Integration of drug safety monitoring in tuberculosis treatment programmes: country experiences

Why active drug safety monitoring?

Monitoring and management of AEs has been recommended by the WHO since 2006 [45]. The careful recording of clinical aspects and actions taken, including the identification and management of AEs, is an intrinsic component of good clinical practice [46] and is included in the International Standards of TB Care [47]. A systematic overview of the occurrence of (common) AEs, and the drugs with which these are treated, is needed to allow the procurement of ancillary drugs to be carefully planned [48]. Furthermore, surveillance of AEs is needed to detect and describe rare AEs [49] that cannot be detected in the small-scale clinical trials on which most (conditional) approvals from drug regulatory authorities are based. Clinical trials do not always include specific sub-populations such as children, pregnant and lactating women, the elderly and patients with comorbidities [8, 50], nor cover all geographical regions with a high burden of DR-TB. Specific populations may require specific dosing and may have altered drug responses compared to the patients included in phase II trials [51]. The lack of drug safety data leads to limited understanding of the burden of AEs due to anti-TB treatment and the net benefit of treating DR-TB and extensively drug-resistant (XDR)-TB, i.e. MDR-TB with additional resistance to second-line injectable drugs and fluoroquinolones, given that it remains unknown to what extent the occurrence of AEs leads to unfavourable treatment outcomes (such as untimely death, treatment failure) and loss to follow-up, especially in resource-constrained countries where the TB burden is highest [52] and detection and clinical management expertise and options more limited.

Many countries have a system of spontaneous reporting of AEs using Individual Case Safety Reports (often referred to as the “yellow form” or “yellow card” system) available from the Council for International Organizations of Medical Sciences (www.cioms.ch). Currently, this form is the only internationally recognised format; however, many different variants of spontaneous AE reporting forms are being used (e.g. [53]). In practice, spontaneous reporting rarely occurs [54, 55], notably for TB. This indicates a lack of knowledge among healthcare workers about the existence of PV authorities, proper cross-training and basic awareness of the importance of this work. Adequate collaboration between public health programmes and medicine regulatory authorities is often lacking [43, 56–58]. In 2011 and 2012 respectively, only four of 46 sub-Saharan African countries [43] and one of five Asian countries [57] included in regional situational analyses had a PV system functionally able to detect, evaluate and prevent medicine safety issues. TB programmes, in particular, had not undertaken active surveillance of AEs. It should be noted that these assessments were done some years ago; the requirement of implementing active PV for patients on ND&R is forcing changes to this landscape (e.g. www.fhi360.org/sites/default/files/media/documents/resource-pv-workshop-report.pdf), although strong collaborations between the national TB programme (NTP) and the national PV centre (NPVC) have not always been established [58].

Active drug safety monitoring in resource-constrained settings

aDSM as recommended by the WHO is now being implemented in most countries with a relatively high burden of RR-/MDR-TB [52], with the support of local and international partners such as the WHO, the KNCV Tuberculosis Foundation (KNCV), Médecins Sans Frontières, Partners in Health, FHI360, Management Sciences for Health, the Union and PATH, and external funding (e.g. from the United States Agency for International Development and the Global Fund Against AIDS, Tuberculosis and Malaria). aDSM envisions real-time recording and reporting of AEs, i.e. prospective data collection. Data are collected nationally, mostly by NTPs.

Collection in a global database is currently conducted through at least four different mechanisms. First, following pre-existing legal mechanisms, in some countries (e.g. Tanzania and Indonesia) AE reports are transferred to the regular PV authorities, which assess them and submit suspected adverse drug reactions (ADRs) to the Uppsala Monitoring Centre that has hosted the WHO programme for international drug monitoring (www.who-umc.org) since 1978. Sagwa et al. [59] have assessed the association between ototoxicity and the use of aminoglycosides and capreomycin in TB treatment, but this study only included reports up to June 2014, i.e. before aDSM was recommended. Two publications from the Nigerian PV programme about AEs in (MDR-)TB treatment were based on reports in their national PV database [60, 61], also before implementation of aDSM in their country. Second, specifically for the surveillance of AEs in the scope of aDSM, the WHO Global TB Programme with the Special Programme for Research and Training in Tropical Diseases has developed the global aDSM database (www.who.int/tdr/research/tb_hiv/adsm/en/) [62]. By the end of January 2019, 16 countries had reported a total of 891 AEs to this database (C. Halleux, personal communication). Third, 27 countries that reportedly faced difficulties in submitting data to the global aDSM database have committed to report to the recently implemented Global TB Network hosted by the World Association for Infectious Diseases and Immunological Disorders (www.waidid.org/) [63, 64]. So far, 18 countries have shared data, which were planned for publication in the second quarter of 2019 [64]. Finally, while the mechanisms noted above are done on a voluntary basis, the Global Drug Facility (www.stoptb.org/gdf/), which provides quality-assured drugs globally including Bdq and Dlm, requires mandatory reporting of all SAEs among those patients receiving Bdq and/or Dlm through the Global Drug Facility.

