Global context of drug regulation Dr Lembit Rägo Coordinator Quality Assurance and Safety Medicines Essential Medicines and Health Products World Health Organization Email ragolwhoint ID: 267587
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Introduction to regulation of medicines and health technologies:Global context of drug regulation
Dr Lembit RägoCoordinatorQuality Assurance and Safety: MedicinesEssential Medicines and Health ProductsWorld Health OrganizationE-mail: ragol@who.intSlide2
ContentSetting the scene. What products we have? What is the situation with medicines quality and regulatory affairs Globally? 3 case studiesAfrica - antimalarial medicines quality survey and falsified antimalrialsPakistan – two "killer" medicines casesCase study from NIS – a biosimilar case
Who is WHO?WHO activities to medicines quality assurance and regulationWhat is WHO doing to strengthen national regulatory authorities?Local production of Essential Medicines and its constraintsConcluding remarksSlide3
What type of regulated products we have?Regulated health productsMedicines, including biological products:Medicines – originator and "generic" productsBiological medicinesVaccinesOther biologicals: Monoclonal antibodies, Interferons etc.Blood productsSimilar biotherapeutic products (biosimilars)Traditional/herbal medicines (complimentary medicines)Medical devices – in vitro diagnostics (IVDs)Slide4
Medicines: originator vs generic medicinesNew medicines or originator productsNeed to prove safety, efficacy and qualityMultisourcse (generic) medicinesFocus on quality, safety and efficacy referred to originator
Safety and efficacy – bridging through bioequivalence studiesInterchangeabilityPharmaceuticalTherapeuticSlide5
What is the situation with medicines quality (QSE) Globally? 1st Case example. Antimalarials/Africa
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Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania
ACTs and
sulfadoxine-pyrimethamine
935 samples collected and screened by Minilab, 306 tested in laboratorySlide6
Falsified/Counterfeit antimalarials also common (1st Case example. Cont). Several notifications about falsified antimalarials – no active ingredient or … containing paracetamolWHO issues also public Drug Alertshttp://www.who.int/medicines/publications/drugalerts/drugalertindex/en/index.htmlSlide7
What is the situation with medicines quality (QSE) Globally? 2nd Case example – Pakistan 1.More than 107 death case and 450 severe ADRs with isosorbide mononitrate manufactured in Pakistan Clinically resembled Dengue feverPassed quality control testing… forensic investigation – contained pyrimethamine in toxic quantitiesReason – totally ignoring GMP and negligence Slide8
What is the situation with medicines quality (QSE) Globally? 2nd Case example – Pakistan 2.Dextromethorphan killing more than 20 peopleAll death cases seemed to be linked to drug addiction… forensic analysis revealed that the medicine contained also high percentage of levomthorphan (potent opiate)API manufacturing quality failureSite in India closed Slide9
What is the situation with medicines quality (QSE) Globally? 3rd Case example – NIS biosimilarA biosimilar approved in a NIS country several years agoPatient complaints, MPs involved …Approval based on … regulations about chemical generic medicines!Company profile – not very credibleQuestion why it was authorized remains open. Slide10
What these case stories are telling?Quality of medicines is still an issue in many jurisdictionsMany countries do not have functional regulatory systems in place for product approval (MA, registration)Dossier assessment weak or absentInspectorates do not function properly Many de facto do not control their markets nor do they control the supply chainNo effective control of imports
No effective licensing of all the activities - manufacturing, retail- and whole sale, hospital pharmaciesNo traceability of products at any point of supply chainLack of capacity doing all the necessary and no system in place to rely on those who have the capacitySlide11
WHO activities in the field of health products regulation (medicines incl. biologicals, medical devices)
Setting policies, norms and standards – for access, rational use, quality, safety and efficacy
Assessment of national regulatory systems, regulatory support and capacity building Promoting regulatory harmonization and information exchange – safety, quality, best practices etc.
