Background

The emergence of drug resistance is a major threat to global tuberculosis (TB) care and control. The World Health Organization (WHO) estimates that up to half a million new cases of multidrug-resistant tuberculosis (MDR-TB) cases (i.e. resistant to, at least, rifampicin and isoniazid) occur each year globally. Current treatment regimens for MDR-TB are far from satisfactory: the overall duration is 20 months or more, requiring daily administration of drugs that are more toxic and less effective than those used to treat drug-susceptible TB, and have a high cost. Among MDR-TB patients started on treatment globally in 2009, only 48% were treated successfully, largely as a result of a high frequency of patient deaths (15%) and loss to follow-up (28%), which is commonly associated with adverse drug reactions, among other factors. In a subset of 200 extensively drug-resistant tuberculosis (XDR-TB) patients in 14 countries, treatment success reached only 33% overall and 26% of the patients died. New drugs that would help build a better, safer, less toxic, shorter and cheaper regimen are therefore urgently needed to reduce patient suffering and mortality.

The landscape of TB drug development has evolved dramatically over the past ten years, and novel drugs are entering Phase III trials for the treatment of MDR-TB. Among these, a new drug, bedaquiline, has recently (December 2012) been granted accelerated approval by the United States Food and Drug Administration (US-FDA) based on Phase IIb data. Similar submissions are currently being made to other national regulatory authorities worldwide. WHO Member States have requested the organization to provide interim policy guidance on the use of bedaquiline as part of the treatment of MDR-TB.

It is acknowledged that developing interim guidance on the use of a new TB drug on the basis of Phase IIb trial data is a novel step for WHO. Issuing interim guidance carries with it the responsibility of ensuring that it provides specific recommendations on the conditions for the use of the drug that reflect the limited data currently available. It will also be necessary for WHO to review, revise and/or update the interim guidance as additional substantive data on efficacy and safety become available. Acceleration of Phase III trials and completion at the earliest opportunity is imperative, as is timely analysis of emerging operational data on the use of the drug. It should also be noted that, in the absence of interim guidance from WHO, uncontrolled and potentially irresponsible use of the drug may adversely affect TB care and control efforts overall – potentially prompting the emergence of bedaquiline resistance and the possible loss of the first new TB chemotherapeutic drug in over 40 years.

Objectives, rationale and methods used to develop the guidance

This document provides interim guidance for the use of bedaquiline in conjunction with other WHO-recommended MDR-TB treatments. It also specifies the essential treatment and management conditions for the use of this drug. The main audiences are national TB control programmes (NTP), other public health agencies, and other public and private partners involved in planning, implementing and monitoring MDR-TB control activities. The principles and recommendations are also relevant for specialist clinicians, technical advisors, laboratory technicians, drug procurement managers, other service providers, other relevant government officials, and implementing partners involved in country-level MDR-TB service strengthening. Individuals responsible for programme planning, budgeting, resource mobilization, and training activities for MDR-TB diagnostic services may also benefit from this guidance.

An Expert Group (EG) was convened by the WHO/Stop TB Department in Geneva, Switzerland from 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 safety data available for this drug, used for the treatment of MDR-TB, are results from Phase IIb studies only (i.e. not Phase III trials), the potential guidance could only be provisional, until further clinical trial and safety data are available.

The overall objective of the EG meeting was to evaluate the added benefit of bedaquiline for the treatment of MDR-TB and, if appropriate, to provide recommendations to WHO for interim guidance to countries on its use in conjunction with other second-line drugs used in MDR-TB treatment.

The specific objectives were:

1. To evaluate the efficacy and safety of bedaquiline in addition to currently WHO-recommended MDR-TB treatments.
2. To evaluate the balance between harms and benefits of the drug, its potential cost-effectiveness, patient and provider preferences and concerns, and the feasibility of introducing the drug into MDR-TB programmes.
3. To provide, as appropriate, recommendations on the use of the drug as part of WHO-recommended MDR-TB treatment regimens, including attention to concerns/constraints relevant to the potential use of a new drug for which Phase III clinical trial data are not yet available.

The EG consisted of researchers, epidemiologists, end-users (clinicians and NTP officers), community representatives and experts in evidence synthesis. Declarations of Interest were managed according to WHO rules.

Publicly available data on the pre-clinical and clinical development of the drug were reviewed to assess efficacy, safety and tolerability of the drug, and complemented by modelling work to assess the potential cost-effectiveness of programmatic implementation. Issues to be addressed in future research were also discussed. In addition, data on final outcomes of the pivotal proof-of-concept Phase II trial (that had not been evaluated by the US-FDA in their accelerated regulatory assessment) were provided to WHO by the manufacturer, allowing more comprehensive review by the EG. To comply with current standards for evidence assessment in formulation of policy recommendations, the GRADE system¹ adopted by WHO for policy and guidelines development was used.

