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: ragol@who.int
Content
 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
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2|
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?
 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)
3|
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
4|
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
SPs
ACTs
70
63
67
Non-compliant
56
60
50
Compliant
100%
90%
44
7
80%
40
%
32
27
30
60%
17
20
80
12
68
17
30%
0
0
0
0
0
5|
50%
40%
8
10
n
ro o
e
m
Ca
12
111
70%
i
Eth
ia
op
a
an
Gh
a
ny
Ke
a
eri
Nig
a
nz
Ta
ni a
12
73
20%
10%
3
2
1
0%
PQ total
Non-PQ
total
AL PQ
AL non-PQ A&A co-p
PQ
A&A co-p
non-PQ
5
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
 http://www.who.int/medicines/publications
/drugalerts/drugalertindex/en/index.html
6|
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
7|
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
8|
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.
9|
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
10 |
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)
11 |
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
12 |
 http://www.who.int/medicines/areas/quality_safety/regul
ation_legislation/assesment/en/index.html
13 |
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
14 |
Prequalification programme – powerful engine for facilitating
quality manufacture
http://apps.who.int/prequal/
15 |
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)
16 |
16
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
17 |
17
Common deficiencies for dossiers
18 |
Common deficiencies observed: quality
19 |
19
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.
20 |
20
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
21 |
21
Capacity building provided a core value of the programme.
Participants in various capacity building workshops organized or coorganized by PQP during 2007‒2012
22 |
22
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
23 |
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.
24 |
Special web site
http://www.who.int/phi/publications/local_production/en/index.html
25 |
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
 ….
26 |
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
Old
industrialised
countries
(EU, US,
Japan,
Canada etc.)
New
emerging
economise
(BRICS)
Lower-middle income
and low income
countries
(including African
countries)
27 |
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
28 |
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)
29 |
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 subregion
 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
30 |
Sustainable local production in Africa needs favourable
environment and … collaboration between countries and
access to markets
Strong national
regulatory
authority (NRA)
Favourable health
and industrial
policies
Favouring
environment
(secure investment
and business
climate, taxes and
customs)
31 |
Knowledge base
and skilled
workforce
Local
production
in Global
context
Infrastructure
(roads, electricity,
water supply)
Good governance
in pharmaceutical
sector, modern
laws and
regulations
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
32 |
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"
33 |
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.
34 |
The time of poor quality medicines for poor people
should be over
Poor people also deserve good quality medicines
Regulators have important role to play to make it
happen
35 |