals Australia Pty Ltd Goods Administration since 1971 for the treatment of leprosy (www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=4 8FA009ED0E79849CA257E340023500A&agid=(PrintDetailsPublic)&actionid=1) (accessed 08.11.2016) Japan Lamprene 50mg capsules registered by Sandoz KK in 1996 for the treatment of leprosy (https://www.nibiohn.go.jp/shinko/orphan/english/pdf/h2603kisyoiyaku- hyo1.pdf; accessed 08.11.2016) Health Canada Not found WHO List of In October 2016, PQ reissued an updated Expression of Interest for the Prequalified Medicinal manufacturers antituberculosis medicines, including clofazimine, which was already Products listed in the previous edition (34), (35). No applications had been received by the time of submission of this application (08.11.2016). France Lamprene 50 mg capsule, registered Novartis Pharma SAS (accessed 08 November 2016 at http://agence- prd.ansm.sante.fr/php/ecodex/frames.php?specid=62768220&typedoc=N&ref=N021 5627.htm) Lamprene 100 mg capsule, registered Novartis Pharma SAS (accessed 08 November 2016 at: http://agence- prd.ansm.sante.fr/php/ecodex/frames.php?specid=67132888&typedoc=R&ref=R021 5626.htm )

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13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) There are reference standards to clofazimine in all four pharmacopoeias

Standard Reference (accessed 08.11.2016) British Pharmacopoeia www.pharmacopoeia.gov.uk/custom/catalogue.php?action=viewinfo&id=663 International Pharmacopoeia apps.who.int/phint/en/p/docf/ (use search function to find Clofazimine) United States Pharmacopeia store.usp.org/OA_HTML/ibeCCtpItmDspRte.jsp?item=18635 European Pharmacopeia crs.edqm.eu/db/4DCGI/View=Y0000313

14. References 1. WHO Model List of Essential Medicines [Internet]. 19th list. Geneva, World Health Organization; 2015. Available from: http://www.who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pdf

2. WHO Model List of Essential Medicines for Children [Internet]. 5th list. Geneva, World Health Organization; 2015. Available from: http://www.who.int/medicines/publications/essentialmedicines/EMLc_2015_FINAL_amended_AUG2015.pdf

3. Global tuberculosis report 2016 (WHO/HTM/TB/2016.13) [Internet]. Geneva, World Health Organization; 2016. Available from: http://www.who.int/tb/publications/global_report/en/

4. 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

5. Guidelines for the programmatic management of drug-resistant tuberculosis, 1st ed. (WHO/HTM/TB/2006.361) [Internet]. Geneva, World Health Organization. 2006. Available from: http://apps.who.int/iris/bitstream/10665/246249/2/9789241546959-eng.pdf

6. Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008. (WHO/HTM/TB/2008.402) [Internet]. Geneva, World Health Organization. 2008. Available from: http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf

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13. The evaluation of a standardised treatment regimen of anti-tuberculosis drugs for patients with multi-drug- resistant tuberculosis (MDR-TB) [STREAM-TRIAL] [Internet]. [cited 3014 Sep 12]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164715/

14. UNITAID Approves Grants of $160 million [Internet]. [cited 2014 Jul 26]. Available from: http://www.unitaid.org/en/press-releases/1352-unitaid-approves-grants-of-160-million

15. WHO Drug Information. Recommended INN List 39. International Nonproprietary Names for Pharmaceutical Substances [Internet]. Geneva, World Health Organization. Vol. 12. 1998. Available from: http://apps.who.int/medicinedocs/index/assoc/s14167e/s14167e.pdf

16. International Package Leaflet LAMPRENE (clofazimine) 50 or 100 mg capsules, soft [Internet]. Geneva, World Health Organization: Drug Regulatory Affairs, Novartis; 2005. Available from: https://www.lamprene.com/fileadmin/pharmaworld/lamprene/lamprene_packing_insert.pdf

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30. Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox H, Holtz TH, et al. Resistance to fluoroquinolones and second- line injectable drugs: impact on MDR-TB outcomes. Eur Respir J. 2013;42(1):156–68.