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

The following outcomes were selected by the EG for evaluation:

1. Cure by end of study – 120 weeks.
2. Serious adverse events during investigational 24 weeks treatment phase.
3. Mortality.
4. Time to culture conversion over 24 weeks.
5. Culture conversion at 24 weeks.
6. Acquired resistance to second-line drugs (fluoroquinolones, amino-glycosides and capreomycin) at 72 weeks.

Summary of available data

Data were available from a series of studies and trials made public by the manufacturer, and supplemented with final outcome results made available to WHO. Main findings on efficacy and safety originated from two Phase IIb trials: (1) C208, a two-stage trial of 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 proof-of-efficacy study; and (2) C209, a single-arm, open label trial.

Expert Group findings

The EG concluded that the randomized, double-blind, design of the pivotal study was of high quality, although information on the desired sample size and on the actual randomization process was not available. The EG was, however, concerned about the use of mITT analysis (and subsequent assumptions made), as well as the representativeness of the study population. Experts were also concerned about the low cure rate at 120 weeks observed in the placebo group, when compared to those reported from recent published reviews. This could indicate that the patients included in the trial were not representative of the MDR-TB population at large and that the effects observed in the bedaquiline arm may not be reproducible under programme conditions.

Concern was also expressed that, in the absence of patient data on drug susceptibility test status in the different arms, the BR used in various sites of the trial may not have been compliant with WHO recommendations. There was further concern on the generalizability of the data to the target patient group (e.g. a greater proportion of HIV co-infected TB cases occurred in the placebo arm; XDR-TB patients were excluded). Lastly, there was concern on the generalizability of study findings to all populations and to all regions in the world. The overall quality of evidence for efficacy was therefore graded as “Low”, i.e. the EG had low confidence in the estimate of effect (or efficacy) of bedaquiline.

The EG expressed concern on the risk of QT prolongation and the additive effect in combination with other MDR-TB drugs reported to prolong QT. The EG also expressed concerns regarding co-morbidities (notably HIV infection and liver diseases), and the effects of alcohol or substance use on the risk of severe adverse events. The evidence for safety as reflected by AEs was therefore graded as “Very low”.

The EG was highly concerned with the observed difference in mortality between the bedaquiline and placebo arms in the C208 stage 2 trial. No clear pattern could be observed, and reason(s) for the imbalance were unclear. The quality of evidence for mortality as a measure of safety was therefore graded as “Very low”.

Lastly, the EG had concerns about the available data on emergence of resistance, due to a high risk of bias, as serial drug susceptibility data on patient strains were not provided (i.e. at enrolment and during follow-up). The quality of evidence for acquisition of resistance to fluoroquinolones, aminoglycosides or capreomycin was, therefore, graded as “Very low”.

Modelling of the incremental cost-effectiveness of adding bedaquiline to WHO-recommended MDR-TB regimens was conducted by an independent consultant contracted by WHO for review by the EG. The model assumed that bedaquiline would be added to treatments for all patients starting MDR-TB treatment. Data from WHO were available on current MDR-TB treatment costs (excluding programme costs) and effectiveness in several high TB burden settings. Several scenarios were explored to appraise the cost-effectiveness of bedaquiline in these settings. Under the model assumptions, 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 of trial results to routine settings. The EG noted that further analysis would be needed to test the robustness of the assumptions in various settings and to separately assess affordability. As the recommendation of the EG was to use bedaquiline only for selected sub-groups of the full MDR-TB patient population, as opposed to all patients with MDR-TB that were considered in the cost-effectiveness analysis, the cost-effectiveness model needs to be further refined such that results are available for these sub-groups specifically.

The final grading of evidence for the use of bedaquiline in MDR-TB treatment was “Very low”. There was modest agreement among the EG that the quality of evidence for possible benefits was “Low” due to imprecision and indirectness, and high agreement that the quality of evidence for possible harms was “Very low” due to imprecision, indirectness and risk of bias. The EG could not reach consensus, however, on the overall balance of harms and benefits and proceeded to a vote (observers and technical resources consultants were excluded). The results were as follows: 10 votes that benefits outweighed harms; 4 votes that harms outweighed benefits; and 2 abstentions (including the chair).

Expert Group recommendations

The EG suggested that, as an interim recommendation, bedaquiline may be added to a WHO-recommended regimen in adult MDR-TB patients under the following conditions (conditional recommendation, very low confidence in estimates of effect, i.e. very low quality of evidence):

• when an effective treatment regimen containing four second-line drugs in addition to pyrazinamide according to WHO recommendations cannot be designed;
• when there is documented evidence of resistance to any fluoroquinolone in addition to multidrug resistance.