Apart from two conference abstracts from Belarus in 2016 [65, 66], up to April 2019 no results on the frequency and type of AEs reported through aDSM had been published. However, there are a limited number of reports on prospectively collected data on AEs in patients treated with ND&R in programmatic settings [14, 17, 18, 23, 67–70]. These eight reports describe partially overlapping cohorts (table 1). Four reports on three cohorts describe the safety and efficacy of regimens containing Bdq [14, 17, 18, 69], one report describes this for Dlm [68], two reports for two cohorts receiving both Bdq and Dlm [23, 70], and one report describes the safety and efficacy of a modified STR in which kanamycin was replaced with Bdq [67]. The safety data obtained from these reports are summarised in table 1. Most reports focused on QT prolongation. There was a large range in the frequency of any AE, with 38% [69] to 96% [18] of the patients reporting at least one AE. A systematic review also concluded that the frequency and type of AEs among RR-/MDR-TB patients reported in the published literature varies greatly across studies [38]. This may in part be due to differences in treatment regimens, patient selection, availability of clinical monitoring tests for early detection of AEs and variable management of AEs. But it probably also illustrates cultural differences, focus on different types of AEs, omissions and mistakes (both in reporting by patients and healthcare workers) and differences in recording. Differential reporting is probably partly owing to the fact that the vast majority of AEs reported by patients are mild and nonspecific, and it is thus left to the clinician's judgement whether or not such an AE should be reported. For example, very low concordance was found between types of AEs reported by clinicians (with associated significant under-recording of AEs by clinicians) as compared to patient's reports in a cross-sectional study of 121 South African DR-TB patients [71]. Increased awareness about AEs and ADRs and why these should be reported may help to improve reporting [72].

Still, there are major constraints in terms of human and financial resources for PV [58], probably because investing in PV systems is considered a luxury in countries where not all those who have health needs even have access to appropriate treatment [56]. Because of the absence of strong PV structures and confusion about PV requirements, some countries have reported that the requirement for active PV has delayed the implementation of ND&R in their country [73, 74].

Country experiences in the introduction of active drug safety monitoring

Translating global policy into practice, the KNCV, in the framework of the United States Agency for International Development-funded Challenge TB project, prepared a generic implementation guide for the introduction of ND&R for the treatment of DR-TB [75]. This document provides practical guidance on all aspects that need to be addressed when introducing ND&R, including the implementation of aDSM, while building on the WHO policy [44]. Challenge TB/KNCV recommend that the countries supported by the project choose the intermediate package of aDSM, if feasible, because the core package is regarded as the bare minimum, while the advanced package is usually not feasible given the limitations in staff and other resources in these countries. Programmes that have adopted the intermediate aDSM package should not forget to stress the importance of early detection and management of AEs that may not be of special interest, because these may affect the patients' quality of life and jeopardise treatment outcomes. Healthcare providers should take the opportunity to report previously unknown AEs to increase knowledge about the safety profiles of ND&R.

Because KNCV sees a central role for the national PV authorities if available in the country [75], we actively involved the NPVCs from the first phase of preparing the country for the introduction of aDSM to avoid duplication of work and to build a sustainable system. This is in line with recommendations by PV experts for a central role of the national PV authorities in all PV-related activities; these experts stress that the PV authorities should decide which products are approved for use in public health programmes and advise them to make the reporting of AE and medication errors mandatory for all organisations acting as “marketing authorisation holders” (note that these can be public health programmes for unregistered products that enter the country through special access arrangements, which is often the case for Bdq, Dlm and repurposed drugs) [56].

Here, we present data from a representative set of countries that were implementing aDSM and collecting data in 2017 in which we assisted in organising active PV for ND&R (table 2). While NPVCs were available in all six of these example countries, until the introduction of aDSM for ND&R they had mainly, or only, conducted spontaneous reporting, with the exception of Vietnam. The overall number of spontaneous reports received per year was low in most countries (1.1 in Myanmar (2015) to 24 in Kyrgyzstan (2014) per million population). An exception was Vietnam, where the PV centre received 108 reports per million population in 2015. The number of reports specifically concerning TB treatment was low in most countries. In Kyrgyzstan, 46 (33%) of the reported AEs were related to drugs used for the treatment of TB, while the Indonesian PV centre received 355 AE reports (16% of the total number of reports received) related to anti-TB drugs in 2014, 54 of which were submitted by the NTP. In Myanmar, there were no AE reports about patients receiving TB treatment before the introduction of aDSM. This indicates that, although treating physicians are generally aware of the occurrence of (well-known) ADRs during TB treatment, there is little awareness of the usefulness of reporting AEs in general, whether new, previously unknown ADRs or clinically well-known but rare reactions of frequently used drugs not yet described in the summaries of product characteristics.

