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Introduction to regulation of medicines and health technologies: Global context of drug regulation. Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines Essential Medicines and Health Products World Health Organization E-mail: Content.

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Introduction to regulation of medicines and health technologies:Global context of drug regulation

Dr Lembit Rägo


Quality Assurance and Safety: MedicinesEssential Medicines and Health Products

World Health OrganizationE-mail:

  • Setting the scene. What products we have? What is the situation with medicines quality and regulatory affairs Globally?
    • 3 case studies
      • Africa - antimalarial medicines quality survey and falsified antimalrials
      • Pakistan – two "killer" medicines cases
      • Case study from NIS – a biosimilar case
  • Who is WHO?
  • WHO activities to medicines quality assurance and regulation
  • What is WHO doing to strengthen national regulatory authorities?
  • Local production of Essential Medicines and its constraints
  • Concluding remarks
what type of regulated products we have
What type of regulated products we have?
  • Regulated health products
    • Medicines, including biological products:
      • Medicines – originator and "generic" products
      • Biological medicines
        • Vaccines
        • Other biologicals: Monoclonal antibodies, Interferons etc.
        • Blood products
        • Similar biotherapeutic products (biosimilars)
      • Traditional/herbal medicines (complimentary medicines)
    • Medical devices – in vitro diagnostics (IVDs)
medicines originator vs generic medicines
Medicines: originator vs generic medicines
  • New medicines or originator products
    • Need to prove safety, efficacy and quality
  • Multisourcse (generic) medicines
    • Focus on quality, safety and efficacy referred to originator
    • Safety and efficacy – bridging through bioequivalence studies
    • Interchangeability
      • Pharmaceutical
      • Therapeutic
what is the situation with medicines quality qse globally 1 st case example antimalarials africa
What is the situation with medicines quality (QSE) Globally?1st Case example. Antimalarials/Africa
  • Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania
  • ACTs and sulfadoxine-pyrimethamine
  • 935 samples collected and screened by Minilab, 306 tested in laboratory


falsified counterfeit antimalarials also common 1 st case example cont
Falsified/Counterfeit antimalarials also common (1st Case example. Cont).
  • Several notifications about falsified antimalarials – no active ingredient or … containing paracetamol
  • WHO issues also public Drug Alerts
what is the situation with medicines quality qse globally 2nd case example pakistan 1
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 fever
  • Passed quality control testing
  • … forensic investigation – contained pyrimethamine in toxic quantities
  • Reason – totally ignoring GMP and negligence
what is the situation with medicines quality qse globally 2nd case example pakistan 2
What is the situation with medicines quality (QSE) Globally?2nd Case example – Pakistan 2.
  • Dextromethorphan killing more than 20 people
  • All 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 failure
  • Site in India closed
what is the situation with medicines quality qse globally 3rd case example nis biosimilar
What is the situation with medicines quality (QSE) Globally?3rd Case example – NIS biosimilar
  • A biosimilar approved in a NIS country several years ago
  • Patient complaints, MPs involved …
  • Approval based on … regulations about chemical generic medicines!
  • Company profile – not very credible
  • Question why it was authorized remains open.
what these case stories are telling
What these case stories are telling?
  • Quality of medicines is still an issue in many jurisdictions
  • Many countries do not have functional regulatory systems in place for product approval (MA, registration)
    • Dossier assessment weak or absent
    • Inspectorates do not function properly
  • Many de facto do not control their markets nor do they control the supply chain
    • No effective control of imports
    • No effective licensing of all the activities - manufacturing, retail- and whole sale, hospital pharmacies
    • No traceability of products at any point of supply chain
  • Lack of capacity doing all the necessary and no system in place to rely on those who have the capacity
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)
standards and who
Standards and WHO
  • 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 Standardization
    • Both complimentary to ICH activities
  • Joint FAO/WHO Expert Committee on Food Additives

international conferences of drug regulatory authorities icdra
International Conferences of Drug Regulatory Authorities (ICDRA)
  • Biennial Global meetings bringing together regulators from around 100 nations
  • Promoting information and best practices exchange, cooperation, harmonization and convergence
  • Several initiatives started in ICDRA environment
    • ICH initial discussions
    • AMRH initiative initial discussions
    • Reports from various harmonization initiatives
Prequalification programme – powerful engine for facilitating quality manufacture