In addition, the EG recommended that:

• a duly informed decision-making process by patients should be followed;
• bedaquiline be used with caution in people living with HIV, as well as in patients with co-morbidities (e.g. diabetes) or people reporting alcohol or substance use, due to limited or no information;
• bedaquiline be used for a maximum duration of 6 months and at suggested dosing (400 mg daily for the first 2 weeks, followed by 200 mg three times per week for the remaining 22 weeks);
• bedaquiline must not be added alone to a failing regimen;
• baseline testing and monitoring for QT prolongation and development of arrhythmia is imperative;
• clinical monitoring and management of co-morbidities (especially cardiac and liver disease) should be in place;
• spontaneous reporting of adverse drug reactions is reinforced at country level and active pharmacovigilance is established among patient groups treated with the drug;
• in the absence of a specific drug-susceptibility test, resistance to bedaquiline should be monitored through assessment of minimum inhibitory concentrations (MICs);
• resistance to other anti-TB drugs should be monitored following WHO recommendations.

The EG also recommended that these interim recommendations be re-assessed in 2015, or earlier if additional data of significance become available that increase the knowledge on safety, toxicity and/or efficacy of bedaquiline. In addition, the EG identified a number of research topics to be addressed to inform future guidance on the use of bedaquiline.

WHO Interim policy recommendations

In view of the aforementioned evidence assessment and advice provided by the EG, WHO recommends that bedaquiline may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB(conditional recommendation, very low confidence in estimates of effects). Given the limited data available on bedaquiline and its use under the various situations that may be encountered in different clinical settings, adequate provisions for safe and effective use of the drug must be in place. Consequently, countries are advised to follow a phased approach to bedaquiline implementation, ideally through observational cohorts, where the following measures are in place. The WHO recommendation for the inclusion of bedaquiline in the adult treatment regimen of MDR-TB is subject to the following 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 safety. Given that the results of the Phase IIb trial showed an excess mortality in the bedaquiline arm versus placebo arm, and that results of Phase III trials are only expected a few years from now, it is particularly important that the introduction of bedaquiline is carefully monitored for safety. It is therefore recommended that the following measures are in place:
   1. Sound treatment and management protocols, including clear patient eligibility criteria, procedures for informed consent and defined roles and responsibilities of all professionals involved. The treatment protocols should allow for the prospective capture of data on key variables for both effectiveness and safety. Safety concerns are best addressed using the cohort event monitoring methodology employed for active pharmacovigilance. Electronic systems will facilitate efficient data management and generation of key indicators.
   2. Treatment protocols are preferably submitted to and approved by the relevant national ethics authority in the country, prior to patient enrolment on treatment.
   3. Preferably, oversight of treatment and management programmes is provided by an independent group of experts in clinical management and public health – for instance, such as a national MDR-TB advisory group.
2. Proper patient inclusion. The current recommendation for the use of bedaquiline applies to adults (≥18yrs) with pulmonary disease. Special caution is needed when bedaquiline is used in persons aged 65 years and older, and in adults living with HIV, as data on efficacy and safety are extremely limited. Use of the drug in pregnant women and children is not advised due to a lack of evidence on safety and efficacy. While patients with exclusive extrapulmonary disease were not included in the bedaquiline trial, the use of the drug in extrapulmonary TB patients may be considered, extrapolating from the data in patients with pulmonary TB.
3. Patient informed consent obtained. Health-care providers should ensure that the patient is: (i) aware of the novel nature of bedaquiline; (ii) appreciates the reason why the drug is being proposed to be included in the regimen; and (iii) recognizes the benefits and potential harms. In addition, health-care workers should obtain the patient's agreement on the inclusion of bedaquiline in the prescribed treatment regimen. This informed consent process must be documented and signed by the patient, and applies to all situations where bedaquiline is employed, including under compassionate 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-TB regimen using conventional second-line medication still exist. In addition, the shortcomings of conventional drug-susceptibility testing (DST) of second line anti-TB drugs must be taken into account: DST of second-line drugs is only considered to be accurate and reproducible for fluoroquinolones, aminoglycosides (kanamycin, amikacin) and capreomycin (a polypeptide).
   1. The WHO-recommended MDR-TB treatment regimen is typically composed of at least pyrazinamide and four second-line drugs considered to be effective (based on drug susceptibility testing (DST) and/or previous use and/or drug resistance surveillance data): a fluoroquinolone (preferably later-generation), a second-line injectable agent, and two bacteriostatic drugs, preferably prothionamide or ethionamide plus cycloserine or p-aminosalicylic acid. Bedaquiline may be indicated if such a regimen is not feasible because of:
      1. in vitro resistance to a drug (see b. and c. below );
      2. known adverse drug reactions, poor tolerance, or contraindication to any component of the combination regimen; or
      3. unavailability or lack of a guaranteed supply of a drug(s).
   2. MDR-TB patients with strains resistant to fluoroquinolones or the second-line injectable drugs (kanamycin, amikacin, capreomycin) represent a particular concern given that these are the two most effective classes of second-line drugs. In such cases, bedaquiline may have a crucial role to play to strengthen a regimen, bringing the number of drugs likely to be effective to a minimum of four, and averting the acquisition of additional resistance and progression towards XDR-TB.
   3. While experience in the use of bedaquiline in the management of XDR-TB is limited, it may have an indication in such patients given the limitations in designing an effective regimen based on existing recommendations in many situations. In patients resistant to both classes of injectable drugs and also to fluoroquinolones (i.e. XDR-TB), bedaquiline may lower the need to include drugs belonging to Group 5, some of which have unproven anti-TB activity, high cost, and/or high toxicity.⁵ Bedaquiline may thus be used with or instead of a Group 5 drug. In these cases, special caution is advised on the potential increase of adverse drug reactions due to potential drug–drug interactions, particularly the synergistic cardiotoxic effect on QT prolongation, necessitating close ECG monitoring.
   4. In line with general principles of TB therapeutics, bedaquiline should not be introduced into a regimen in which the other companion drugs are known or believed to be ineffective or are failing to show effectiveness. This implies that bedaquiline should not be added alone to a failing regimen, and should be introduced well before the regimen fails completely.
   5. Bedaquiline should be used strictly at the dose recommended by the manufacturer, i.e. 400mg daily for the first two weeks, followed by 200mg three times per week at least 48 hours apart, for a total maximum duration of 24 weeks. Available data suggest better uptake of bedaquiline when administered with food.
5. Pharmacovigilance and proper management of adverse drug reactions and prevention of drug–drug interactions.
   1. Special measures need to be put in place to ensure the early detection and timely reporting of adverse events using active pharmacovigilance methods, such as ‘cohort event monitoring’. Any adverse drug reaction attributed to bedaquiline should also be reported to the national pharmacovigilance centre as part of the spontaneous reporting mechanism in the country. As for any other drug in the MDR-TB regimen the patient should be encouraged to report to the attending health worker any adverse event that occurs during the time the drug is being taken. Such occurrences should also trigger a rapid response to manage these untoward effects in the patient.
   2. When introducing bedaquiline into a regimen, there is also the potential for its interaction with other medications administered concurrently, with additive or synergic adverse effects. Other second-line drugs that are likely to be administered with bedaquiline, particularly clofazimine and moxifloxacin, may increase the risk of cardiotoxicity. Thus, if the drug is introduced into the MDR-TB treatment regimen, monitoring of patients for cardiac dysrhythmias or QT prolongation (i.e. using ECG), liver dysfunction, renal impairment, and other effects as denoted in the product briefing package is mandatory.
   3. Caution should be exercised when giving bedaquiline together with accompanying drugs that may inhibit liver function (e.g. the effect of ketoconazole or lopinavir/ritonavir on the enzyme CYP3A4), as these could increase bedaquiline concentrations, resulting in toxicity, or with accompanying drugs that may induce liver function (e.g. the effect of rifampicin on the enzyme CYP3A4), as these could result in sub-therapeutic bedaquiline concentrations, resulting in reduced efficacy. Of note, very limited data are available on drug–drug interactions with antiretroviral medicines, and these are based on single dose studies conducted in healthy normal volunteers. Therefore, people living with HIV who will be receiving bedaquiline as part of MDR-TB treatment should have their antiretroviral therapy (ART) regimens designed in close consultation with HIV clinicians and ART specialists.
   4. Lastly, caution is advised in patients with pre-existing health conditions that may be exacerbated or worsened by bedaquiline. Currently there are no data on the efficacy and safety of bedaquiline in patients with co-morbid conditions such as diabetes, liver and/or renal dysfunction, malignancies, alcohol and substance use, and therefore careful screening for these conditions prior to treatment initiation is required.

WHO strongly recommends the acceleration of Phase III trials in order to generate a more comprehensive evidence base to inform future policy guidance on bedaquiline. WHO strongly urges the development of accurate and reproducible DST methods for bedaquiline and other second-line drugs.

Footnotes

1

GRADE: Grading of Recommendation Assessment, Development and Evaluation.

4

QTcF: QT interval corrected for heart rate according to the Fridericia method.

5

Group 5 drugs belong to different classes of medicines and are not recommended by WHO for routine use in DR-TB patients.