31. Van Rensburg CEJ, Anderson R, O’Sullivan JF. Riminophenazine compounds: pharmacology and anti-neoplastic potential. Crit Rev Oncol Hematol. 1997 Jan 1;25(1):55–67.

32. Bloss E, Kuksa L, Holtz TH, Riekstina V, Skripconoka V, Kammerer S, et al. Adverse events related to multidrug- resistant tuberculosis treatment, Latvia, 2000-2004. Int J Tuberc Lung Dis. 2010 Mar;14(3):275–81.

33. Médecins Sans Frontières (MSF). DR-TB drugs under the microscope. Sources and prices for drug-resistant tuberculosis medicines [Internet]. 4th ed. MSF Access Campaign; 2016. Available from: http://www.msfaccess.org/sites/default/files/TB_report_4ed_UnderMicroscope_ENG_2016.pdf

34. 14th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Team - Medicines [Internet]. Geneva, World Health Organization; 2016. Available from: http://apps.who.int/prequal/info_applicants/eoi/2016/EOI- TuberculosisV14.pdf

35. 13th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Team - Medicines [Internet]. Geneva, World Health Organization; 2015. Available from: http://apps.who.int/prequal/info_applicants/eoi/2015/EOI- TuberculosisV13_1.pdf

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Annex 1. Drug information sheet (4)

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Annex 2a. GRADE tables – clofazimine – adults

Author(s): Ronald L, Cerigo H, Fox G, Menzies R Question: Clofazimine compared to no clofazimine for the treatment of adults with rifampicin-resistant or multidrug-resistant tuberculosis Setting: Treatment of adults with RR-/MDR-/XDR-TB using conventional regimens lasting about 24 months and shorter MDR-TB regimens, in low and high resource settings, within hospital or ambulatory models of care (as well as non-tuberculosis mycobacteria (NTM) in some outcomes for SAE) Bibliography: Quality assessment № of patients Effect Quality Importance № of Study Relative Absolute Risk of bias Inconsistency Indirectness Imprecision Other considerations clofazimine no clofazimine studies design (95% CI) (95% CI)

Treatment success vs failure/relapse/death in MDR-TB patients on clofazimine (assessed with: individual patient data meta-analysis (2010))1

31 observational very serious serious not serious not serious none 459/806 (56.9%) 2 3292/4970 (66.2%) adjusted OR 1.4 10 more per CRITICAL ⨁◯◯◯ studies 3 (0.4 to 4.0) 1,000 (from 220 VERY LOW fewer to 340 more)

Treatment success vs failure/death in non-XDR MDR-TB patients with clofazimine in their regimen (assessed with: 1 RCT 2010-2011 (Tang et al, China, 2015))

1 randomised serious 4 not serious 5 not serious serious 5 strong association 39/49 (79.6%) 6 28/47 (59.6%) 7 not estimable 200 more per CRITICAL ◯ trials 1,000 ⨁⨁⨁ (from 60 MODERATE fewer to 450 more) 13

Treatment success vs failure/relapse/death (assessed with: 1 RCT + 5 cohorts of MDR/XDR patients)8

6 observational very serious serious not serious serious none 75/102 (73.5%) 10 68/92 (73.9%) 11 not estimable 10 fewer per CRITICAL ⨁◯◯◯ studies 9 1,000 (from 210 VERY LOW fewer to 170 more)

Serious adverse events resulting in drug discontinuation in MDR-/XDR-TB patients on clofazimine (assessed with: comparative studies)12

5 observational very serious serious not serious serious none 2/81 (2.5%) 281/658 (42.7%) not estimable CRITICAL ◯◯◯ studies ⨁ VERY LOW

Serious adverse events resulting in drug discontinuation in NTM patients on clofazimine (assessed with: uncontrolled studies)12

6 observational very serious serious serious serious none 25/195 (12.8%) not estimable CRITICAL ◯◯◯ studies ⨁ VERY LOW

Serious adverse events resulting in drug discontinuation in NTM patients on clofazimine (assessed with: comparative studies only)12

4 observational very serious serious serious serious none 6/181 (3.3%) 15/167 (9.0%) not estimable CRITICAL ◯◯◯ studies ⨁ VERY LOW

