WHO approach to pharmacovigilance of anti-TB drugs

Ernesto Jaramillo

JOINT PARTNERS FORUM FOR STRENGTHENING AND ALIGNING TB DIAGNOSIS AND TREATMENT

GLI / GDI Partners Forum Organized by the World Health Organization (WHO) Global TB Programme

Geneva, 27-30 April 2015

Pharmacovigilance

Pharmacovigilance (PV) is defined by the WHO as the “science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.”

•a public health surveillance activity

•a fundamental activity to inform the management of patient safety in health care

Spontaneous reporting

Targeted reporting

Active PV

3 Methods of Pharmacovigilance

Active pharmacovigilance

• Using a set of questions and an array of laboratory, clinical tests at defined periods of time, before, during and after treatment.

• It is similar to what to do in a longitudinal epidemiological study.

Cohort Event Monitoring (CEM)

• A standard method of active PV

• Monitor AEs in patients who receive a particular medication or treatment regimen

• Patients are followed up prospectively in groups

• All AEs are registered

– during treatment and usually for a given time after its end.

– known or unknown to the target treatment

Why to do active PV for TB? Treatment should not worsen patient’s suffering

• New TB medicines conditionally approved

• Compassionate use

• Off-label use or repurpose of medicines for MDR-TB treatment e.g. Linezolid, clofazimine or Shorter regimens

• Combination of new drugs and existing TB drugs poses potential for previously unrecognised drug interactions

• Planning/budgeting medicines to manage ADRs

• Public confidence/ NTP credibility

Why is WHO recommending CEM when bedaquiline or delamanid are used? (1)

• The recommendation supported by the independent experts who reviewed the information available on safety of bedaquiline and delamanid (2013 and 2014 respectively)

• Both medicines are still relatively new and only a limited number of patients have been treated with them.

Why is WHO recommending CEM when bedaquiline or delamanid are used? (2)

• Their conditional/accelerated approval by drug regulatory authorities ahead of the completion of Phase 3 trials for TB patients with limited treatment options

• In the situation of BDQ and DLM, spontaneous reporting is not expected to represent an appropriate level of care and CEM is necessary to improve early and systematic detection of harms.

IMPLEMENTING CEM FOR TB

Roles and Responsibilities

• This will be under the responsibility of two main players:

– National pharmacovigilance centre (NPVC)

– National TB control programme (NTP)

• Technical and donor agencies to support NPVs and NTPs to build capacity and promote international standards of CEM

9 steps for the implementation of CEM No. 9 STEPS for implementation

of CEM

Lead Responsibility Needed ahead of patient recruitment?

1 Establishment of CEM committee & secretariat

NPV centre (if available) Yes

2 Management and supervision - At start: NPV centre - At “maintenance” stage: NTP

Yes

3 Preparation of CEM protocol, including plan for data analysis and communication

NPV centre In part

4 Design and production of forms for data collection

NPV centre Yes

5 Submission for ethics approval NPV centre Only if required

6 Staff training NPV centre (+NTP) Yes

7 Collection of data NTP Yes

8 Electronic database for MDR-TB patients on treatment, for consolidation of PV data

- If none exist: NPV centre - If PMDT database exists: NTP

Not essential initially

9 Relationship/causality assessment and signal identification

NPV centre Specialist skills can be established later

Implementing the PV policy to serve best the needs of the patient

• It is important to ensure that the following essential elements are in place prior to the start the enrolment of patients on a new drug or regimen:

1. agreement between the NTP and the NPVC on the process to implement CEM for TB drugs

2. preparation for the collection of data (e.g. forms)

3. staff properly trained to collect the data.

• Full capacity for CEM could be built over the following months.

RECENT DEVELOPMENTS ON PV FOR TB

Workshop on pharmacovigilance, cohort event monitoring and treatment of MDR-TB

Copenhagen, Denmark. 3-7 March 2014

NTP and PV representatives from 8 countries in Eastern Europe & Vietnam

– CEM

– Lessons learnt & experiences from countries

– National plans

Inter-regional workshop on PV for TB Hanoi, Viet nam. 12-14 November 2014

Consensus on

Minimum data collection elements for CEM

CEM indicators

Roles and responsibilities of stakeholders

Participated by

10 countries

Key technical and funding partners

Countries with active PV for MDR-TB as per WHO guidance

Conventional MDR-TB regimens

• Viet Nam (advanced)

MDR-TB regimens with new/repurposed drugs

• Belarus (advanced)

• India, Indonesia, Kazakhstan, Thailand, Philippines (planning/developing)

• Armenia, Azerbaijan, Georgia, Rep Moldova, Russian Fed, Ukraine (trained in 2014)

Shorter MDR-TB regimens

• Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Côte d’Ivoire, DR Congo, Lao PDR, Niger, Rwanda, Swaziland, Uzbekistan (started or protocol compliant with WHO)

• Afghanistan, Morocco, Myanmar, Pakistan, Thailand… (planning)

Belarus projects

• CEM on ARV/Anti-TB drugs

• CEM for Linezolid in MDR-TB patients

• Preparing CEM for bedaquiline (start mid-

2015)

Viet Nam

• Established CEM for patients on MDR-TB treatment with SLDs

Integrated in eTBManager - the existing electronic data collection system for MDR-TB

• Preparing CEM for BDQ and 9-month regimen

http://www.who.int/tb/challenges/pharmacovigilance/en/

• FAQs on WHO policy on pharmacovigilance (April 2015)

• Meeting report of the Inter-regional workshop in Hanoi (Nov 2014)

• Sample data collection forms

• Companion Handbook to PMDT Guidelines (August 2015)

• WHO Practical handbook on pharmacovigilance

Revised 2014 Version

Acknowledgements • Dennis Falzon, Christian Lienhardt, Linh Nguyen,

Fraser Wares (WHO/GTB)

• Leticia Megias, Shanti Pal (WHO/Safety and Vigilance)

• KNCV (Susan van den Hof, Edine Tiemersma)

• US CDC (Ekaterina Kurbatova)

• Jennifer Furin

• Participants attending the pharmacovigilance workshop in Copenhagen, Denmark (March 2014)

• Participants attending the pharmacovigilance workshop in Hanoi, Viet Nam (November 2014)