To introduce active PV in these countries, KNCV organised several joint training sessions for clinical staff and staff from the PV unit to bolster understanding of PV and related processes, particularly on the detection, clinical management and reporting of AEs and on causality assessment. Key activities further included the formation of a technical working group on PV representing all key stakeholders, which should facilitate collaboration between the NTP and the NPVC in conducting active PV; developing a national guidance document on the introduction of ND&R, including the detection, clinical management and reporting of AEs with a roadmap for scale-up; organising access to monitoring tests required for the safe introduction of ND&R; developing a specific (aDSM) reporting form for AEs; and setting up the AE report flow from facility level to national and global levels. The implementation process was strengthened by on-the-job training of staff involved, including supportive supervision visits and (distance) mentoring.

Four of the countries chose to adopt the aDSM intermediate package; because of limited human resources, in Myanmar the core aDSM package was adopted (table 2). Indonesia initially selected CEM, because at that time, the WHO aDSM guidance document [44] was not yet available. A PV officer with a medical doctor's or pharmacist's degree was hired for each of the three pilot centres implementing the ND&R to facilitate the NTP's efforts to systematically collect and record safety data using Global Fund resources. The main issues with the implementation of CEM were the workload; the high turnover of PV officers; confusion over the responsibilities of the NTP and the NPVC (e.g. who should initiate the causality assessment?); and limitations in human resource capacity, causing considerable delays in the conduct of causality assessment. Because of these challenges, the programme decided to shift to the core aDSM package for further scaling-up the aDSM.

In all countries, there were limited human resources for PV and frequent personnel changes, which affected the level of expertise in the validation of reports, causality assessment and signal detection. As a consequence, receipt of AE reports was not always acknowledged, reports were not regularly checked and causality assessment was delayed. Most countries were necessarily focusing on assessing the SAEs first, while assessment of the AEs of special interest was postponed. Because feedback on their reports, including the results of causality assessment, was often not sent to the reporters, clinicians were not motivated to send in new reports. The commonly weak link between the NPVCs and the NTPs hindered data and result sharing and lowered the motivation of NTPs to strengthen AE reporting. Clinicians were often over-burdened with their clinical duties and administrative tasks, and having to report AEs further increased their workload.

There was also lack of clarity about which authority (the NPVC or the NTP) holds the final responsibility for the active PV programme. This has led to problems in the organisation of causality assessment meetings in some countries. Currently, active PV is often limited to specific sites piloting the ND&R. However, further scaling-up of aDSM to cover all DR-TB patients on treatment is needed to ensure that their safety is sufficiently monitored.

In countries where aDSM is functioning relatively well (such as Vietnam and Kyrgyzstan), the NTP and the NPVC have managed to establish a strong collaboration, organising regular meetings and joint causality assessment exercises. aDSM is, hence, mutually owned and responsibilities are shared.

Table 3 shows an overview of the number of patients enrolled in aDSM and the number of reports received. There were AE data available for 477 patients on longer regimens with Bdq from six countries; for 100 patients on longer regimens with Dlm from three countries; for eight patients on longer regimens with Bdq and Dlm from Myanmar only; for 263 patients on STR from three countries; and for 265 patients on the standard longer DR-TB regimen from Vietnam only. The average number of AEs and SAEs reported per patient was higher for Bdq-containing regimens then for the other regimens, but this was distorted at least in part by different levels of active PV being applied (e.g. CEM in Vietnam). Ethiopia, Kyrgyzstan and Myanmar were the only countries from which data from patients on Bdq-containing and Dlm-containing regimens could be compared; there was no consistent pattern of higher frequency of AEs for patients on Bdq. Kyrgyzstan and Myanmar also provided a comparison between STR and the longer regimens, and the number of AEs per patient was lower for STR patients than for patients on longer regimens (with Bdq and/or Dlm).

Key lessons from example countries

The introduction of active PV/aDSM has faced many challenges because the NTPs and the PV authorities had limited awareness of aDSM or active PV for ND&R. Consultation and raising awareness helped to open an active dialogue between the NTP and the NPVC so that they could gain a common understanding of the issues and jointly plan the way forward.

Our experience showed that it worked best to build on a country's existing PV system, which in some settings meant revitalising the existing dormant one. A significant amount of capacity building on PV/aDSM at all levels of the health system was required in most countries. High staff turnover threatens the expertise and capacities built, underlining the importance of continuous training, including on-the-job and step-down mentoring, in order to create a large and sustainable pool of staff with sufficient knowledge on aDSM.

Most healthcare providers indicated that they would appreciate receiving regular feedback on their reports that goes beyond an acknowledgement of receipt. Although funding and capacity are usually lacking to send individual feedback reports, there are good examples of regular newsletters sharing updates from the PV centre, such as the MESO newsletter in Indonesia that includes an overview of PV reports received in the past period (by reporter, type of AE and drug class) and newly detected signals (http://e-meso.pom.go.id/web/index.php?act=bulletinmeso&lang=1&action=&eventId=38&newsId=).

Because there is usually very limited funding for PV activities both in public health programmes and for NPVC/drug regulatory authorities, partner support is still required to set up active PV systems and strengthen collaborating mechanisms.

Global reporting of aDSM data is being promoted. However, the current existence of at least four different global database initiatives may result in the collection of fragmented data, without yielding a clear overall picture of the frequency and types of AEs among patients on ND&R.