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:


- Tuberculosis

- Malaria

- Reproductive Health

- Selected individual products for other diseases (Flu, Zinc sulphate)



Extensive collaboration:

working with regulators … for regulators

  • Not duplicating work done be stringent regulatory authorities
    • SRA approval of new and generic products – abridged procedure
    • US 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 settings



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 millionof whom were taking WHO-prequalified antiretrovirals (ARVs);
    • and sales of WHO-prequalified artemisinin-based combination antimalarials exceeded 180 million individual treatmentcourses in 2010)
  • UNAIDS. World AIDS Day Report 2012. Geneva, UNAIDS, 2012.
  • WHO. World Malaria Report, 2011. Geneva, World Health Organization, 2011.



PQP achievements 2009‒2012:

  • 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 regions



Capacity building provided a core value of the programme. Participants in various capacity building workshops organized or co-organized by PQP during 2007‒2012


access to essential medicines remains a problem
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 problem
  • Chronic 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 countries
concept of local production specific to local production who activities
Concept of local production*: Specific to local production WHO activities
  • Project: 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.
special web site http www who int phi publications local production en index html
Special web site
relevant publications
Relevant publications
  • Local production for access to medical products: Developing a framework to improve public health, 2011
  • Local production for access to medical products: Developing a framework to improve public health, 2011
  • Trends in local production of medicines and related technology transfer, 2011
  • Pharmaceutical production and related technology transfer: Landscape report, 2011
  • Pharmaceutical production and related technology transfer: Landscape report, 2011
  • ….
chances for developing countries and least developed countries
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
industrialised countries
Industrialised countries
  • Substantial industrial capacity
  • Not much dependent on local manufacture, less generic markets
  • Base for research based industries - consolidating into few giants with new functions – marketing powerhouses, contracting a lot out
  • Generic industries merging and going Global
  • Machinery/lab equipment monopoly shifting away – China producing production and lab equipment
  • Increasing Globalization and work sharing
    • 80 % APIs from India and China, also a lot of excipients and packing materials
    • Contract manufacturing for FPPs (India)
    • R&D – more and more in "developing world" – clinical trials, basic research slowly following
new emerging economies
New emerging economies
  • Increasing industrial capacity in many areas with needs for new markets, still at large generic markets but with increasing share of originator products
  • Increasingly part of work sharing and taking over certain functions
    • API, excipients, packaging materials, machinery production etc.
  • Participating in Global R&D
    • Clinical trials increasing, CROs developing, basic research
  • Developing its own original R&D for new products
  • Generic industries developing and consolidating, going Global reaching out to old industrialised country markets (India) and developing country markets (China)
lower middle income and low income countries including african countries
Lower-middle income and low income countries(including African countries)
  • Local manufacture may (?) be more important, mostly generic markets
  • Bigger 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-region
  • Many have either no or only limited industrial capacity
  • Relative lack qualified human resources and knowledge base
  • Less business freedom and less attractive investment environment
  • Local policies may disfavour local manufacturing
  • More problems with good governance in pharmaceutical sector
Sustainable local production in Africa needs favourable environment and … collaboration between countries and access to markets
who position and experiences particularly in the light of improved access to essential medicines
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 right
    • Dramatic quality problems have occurred (e.g.Pakistan examples)
    • Locally produced essential medicines may be of lower quality and higher price
    • Health 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 sera
  • Locally produced medicines must meet international standards for Quality, Safety and Efficacy
    • Risk-based step-by-step approach possible, but no compromise on final goal
concluding remarks 1
Concluding remarks (1)
  • Governments' commitment to create enabling environment for access to quality medicines in all of its complexity is important
    • Good Governance principles implemented, especially in pharmaceutical sector, are one of the foundation
  • Efficient highly qualified national regulatory authority is a must
  • Sub-regional and regional collaboration between governments and regulators is vital to create a predictable harmonized "quality market for quality products"
concluding remarks 2
Concluding remarks (2)
  • WHO has promoted regulatory capacity building, collaboration and harmonization long time and will continue to do so being open to new ideas
    • Making 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.

The time of poor quality medicines for poor people should be overPoor people also deserve good quality medicines

Regulators have important role to play to make it happen