Assuring safety and quality of selected products for United Nations family through prequalification programme
(medicines, vaccines, diagnostics)Slide12
WHO is mandated to “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products” (Article 2, WHO Constitution);
WHO Expert Committee on Specifications for Pharmaceutical Preparations WHO Expert Committee on Biological StandardizationBoth complimentary to ICH activities Joint FAO/WHO Expert Committee on Food AdditivesStandards and WHOSlide13
http://www.who.int/medicines/areas/quality_safety/regulation_legislation/assesment/en/index.htmlSlide14
International Conferences of Drug Regulatory Authorities (ICDRA)Biennial Global meetings bringing together regulators from around 100 nationsPromoting information and best practices exchange, cooperation, harmonization and convergenceSeveral initiatives started in ICDRA environmentICH initial discussionsAMRH initiative initial discussionsReports from various harmonization initiativesSlide15
Prequalification programme – powerful engine for facilitating quality manufacturehttp://apps.who.int/prequal/Slide16
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Prequalification of Medicines Programme
Since 2001 the UN Prequalification Programme managed by WHO is ensuring that medicines procured with international funds are of assessed and inspected for
quality, efficacy and safety,
involves
Prequalification programme for medicines (finished dosage forms)
Prequalification of active pharmaceutical ingredients (APIs)
Prequalification of quality control (QC) laboratories
The Prequalification Programme is
an action plan
for expanding access to priority essential medicines in the following four areas:
- HIV/AIDS
- Tuberculosis
- Malaria
- Reproductive Health
- Selected individual products for other diseases (Flu, Zinc sulphate)Slide17
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Extensive collaboration: working with regulators … for regulators
Not duplicating work done be stringent regulatory authorities
SRA approval of new and generic products – abridged procedureUS FDA tentative approvals – based on confidentiality agreement including in the PQ products list
European Medicines Agency (EMA) – Art 58 … and beyond
Collaboration with EDQM, in particular in the area of APIs (confidentiality agreements with US FDA, EDQM, EMA …)
Active participation and involvement of
Regulatory authority experts from well resourced and less resourced settingsSlide18
Common deficiencies for dossiersSlide19
Common deficiencies observed: quality
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Key achievements
Contribution to increased access to quality medicines, for example:
in 2012, 8 million people living with HIV and in need of treatment were receiving treatment, around
6.5 million
of whom were taking WHO-prequalified antiretrovirals (ARVs);
and sales of WHO-prequalified artemisinin-based combination antimalarials exceeded
180 million individual treatment
courses in 2010)
UNAIDS.
World AIDS Day Report 2012
. Geneva, UNAIDS, 2012.
WHO.
World Malaria Report, 2011.
Geneva, World Health Organization, 2011.
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PQP achievements 2009‒2012:
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In addition:
prequalification of
28 active pharmaceutical ingredients
(APIs), all of which can be used for manufacturer of UNITAID priority products
prequalification of
19 medicines quality control laboratories
(QCLs), so that prequalified QCLs can now be found in all six WHO regionsSlide22
Capacity building provided a core value of the programme.
Participants in various capacity building workshops organized or co-organized by PQP during 2007‒2012
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Access to essential medicines remains a problem*In spite of progress, especially with communicable diseases (HIV/AIDS, malaria and TB), the access to essential medicines remains a huge problemChronic diseases—mainly cardiovascular disease, cancer, chronic respiratory diseases, and diabetes—were estimated to cause more than 60% (35 million) of all deaths in 2005; more than 80% of these deaths occurred in low-income and middle-income countries. NCDs have negative impact on individuals, and family economic production and wellbeing. For example, estimated loss in national income from heart diseases, stroke and diabetes in 2005 were $18 billions in China, $11 billion in the Russian Federation, $9 billion in India and $43 billion in Brazil.
Access to medicines for mental disorders remains poor – up 70% may not get treatment in low-income countriesSlide24
Concept of local production*: Specific to local production WHO activitiesProject: Improving access to medicines in developing countries through technology transfer related to medical products and local production. Implemented by the Department of Public Health Innovation and Intellectual Property of the World Health Organization (PHI/HIS/WHO) in partnership with the United Nations Conference on Trade and Development (UNCTAD) and the International Centre for Trade and Sustainable Development (ICTSD) with funding from the European Union (EU).
