2. Active TB drug-safety monitoring : rationale and mechanisms in the context of TB & MDR-TB treatment Multi-partner training package on active TB drug safety monitoring and management (aDSM) July 2016

Objectives of the presentation By the end of this presentation, the participant is expected to be able to: describe why drug safety monitoring is important identify the recent changes in TB treatment policy which make the case for drug safety monitoring in TB programmes stronger describe why TB drug safety monitoring and management should rely on active rather than spontaneous surveillance describe the main components of aDSM

Why drug-safety monitoring ? Adverse drug reactions can lead to reduced quality of life treatment interruption treatment failure avoidable morbidity deaths added costs to the service (e.g. hospitalization) …

16th World Health Assembly, 1963 Assembly Resolution 16.36 - Clinical and Pharmacological Evaluation of Drugs INVITES Member States to arrange for a systematic collection of information on serious adverse drug reactions observed during the development of a drug and, in particular, after its release for general use.

Drug-safety and the TB patient (1) Both first- and second-line TB medicines are known to cause adverse reactions, sometimes with significant sequelae. Most patients on second-line treatment can be expected to have one or more adverse reactions owing to more numerous/variable drug combinations and longer duration of regimens when compared with first-line regimens The extent & quality of drug safety monitoring varies by TB programme as it has not been a standard feature of monitoring frameworks in TB programmes (in contrast to bacteriological status and treatment outcomes). In their drive to scale up DR-TB treatment, programmes may not have prioritized this aspect of care among other challenges they faced

Drug-safety and the TB patient (2) Even mild and common adverse reactions can affect treatment outcomes. Some can cause permanent disability, be life-threatening, or even lead to death New TB medicines (bedaquiline, delamanid) and novel regimens are being conditionally approved, ahead of trial completion, with limited experience in use under programmatic conditions and insufficient observations to capture rare events A number of medicines (linezolid, clofazimine…) are used in 2nd line regimens beyond their indication Combination of new & old TB drugs -> risk for as-yet unrecognized drug-drug interactions

Drug-safety and the TB patient (3) Expanded use of 2nd line treatment regimens in geographical areas and in patient subgroups in whom exposure to such treatment is relatively new and caregivers unfamiliar to the safety profile Early recognition and management of adverse reactions can improve adherence and treatment outcomes Adverse reactions pose a risk not only to the individual patient but also to the whole treatment programme. They may harm public confidence in a national treatment programme or in a new medicine or regimen which could bear promise

2 main approaches to drug-safety monitoring Spontaneous Active

Spontaneous reporting (1) Also called “passive” or “voluntary” reporting The most common form of pharmacovigilance In some countries it is mandatory Reporting depends on the motivation of the reporter Has played a major role in the identification of safety signals But … Reporting rates generally very low and subject to bias No database of users or information on overall drug utilization

Spontaneous reporting (2) Health professionals and others (including patients sometimes) encouraged to report safety concerns Standardized notification forms are commonly used (“yellow forms”) Reports go to the national authority responsible for pharmacovigilance

Active drug-safety monitoring Different from spontaneous because proactive efforts made to detect adverse events; follow-up for AEs may continue after treatment ends (e.g. when medicines with long half-life are used) Events detected by asking patients directly, screening patient records The most comprehensive form of active surveillance is cohort event monitoring (CEM) aDSM is a form of active pharmacovigilance

WHO guidance on treatment & management of drug-resistant TB, 1996-2016 2016

BEDAQUILINE : WHO interim policy guidance (June 2013) “Bedaquiline may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB” conditional recommendation, very low confidence in estimates of effect Subject to the following 5 conditions: 1. Treatment under close monitoring 2. Proper patient selection 3. Patient informed consent 4. Treatment as per WHO recommendations 5. Active pharmacovigilance in place

DELAMANID : WHO interim policy guidance (October 2014) “Delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB” conditional recommendation, very low confidence in estimates of effect Subject to the following 5 conditions: Proper patient inclusion Treatment as per WHO recommendations Treatment is closely monitored Active pharmacovigilance in place Patient informed consent obtained

