2. Regulators’ group report John Skerritt National Manager Therapeutic Goods Administration Australian Department of Health

3. Several priorities identified at the March ‘14 meeting of AQMTF required action by medicines regulators So……AQMTF requested that a Regulators’ Group be established to develop options for consideration by AQMTF for: - improving the availability of, and access to, quality medicines and diagnostics - help to contain the spread of artemisinin resistance - strengthen capacity to monitor quality of products and to take action when substandard products are detected

4. We recognised that much high quality analysis has already been done on priorities for better malaria control, access to quality medicines and managing drug resistance e.g. by WHO, Global Fund, governments, donors and APLMA itself

5. Major reports were reviewed

6. A strongly-held view emerged that the role of the Regulators’ Group was not to duplicate recommendations of these studies, but from a regulatory perspective to provide more detailed advice about specific priorities and actions In most cases – such as improving the access to quality antimalarials - it was agreed that regulatory action would only be part of a potential solution

7. Participants in the Regulators’ Group meeting in Bangkok (May 14-15) included Regulators and Public Health representatives from Australia, India, Malaysia, Cambodia, Japan, Thailand, Lao People’s Democratic Republic, Philippines, Singapore, Viet Nam, Indonesia, WHO, Population Services International and DFAT Australia.

8. The Regulators’ group is co-chaired by Australia and India in alignment with the AQMTF

9. It took a practical “ground-level” view rather than a “high level” general view.

10. A two stage survey of countries was initially carried out - of current regulatory frameworks within each country as they relate to the regulation of malaria products - broader issues on access to malaria products, and the roles of different organisations in providing access Responses were received from 14 countries: Australia, Brunei, Cambodia, India, Indonesia, Japan, Lao PDR, Malaysia, Myanmar, PNG, Philippines, Singapore, Thailand and Viet Nam

11. The surveys: Market Authorisation - All respondents indicated that it is a legal requirement to license antimalarial medicines in their country before supply - But over 30 different medicines/combinations and more than 90 different strengths/dose forms had been licensed - Only 8 of these align with the WHO Essential Medications List - Regulators identified 14 further medicines or combinations known to be supplied in their countries without licence - Only a few countries regulate Rapid Diagnostic Tests (IVDs)

12. The surveys: Medicines Quality - All regulators indicated that they had responsibility for monitoring quality of medicines supplied in their country - Often in partnership with other government authorities, though some indicated that they had limited capacity - SSFFC medicines were recently identified in four countries - Regulators stated that their postmarket or pharmacovigilance roles and compliance and enforcement powers were usually less well defined than their premarket authorisation role

13. Structure of the report

14. . KEY AREA 1: Ensuring that the quality of malaria commodities is consistent with international standards

15. Recommendation 1: Implement specific regulatory market authorisation actions to improve access to the most appropriate antimalarial medicines and diagnostics Recommendation 2: Establish fast-track regulatory approval mechanisms to encourage market availability of fixed dose combination formulations (rather than co- blistering) and combinations of new active ingredients, to improve patient compliance and provide flexibility for addressing changes in antimalarial resistance

16. Artemesinin: not a silver bullet if used alone orally

17. Recommendation 3: Implement regulatory actions to improve access to appropriate Rapid Diagnostic Tests for the diagnosis of malaria Recommendation 4: Undertake action to withdraw inappropriate malaria treatments Recommendation 5: Implement communication initiatives to improve quality use of antimalarials

18. . KEY AREA 2: Removing oral artemisinin monotherapy and Substandard/ Spurious/ Falsely- labelled/ Falsified/Counterfeit (SSFFC) products

19. Removing artemisinin monotherapies

20. Recommendation 6: Use the range of regulatory options permitted by law in each country to a greater extent, and where required strengthen the legal basis of regulatory powers, to support the halt of oAMT Recommendation 7: Implement systematic programs for monitoring the quality of ACT particularly in districts where artemisinin resistance has been detected/suspected Recommendation 8: Use robust commodity market assessment and monitoring methods to inform regulatory policy and practice across the region

21. KEY AREA 3: Strengthening regulatory capacity and regional collaboration of National Regulatory Authorities with responsibility for malarial medicines and diagnostics

22. Recommendation 9: Strengthen regional collaboration between NRAs to build capacity and increased convergence of good regulatory practices Recommendation 10: Where possible, work through existing national and regional initiatives to deliver capacity building support to assist countries with monitoring quality of malaria diagnostics and medicines Recommendation 11: Governments to provide adequate support, powers and investment to National Regulatory Authorities

23. . KEY AREA 4: Improving access to and supply of quality preventative measures and therapies, particularly for high- risk groups

24. Recommendation 12: National Regulatory Authorities to more proactively work with other government agencies, malaria control programs and stakeholders, recognising the particular vulnerability of mobile and remote populations and the prevalence of artemisinin resistance in border regions

25. From recommendations to actions - Supporting the 12 recommendations are 42 proposed actions - 24 of which are prioritised for immediate action - For each action, ‘Lead’ or ‘Support’ roles are suggested - Only some of the actions are relevant for particular stakeholders, such as public health programs, WHO, government policy makers, donors and regulators - Context for implementing actions provided in the report - Anticipated that the specific actions could guide future investment by governments, WHO and donors.