Objective of the project: To increase access – especially for the poor in developing and least developed countries – to medicines, vaccines and diagnostics.Slide25
Special web site http://www.who.int/phi/publications/local_production/en/index.htmlSlide26
Relevant publicationsLocal production for access to medical products: Developing a framework to improve public health, 2011Local production for access to medical products: Developing a framework to improve public health, 2011Trends in local production of medicines and related technology transfer, 2011Pharmaceutical production and related technology transfer: Landscape report, 2011Pharmaceutical production and related technology transfer: Landscape report, 2011
….Slide27
Chances for Developing Countries and Least Developed Countries*Old concepts do not hold – three "power centres" for pharmaceutical manufacturing with different logic and interest but – convergence on going Slide28
Industrialised countriesSubstantial industrial capacityNot much dependent on local manufacture, less generic marketsBase for research based industries - consolidating into few giants with new functions – marketing powerhouses, contracting a lot outGeneric industries merging and going GlobalMachinery/lab equipment monopoly shifting away – China producing production and lab equipment
Increasing Globalization and work sharing80 % APIs from India and China, also a lot of excipients and packing materialsContract manufacturing for FPPs (India)R&D – more and more in "developing world" – clinical trials, basic research slowly followingSlide29
New emerging economiesIncreasing industrial capacity in many areas with needs for new markets, still at large generic markets but with increasing share of originator productsIncreasingly part of work sharing and taking over certain functionsAPI, excipients, packaging materials, machinery production etc. Participating in Global R&DClinical trials increasing, CROs developing, basic research
Developing its own original R&D for new productsGeneric industries developing and consolidating, going Global reaching out to old industrialised country markets (India) and developing country markets (China)Slide30
Lower-middle income and low income countries(including African countries)Local manufacture may (?) be more important, mostly generic marketsBigger dependence on outside country/region resources (almost 100% for APIs, excipients, packing materials machinery) Less part of Global R&D – less clinical trials, in many no CROs, no participation in basic research
Generic companies small and not reaching further than country or sub-regionMany have either no or only limited industrial capacityRelative lack qualified human resources and knowledge baseLess business freedom and less attractive investment environmentLocal policies may disfavour local manufacturingMore problems with good governance in pharmaceutical sectorSlide31
Sustainable local production in Africa needs favourable environment and … collaboration between countries and access to marketsSlide32
WHO position and experiences (particularly in the light of improved access to essential medicines)Local manufacturing may facilitate access but is not a goal in its own rightDramatic quality problems have occurred (e.g.Pakistan examples)Locally produced essential medicines may be of lower quality and higher priceHealth care providers and patients do not care where the medicines come from provided they are safe, of good quality and affordable
Some products likely more feasible for local production than others e.g. blood products, antivenom seraLocally produced medicines must meet international standards for Quality, Safety and EfficacyRisk-based step-by-step approach possible, but no compromise on final goalSlide33
Concluding remarks (1) Governments' commitment to create enabling environment for access to quality medicines in all of its complexity is importantGood Governance principles implemented, especially in pharmaceutical sector, are one of the foundationEfficient highly qualified national regulatory authority is a mustSub-regional and regional collaboration between governments and regulators is vital to create a predictable harmonized "quality market for quality products"Slide34
Concluding remarks (2)WHO has promoted regulatory capacity building, collaboration and harmonization long time and will continue to do so being open to new ideasMaking medicines is not any more a "local" business and the era of only locally operating regulators with different standards starts to end Through its prequalification programme and other technical activities WHO has obtained
unique experience and expertise about the problems existing. WHO has also given substantial technical help to local manufacturers including API manufacturers in China and FPP manufacturers in several regions including Africa. Slide35
The time of poor quality medicines for poor people should be over
Poor people also deserve good quality medicinesRegulators have important role to play to make it happen