12

CI: Confidence interval ; RE=Random effects

1. Outcomes were compared in persons who received clofazimine vs those who received no Group 5 drugs. Adjusted estimate from propensity score matching was done, patients with clofazimine matched to patients from centres where clofazimine was not used 2. RE value on pooled meta-analysis : 63% (95% CL: 49-78%) 3. RE value on pooled meta-analysis : 62% (95% CL: 45-79%) 4. method of randomization not described, and no blinding - increasing risk of allocation bias, and ascertainment bias 5. One study in 5 centres in one country (China) only 6. 95% CL: 68-91% 7. 95% CL: 46-74% 8. Benefit was seen in one RCT, but in 5 small observational studies patients receiving clofazimine had worse outcomes. These regimens were individualized so there is risk of bias (confounding by indication). 9. 1 RCT + 5 cohorts 10. Adjusted proportion 73%; 95% CL: 64-82% 11. Adjusted proportion 89%; 95% CL: 73-100% 12. Adverse events reported in patients taking clofazimine were attributed to the drug by authors who were unblinded and used non-standardized methods to define, ascertain and report AE. No valid comparison possible with patients not taking clofazimine, because adverse events in patients not receiving clofazimine could be due to other drugs received concomitantly 13. P=0.04; treatment failure also significantly lower than in control (11% vs. 29%; P=0.03)

Annex 2b. GRADE tables – clofazimine – children

Author(s): Elizabeth Harausz, Tony Garcia-Prats, Simon Schaaf, Stephanie Law, Dick Menzies, Jennifer Furin, Tamara Kredo and Anneke C. Hesseling on behalf of the Paediatric MDR-TB IPD Group Question: Clofazimine compared to no clofazimine for children with MDR tuberculosis (excluding confirmed XDR-TB) Setting: International Bibliography: Pediatric IPD 2015 Quality assessment № of patients Effect Quality Importance № of Study Relative Absolute Risk of bias Inconsistency Indirectness Imprecision Other considerations clofazimine no clofazimine studies design (95% CI) (95% CI)

Treatment success vs. Fail/Relapse/Die - confirmed cases (IPD analysis): N=623

9 observational serious serious not serious serious none 18/23 (78.3%) 516/600 (86.0%) OR 0.46 46 more per CRITICAL ⨁◯◯◯ studies (0.02 to 10.00) 1 1,000 (from 81 VERY LOW fewer to 170 more)

Treatment success vs. Fail/Relapse/Die - unconfirmed cases (IPD analysis): N=219

2 observational serious serious not serious serious none 4/4 (100.0%) 208/215 (96.7%) OR 0.25 47 more per CRITICAL ⨁◯◯◯ studies (0.12 to 5.30) 2 1,000 (from 14 VERY LOW fewer to 107 more)

CI: Confidence interval; OR: Odds ratio

1. Effect estimates for the confirmed are adjusted for age, HIV status, gender, TB disease severity and site (random effects model with clustering by site) 2. Effect estimate is not adjusted

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Annex 2c. GRADE table – clofazimine-containing shorter MDR-TB regimen

Author(s): Ahmad Khan F, Hamid Salim MA, Schwoebel V, Trébucq A, DuCros P, Casas E, Falzon D, Menzies D (10 November 2015) Question: Standardised shorter regimens compared to conventional longer regimens for the treatment of MDR-TB (all cases; regardless of pyrazinamide or fluoroquinolone susceptibility) Setting: Among patients who had no history of previous treatment with second-line drugs; shorter regimens refers to those lasting up to 12 months; longer regimens last 18 months or more. Note that the “conventional longer regimens” group pools data from studies that differed in the combination and number of drugs, in the duration of treatment, and in the use of a standardized versus an individualized approach – hence the pooled estimates do not necessarily reflect the outcomes associated with the regimen recommended in the 2011 WHO DR-TB guidelines. Bibliography: Results for shorter regimens from aggregate meta-analysis combining preliminary data from three series (1,2,3), with data from three published studies (4,5,6). Results for conventional longer regimens from aggregate meta-analysis using data from 31 studies of conventional MDR regimens (7) 1. Médecins Sans Frontières Swaziland, preliminary outcomes, unpublished data. 2. Médecins Sans Frontières Uzbeksitan, preliminary outcomes, unpublished data. 3. Trébucq A, Schwoebel V, Ghislain Koura K, Roggi A, Rieder HL. Observational study on the evaluation of the tolerance and effectiveness of a short 9 months treatment for multidrug resistant tuberculosis patients: preliminary report for the World Health Organization. The International Union Against Tuberculosis and Lung Diseases (The Union). October 16 2015 4. Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients. The International Journal of Tuberculosis and Lung Disease. 2014 Oct 1;18(10):1180-7 5. Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, Hanki Y, Van Deun A. High cure rate with standardized short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. The International Journal of Tuberculosis and Lung Disease. 2014 Oct 1;18(10):1188-94 6. Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. The International Journal of Tuberculosis and Lung Disease. 2015 May 1;19(5):517-24. 7. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Becerra MC, Benedetti A, Burgos M, Centis R, Chan ED. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Medicine. 2012 Aug 1;9(8):1212