26. . Recommendation 1: Implement specific regulatory market authorisation actions to improve access to the most appropriate antimalarial medicines and diagnostic tools IMMEDIATE ACTIONS Ensure that all relevant WHO prequalified essential medicines and diagnostics have market authorization in affected countries Fast track regulatory evaluation for market authorisation of equally effective but less expensive “partner” antimalarial components of Artemisinin Combination Therapies (ACTs) NRAs to work with National Malarial Control Programs and Procurement Agencies to develop quality standards consistent with nationally/internationally recognised requirements to support procurement and that only products of appropriate quality are procured, irrespective of funding source = lead role required by National Regulatory Authorities (NRAs)

27. Recommendation 1 (continued): Implement specific regulatory market authorisation actions to improve access to the most appropriate antimalarial medicines and diagnostic tools LATER ACTIONS Work with industry and public health systems to ensure appropriate ACTs have market authorisation in each country, particularly those required to address current or potential resistance Ensure that only malaria medicines at the doses recognised in clinical treatment guidelines are approved by NRAs For countries where regulatory powers currently only extend to medicines use within the public health system, extend these powers to medicines used in the private and informal sectors

28. Recommendation 2: Establish fast-track regulatory approvals to encourage availability of fixed dose combinations (and combinations of new active ingredients) to improve patient compliance and provide flexibility for addressing changes in antimalarial resistance LATER ACTIONS Develop more consistent national regulatory frameworks to ensure that RDTs are assessed to nationally/ internationally agreed standards for performance and stability, and that instructions for use are appropriate Develop a capacity building program to establish local mechanisms for assessing diagnostics and their quality management by building on WHO prequalification of in vitro diagnostics IMMEDIATE ACTION Recommendation 3: Implement regulatory actions to improve access to appropriate Rapid Diagnostic Tests (RDTs) for malaria

29. Recommendation 4: Undertake action to withdraw inappropriate malaria treatments IMMEDIATE ACTIONS Where possible, NRAs to withdraw the registration of medicines that are still registered for malaria but no longer recommended because of safety, known resistance or lack of efficacy Together with public health authorities, NRAs to review the drugs currently authorised to ensure registered doses are appropriate and consistent with WHO guidelines/ National Drug Policy Revoke licences for products containing sub therapeutic levels of antimalarials or irrational combinations of active ingredients LATER ACTIONS Ensure that ineffective antimalarials are no longer included in national formularies or national essential medicines lists Discourage (and deregister where possible) “cocktails” of inappropriate medicines used for malaria prevention or treatment

30. Recommendation 5: Implement communication initiatives to improve quality use of antimalarials LATER ACTIONS Strengthen communication about the appropriate use of products to doctors, pharmacy and clinic workers and patients through – the process of formal approval of product / consumer medicines information by the regulator – as well as broader public communication activities

31. Recommendation 6: Use the range of regulatory options permitted by law in each country to a greater extent Where required, strengthen the legal basis of regulatory powers to support the halt of oAMT along the supply chain IMMEDIATE ACTION NRAs to ensure sufficient regulatory power exists and enforcement actions are implemented to allow for: – forbidding or withdrawing market authorisation for oAMT – suspension of manufacture and import licences – Forbidding/ withdrawing export licenses for oAMT manufacturers – active monitoring of premises of oAMT and SSFFC drugs and RDTs – recall and destruction of oAMT and SSFFC finished products LATER ACTION Develop communication programs aimed at consumers, healthcare providers and industry on hazards of oAMTs and substandard and counterfeit medicines, including how to report these to authorities

32. Recommendation 7: Implement systematic programs for monitoring quality of Artemesinin Combination Therapies (ACTs), particularly in districts where artemesinin resistance has been detected/suspected IMMEDIATE ACTIONS Increase post-market surveillance of ACTs across the full distribution chain including periodic re-testing of licensed products Increase the focus on product shelf-life and storage of medicines and RDTs as a contributor to their substandard performance Regularly and systematically report incidents of suspected cases of SSFFC products and actions taken through WHO rapid alert systems Ensure adequate access by NRAs to accredited analytical testing facilities. Where facilities do not exist (and for complex analyses), develop mechanisms for sending samples to partner countries Work with regional governments to streamline importation of suspect samples for testing in accredited regional laboratories so that timely regulatory action is possible

