Introducing the longer and shorter MDR-TB regimens entails a series of steps that are the same as those necessary when an NTP introduces a new MDR-TB treatment component. Some key points are summarized below.
Policy and operational documents
Policy and operational documents that govern the main components of the programme would need to be revised. Such documents include the national strategic plan for TB, treatment guidelines and algorithms, diagnostic algorithms, the essential medicines list, regulations (e.g. importation of clofazimine and pretomanid), drug orders and training material. No immediate changes are usually needed to the second-line TB treatment register (although WHO is revising the definitions and reporting framework for TB in 2020) (26). The TB treatment card may be changed to allow the tabulation of results of periodic testing for treatment response and adverse reactions (this may have already been done for the purposes of aDSM) (19). Any changes should also cover for use of the regimen in private practice.
National MDR-TB expert committee and/or technical working group
A national MDR-TB expert committee or technical working group (the consilium or its equivalent structure within the NTP) will assist health care providers as early as possible to:
• coordinate policy changes and activities related to the introduction of the revised MDR-TB regimens in both the public and private sectors (e.g. training, communication, establishing patient eligibility for the different MDR-TB regimens);
• train staff in the clinical aspects of aDSM;
• provide patient support; and
• provide technical and clinical advice.
Additional support may be provided by other experts at national and international (e.g. regional Green Light Committee (rGLC)) level. This needs to consider any phased implementation process, such as the initial introduction in one or a few centres before full scale-up, or whether implementation is also occurring in the private sector
Electronic recording and reporting
There is a need to improve the quality of patient data using standardized variables, such as data on DST pattern, prescribed treatment, treatment outcomes and adverse drug reactions. Collection and utility of these data are important for future evidence-based recommendations, especially given the lack of RCTs on the management of drug-resistant TB (126). If digital patient records do not already exist, it is important that the programme management considers their introduction, at least for surveillance, if not for case management as well (127). If patient records are already digital, changes may be needed in the electronic recording and reporting system to allow individuals belonging to MDR-TB regimen cohorts of interest (e.g. shorter regimen, bedaquiline-containing regimens and operational research subgroups) to be identifiable, and for certain options to be included in the monitoring framework (e.g. addition of clofazimine and registration of ECG findings). It is crucial for programmes to maintain such data diligently and prospectively, so that they can contribute to programme evaluation and to global policy-making (the development of the WHO consolidated guidelines benefited hugely from experience of patient treatment within programmes) (29, 30). The treatment outcome cohort reports for MDR/RR-TB need not change (for the digital and paper version). Moreover, electronic tools can enhance the quantification of consumables; for example, volumes of medicine can be calculated automatically using QuanTB, an application that is available for download free of charge.²⁸
Estimates (epidemiological and logistics)
Estimates are needed by the NTP and other health care providers, to determine the number of MDR/ RR-TB patients eligible for the longer and shorter MDR-TB regimens, to revise the budget accordingly, and to submit the corresponding requests for drug orders taking into account the existing stock of medicines. These estimates of MDR/RR-TB patients likely to be enrolled are based on current notification trends and an expected increase as per national and subnational plans. The programme first establishes the number of MDR-TB enrolments expected in the coming years, depending on the future increase in programme capacity (e.g. as part of a project supported by a grant from the Global Fund to Fight AIDS, TB and Malaria). Then, based on knowledge from surveillance, eligibility and estimated rate of scale-up, different patient groups are defined; for example, those expected to receive different variants of the longer MDR-TB regimens and those likely to receive a shorter MDR-TB regimen. When estimating the caseload to put on treatment, it is necessary to factor in not just eligibility, but also what would be feasible to achieve within a given time, to ensure that all elements are in place for starting and maintaining patients on treatment (e.g. training and provision of an adequate framework for patient monitoring and support). Associated programme and patient costs other than the medicines themselves usually dominate the total cost for both longer and shorter MDR-TB regimens (e.g. treatment of adverse events, hospitalization, diagnostic consumables, other clinical care and social support); however, total costs are expected to be lower for shorter regimens, given the shorter duration of treatment.
Management of the supply chain and storage conditions for pharmaceuticals
Management of the supply chain and storage conditions for pharmaceuticals have to be reviewed to ensure that TB drug orders are made in good time and are correctly quantified to avert overstocking or shortages. The NTP must ensure an uninterrupted supply of TB medicines through proper quantification, supply planning and rigorous quarterly monitoring, with a functional early warning system to avoid stock-outs and subsequent treatment interruptions. Likewise, other consumables (e.g. medicines for symptomatic relief and adverse reactions, syringes, diagnostic kits, medication for management of adverse effects, masks and N95 respirators) will be needed to ensure that the intervention is delivered as per internationally recommended standards (128). The principles for the quantification of medicines needed for the longer and shorter MDR-TB regimens are similar. The health care provider needs to have some basic details about how many patients will be treated and when they will start; the expected increment in caseload over successive years; the average body weight of the patients; whether children will also be enrolled; the expected losses (from interruptions, deaths and transfers to another regimen); current stock on hand, including expiry dates and orders of medicines already in the pipeline and not yet delivered; and whether some medicines will be exchanged during the period (e.g. amikacin has been replaced by bedaquiline following the 2019 revision). It is best to split an order of medicines, the first part for the patients expected to be started within 6 months, and then to adjust the second part of the order based on the actual enrolments. Technical assistance to strengthen the procurement and supply and to establish an early warning system for stock-outs can be accessed via the Global Drug Facility (GDF; email email@example.com), regional Green Light Committee (GLC) secretariats housed in WHO regional offices, or WHO country offices. GDF provides support to many national TB programmes on the procurement and supply chain aspects of phase-in and phaseout plans of products or regimens and can procure child-friendly formulations.
Active TB drug safety and monitoring (aDSM) is particularly important given the increased use of newer and repurposed medicines in combination MDR-TB regimens. aDSM defines the active and systematic clinical and laboratory assessment of patients on MDR-TB treatment to detect, manage and report suspected or confirmed drug toxicities (19). aDSM applies the principles of active pharmacovigilance to the specific needs and context of national TB programmes and is embedded within the routine patient monitoring function (e.g. treatment outcome cohort monitoring) of NTPs. The management of patient safety is an inherent part of aDSM, inseparable from its monitoring component. The recording and reporting activities of aDSM primarily target serious adverse events as a priority requirement, but any adverse event during treatment administration that may or may not be related to drug toxicity needs to be managed to limit harms to patients. MDR-TB treatment sites may also monitor non-serious adverse events which are of clinical significance or of special interest to the programme, as part of more comprehensive aDSM. In aDSM, besides the spontaneously reported reactions, adverse events are also elicited as part of a patient monitoring plan comprising a set of questions and oftentimes an array of laboratory or clinical tests at defined periods of time, before, during and after treatment.
When planning important changes for the national TB treatment policy to align to the latest WHO recommendations, the programme needs to balance the will to provide the best possible options for patients according to the latest evidence with the programmatic circumstances and the implications of such changes (e.g. need to re-train staff, reprogramming funds). Table 10.1 presents another checklist for chief considerations for the programme manager when implementing the MDR-TB regimens that are currently recommended. The programme needs to balance the need to provide access to new medicines for which the evidence is still incomplete with the need to protect patients from avoidable toxicity, the emergence of resistance to the new agents and observance of proper ethical conduct and respect for patient rights.
²⁸ Available at http://siapsprogram.org/tools-and-guidance/quantb/.