Quality assessment № of patients Effect Quality Importance № of Study standardised conventional Relative Absolute Risk of bias Inconsistency Indirectness Imprecision Other considerations studies design shorter regimens longer regimens (95% CI) (95% CI)

Treatment success vs. failure/relapse (assessed with: indirect comparison of two aggregate data meta-analyses (one of shorter regimens and one of longer regimens) )1

37 2 observational very serious serious not serious serious strong association 1008/1033 (97.6%) 4033/4639 (86.9%) not estimable 5 5 CRITICAL ⨁◯◯◯ studies all plausible residual 3 4 confounding would reduce VERY LOW the demonstrated effect

Treatment success vs. failure/relapse/death (assessed with: indirect comparison of two aggregate data meta-analyses (one of shorter regimens and one of longer regimens)1

37 2 observational very serious serious not serious serious strong association 1008/1116 (90.3%) 4033/5850 (68.9%) not estimable 5 5 CRITICAL ◯◯◯ studies all plausible residual 6 7 ⨁ confounding would reduce VERY LOW the demonstrated effect

Treatment success vs. failure/relapse/death/loss to follow-up (assessed with: indirect comparison of two pooled individual patient meta-analyses)1

37 2 observational very serious serious not serious serious strong association 1008/1205 (83.7%) 4033/7665 (52.6%) not estimable 5 5 CRITICAL ◯◯◯ studies all plausible residual 8 9 ⨁ confounding would reduce VERY LOW the demonstrated effect

CI: Confidence interval ; RE=Random effects

1. In the shorter regimen meta-analysis, data on relapse were only available from the published studies (references 4,5 and 6); in the conventional regimen studies relapse was ascertained in 14 cohorts overall (reference 7) 2. 6 studies of shorter regimens, 31 studies of conventional regimens 3. unweighted proportion; weighted proportion from RE meta-analysis: 97.6% (95%CLs: 92.4%- 99.2%) 4. unweighted proportion; weighted proportion from RE meta-analysis: 91.2% (95%CLs: 86.1%- 94.6%) 5. due to methodological differences in the studies the relative and absolute risks are not shown. The shorter MDR-TB regimens dataset consists of recently conducted studies - some ongoing - in which patients were carefully selected, in which all data were prospectively collected as part of a research protocol, and in which patients were uniformly treated with a standardized regimen. By contrast, the studies in the conventional longer regimens dataset are on average older, many were retrospective series, and many used data collected for clinical purposes. The great majority of patients in the conventional regimens group received individualized therapy, with many regimens that differ from one another in the number and type of drugs used, and the duration of treatment 6. unweighted proportion; weighted proportion from RE meta-analysis: 90.3% (95%CLs: 87.8%- 92.4%) 7. unweighted proportion; weighted proportion from RE meta-analysis: 78.3% (95%CLs: 71.2%- 84%) 8. unweighted proportion; weighted proportion from RE meta-analysis: 83.7% (95%CLs: 79.2%- 87.4%)

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9. unweighted proportion; weighted proportion from RE meta-analysis: 61.7% (95%CLs: 53.1%-69.6%)

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