Key changes relevant to aDSM WHO guidelines for the treatment of drug-resistant tuberculosis. 2016 update Key changes relevant to aDSM A shorter MDR-TB treatment regimen is recommended for rifampicin-resistant (RR-TB) and multidrug-resistant TB (MDR-TB) patients, under eligibility criteria The design of longer MDR-TB regimens uses a different regrouping of component medicines from the previous one Recommendations for the treatment of children with RR-/MDR-TB are based on a first-ever individual-level patient meta-analysis from observational studies of children

Shorter MDR-TB regimen “In patients with rifampicin-resistant TB or MDR-TB, who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of a conventional regimen” 4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E Standardized regimen; limited modifications permissible Recommendation applies to adults, children, PLHIV Monitoring for effectiveness, relapse, and harms Results from trials expected to provide high-certainty evidence in near future

Regrouping of medicines used in MDR-TB regimens, 2016 GROUP A Fluoroquinolones Levofloxacin Moxifloxacin Gatifloxacin GROUP B Second-line injectable agents Amikacin Capreomycin Kanamycin (Streptomycin) GROUP C Other Core Second-line Agents Ethionamide / Prothionamide Cycloserine / Terizidone Linezolid Clofazimine GROUP D Add-on agents (not core MDR-TB regimen components) D1 Pyrazinamide Ethambutol High-dose isoniazid D2 Bedaquiline Delamanid D3 p-aminosalicylic acid Imipenem-Cilastatin Meropenem Amoxicillin-Clavulanate (Thioacetazone)

Adverse events monitoring among the research gaps identified following the 2016 update of the MDR-TB treatment guidance Complete recording of adverse events and standardized data recording on organ class, seriousness, severity, and certainty of association, to allow reliable comparison of the association between adverse events and exposure to different medicines Pharmacokinetic studies to determine optimal drug dosing and safety (especially in pregnancy) RCTs to define the benefits and harms of chemoprophylaxis for child and adult contacts of rifampicin-resistant TB (with and without additional resistance patterns) Adverse reactions from the long-term use of fluoroquinolones in preventive treatment The effectiveness/safety of the shorter MDR-TB regimen in subgroups which have been systematically excluded from study protocols (e.g. children, patients with different forms of extrapulmonary TB)

Introducing : active TB drug safety monitoring and management (aDSM) “active and systematic clinical and laboratory assessment of patients on treatment with new TB drugs, novel MDR-TB regimens or XDR-TB regimens to detect, manage and report suspected or confirmed drug toxicities” apps.who.int/iris/bitstream/10665/204465/1/WHO_HTM_TB_2015.28_eng.pdf

aDSM components Clinical monitoring active and systematic clinical and laboratory assessment during treatment to detect drug toxicity and AEs Management of AEs in a timely manner Systematic and standardized recording and reporting of AEs Data collection to include safety data At least all SAEs reported and assessed for causality Close coordination between national TB and PV structures

aDSM “packages” Core: requiring monitoring for and reporting of all SAEs Intermediate: includes SAEs as well as AEs of special interest Advanced: includes all AEs of clinical significance

aDSM eligibility aDSM applies primarily to the following: MDR-TB patients treated with bedaquiline, delamanid and other new medicines; MDR-TB patients enrolled on treatment with novel regimens (including the shorter MDR-TB regimen); All XDR-TB patients on second-line treatment, as these regimens usually include multiple repurposed drugs Once coverage of these patients groups is adequate, aDSM can extend to other MDR-TB patients on treatment

Conclusions (1) The certainty in the evidence underpinning MDR-TB treatment policy is largely low or very low. Gaps remain in the knowledge and in the available treatment options (e.g. establishing and administering a correct paediatric dose; drug-drug interactions) The recommendations for the use of novel treatment options come with a condition to undertake appropriate drug safety monitoring and management

Conclusions (2) Adverse event monitoring varies between treatment sites and has not been a standard component of TB programmes up to now There is a need to introduce adverse event monitoring in an effort to make treatment programmes safer and to improve the knowledge on the safety profile of new drugs and regimens aDSM is the proposed framework to establish active monitoring for drug safety concerns within the context of TB treatment programmes