33. Recommendation 8: Use robust commodity market assessment and monitoring methods to inform regulatory policy and practice across the region IMMEDIATE ACTIONS Utilize rapid supply chain assessments and targeted outlet surveys to generate a consistent baseline picture of the total antimalarial product market across the region Analyze baseline data to ascertain if time-limited price subsidy interventions are warranted (in conjunction with regulatory enforcement) to accelerate displacement of oAMTs and improve access to quality assured ACT and RDTs LATER ACTIONS Assess the impact of interventions, regulatory and market-based, on access to quality antimalarials and diagnostic relative to SSFFC products through outlet surveys and real-time monitoring

34. Recommendation 9: Strengthen regional collaboration between NRAs to build capacity and convergence of good regulatory practices IMMEDIATE ACTIONS Fast-track national registration of an agreed list of WHO prequalified medicines through sharing of assessment reports generated by the WHO Prequalification process, if permissible under the regulatory framework of the respective country and worksharing on drug applications between countries Develop mechanisms for collaboration between regulators on GMP inspections of local manufacturers of antimalarials Strengthen collaboration with major “stringent” regional regulators and WHO Prequalification programs, and increase investment in training programs Support efforts for harmonisation of regulatory requirements and processes for market authorisation of rapid diagnostic tests

35. Recommendation 9 (continued): Strengthen regional collaboration between NRAs to build capacity and convergence of good regulatory practices IMMEDIATE ACTIONS Support cross-border coordination of regulatory and enforcement actions, especially as they relate to high-risk and hard-to-reach populations Strengthen local and regional exchange of intelligence on counterfeit and substandard products Recognise and endorse the WHO Member State Mechanism on SSFFC workplan, identifying priority actions and resources for NRA participation. Translate SSFFC norms and standards into use Encourage multi-country rather than single country involvement in major regional and donor antimalarial initiatives Existing processes and governance mechanisms should be utilised wherever possible

36. Recommendation 10: Where possible, work through existing national and regional initiatives to deliver capacity building support to assist countries with monitoring and testing the quality of malaria diagnostics and medicines IMMEDIATE ACTIONS Strengthen capacity for post-market surveillance of malaria diagnostics and medicines across the distribution chain, including manufacturers, importers, wholesalers and health posts Specific actions include: – Strengthening pharmacovigilance capacity including reporting of treatment failure and adverse events – Strengthen oversight of manufacturers and the supply chain through greater GMP inspection capacity – Improved laboratory testing capacity and use of consistent lab accreditation standards for testing of suspect products – Training in regulatory compliance and enforcement

37. Recommendation 10 (ctd): Where possible, work through existing national and regional initiatives to deliver capacity building support to assist countries with monitoring and testing the quality of malaria diagnostics and medicines LATER ACTIONS Strengthen market authorisation roles for both medicines and Rapid Diagnostic Tests (RDTs) by increasing the capacity of NRAs to work in collaboration with the WHO prequalification program Explore potential for formal worksharing between regional NRAs Develop regulatory frameworks for market authorisation of in vitro diagnostics (which include RDTs) Develop the capacity of NRAs to produce communication materials and education programs on appropriate use of antimalarials and diagnostics and the dangers of poor quality medicines Evaluate portable technologies such as the USFDA rapid CD3 device for the detection of counterfeit medicines

38. RDT performance has not been well addressed thus far by Regulators…

39. Recommendation 11: National governments to provide adequate support, powers and investment to NRAs IMMEDIATE ACTIONS Strengthen and formalise linkages between NRAs, public health authorities and national malaria control programs, including involvement of both functions at National and Regional meetings Review the adequacy of powers available to NRAs, with a view to putting in place powers with similar intent in different countries to enable coordinated responses to SSFFC and oAMT medicines Ensure NRA functions receive a sufficient share of funding within national budgets and international programs to enable these recommendations to be adequately implemented LATER ACTIONS Investment in technical capacity building within NRAs

40. Recommendation 12: NRAs to more pro-actively work with other government agencies, malaria control programs and stakeholders, recognising the vulnerability of mobile and remote populations and the prevalence of artemesinin resistance in border regions LATER ACTIONS NRAs to work with: – Public health authorities when they receive information on adverse events, treatment failure or resistance to medicines – Police where smuggling of oAMTs across borders is suspected – National medical research centres, to develop strategies for the use of diagnostic tests to detect artemesinin resistance markers and integrate guidelines for alternative therapy into medicines product and prescribing information as required Strengthen the involvement of NRAs in communicating and managing shortages of malaria medicines and RDTs – e.g. by implementing streamlined regulatory approaches to facilitate short- term access to antimalarials approved by another regulator

41. Conclusions and Next Steps - To date, regulators have not usually been engaged consistently with malaria issues and responses by regulators to issues such as oAMT resistance have been fragmented - Implementation of several of the recommendations would have a broader impact in strengthening access to quality medicines in the Asia-Pacific - Importance for building on existing national and regional regulatory, health and malaria control programs rather than creating new centres or programs - Recommendations and actions will need to be integrated with other outputs from AQMTF /APLMA.