WHO Essential Drugs Strategy

1
Global Review of Medicines Regulation Current
Highlights and Future Trends
National Regulatory Conference 2005 Kuala
Lumpur, Malaysia 6 September 2005
Dr Lembit Rägo Coordinator, Quality Assurance
and Safety Medicines Medicines Policy and
Standards World Health Organization E-mail
ragol_at_who.int
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Content

• Introductory remarks
• Global regulatory environment
• Harmonization
• New challenges and trends
• Role of WHO
• Challenges remaining

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Medicines regulation What is it all about?
Taste
Smell
Appearance
Usual perceptions may not help in making
judgements about medicines
4
Why Stringent Standards for Medicines?

• Medicines are different from other goods as
  patients (consumers) and even health care
  professionals are not able to judge their
  "quality" or "fitness for use"
• " drugs are a public good and not simply just
  another commodity first for their high social
  value, and then because consumers and prescribers
  are unable to assess their quality, safety and
  efficacy" (Dr Gro Harlem Brundtland, former
  Director General of the World Health
  Organization)
• This is the reason why medicines belong to one of
  the most regulated group of products

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What Standards for Medicines?

• Medicines must meet quality, safety and efficacy
  criteria.
• These three sets of requirements are
  complementary to each other and each product has
  to be of good quality, safe and efficacious.
• It is possible that a product is of good quality,
  but may not necessarily be effective or safe
• It is possible that a product is effective, but
  may not necessarily be of good quality or safe
• It is possible that a product is safe but may not
  be of good quality or effective

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What type of medicines we have? 1. Innovator
products

• For these products one has to prove their safety,
  efficacy and quality. Basis for these criteria is
  created by respective scientific disciplines.
  Implementation is executed through respective
  laws and regulations.
• Proving safety and efficacy is the key for these
  products. It is based on the results of
  pre-clinical (i.e. animal toxicology) and
  clinical (clinical studies carried out in healthy
  volunteers and patients) research
• Innovator (or originator) products
• New innovative products that nobody yet has
  marketed, usually based on the new active
  ingredient (chemical compound which is
  responsible for its effects in human subjects)
• The manufacturer has also to prove that its
  processes to produce the product and methods
  invented to control its quality are meeting
  established quality requirements.

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Who sets the scene for regulating innovator
products?
8
International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use Six Co-sponsors -
members of Steering Committee European
Commission EC European Federation of
Pharmaceutical Industry Associations EFPIA J
apanese Ministry of Health and Welfare MHW Japa
nese Pharmaceutical Manufacturers
Association JPMA US Food and Drug
Administration FDA Pharmaceutical Manufacturers
Association PhRMA
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ICH Steering Committee Observers

• World Health Organization (WHO)
• Canada - Health Protection Branch
• European Free Trade Area (EFTA)

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ICH SC latest press release 2005
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ICH Global Cooperation Group (GCG)
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ICH Global Cooperation Group (GCG) - challenges

• Very different by composition (countries with
  very different level of socioeconomic
  development) and objectives regional
  harmonization initiatives
• Often in some countries indirectly involved ABC
  not yet fixed whereas other countries may have
  much higher levels of development
• Relatively low level of resource investments
  available in harmonization as compared to ICH
• Some may more have interest in regulating generic
  medicines well first (but this is not exactly ICH
  objective)

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How can non-ICH countries benefit from ICH
products? Challenges for policy makers

• Priority setting (ABC first) may be long way to
  go
• Real control of market, functional DRA and
  inspectorate
• Basic quality assurance measures like GMP, etc.
• If market 90 generics, regulate well generics
  first
• Implementation of ICH products vs recognition of
  registrations based on ICH guidelines?
• Availability of resources
• What is the cost of implementation of ICH
  guidelines and training?
• What is the minimum number of regulators needed
  to assess a new drug according to ICH guidelines
• Step-by-step approach

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Where are we going with innovation?

• Do we need new medicines?
• Which type of new medicines we need?
• What needs to be done to get new medicines out?
• Is increase of spending on RD the only solution?
• What about new medicines for public health needs?
• What can regulators do?

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New initiatives to streamline drug approval
process
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Research spending
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and product submissions to FDA
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Increase in certain segments of development costs
19
Project Failure is Highest in Phase II
Mean Probability Of Success Of Completing Stage
PoS
CMR data based on cohort approach looking at
fate of NCEs entering phase 1996-1998, with
progression decision made by 2001
adapted from Ashton GA, Joshua PJ. Industry
success rates 2002. CMR International Ltd
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Three dimensions of Critical Path
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Poorly developed areas Paediatric medicines

• Paediatric indications based on evidence only
  approximately 50 of use has backing by clinical
  research
• Incentives for paediatric research created in
  several countries (exclusivity rights increased
  etc.)
• US
• EU
• Not much specific regulatory guidance
• Lack of paediatric formulations needed ARVs

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Recent safety concerns and withdrawals COX2
inhibitors in focus

• Are regulatory models used to assess safety
  appropriate?
• Independence of pharmacovigilance from
  authorization staff
• US Congress interested and investigates issues
• Can safety be predicted in a better manner?
• Are new regulatory guidance documents needed?

23
Pharmacogenetics (PGx) significant potential to
address some of the challenges

• Pharmaceutical companies and regulators are
  actively exploring PGx applications. Draft
  guidance issued by some regulators, discussions
  in ICH environment
• CIOMS report Impact of Pharmacogenetics on Drug
  Discovery and Development,
• key development drivers and hurdles relevant to
  the
• implementation of PGx in drug development
• the potential role PGx may play in the drug
• development process

24
New regulatory pathways to assure quality, safety
and efficacy of medicines for public health needs
in developing world

• WHO Prequalification Program
• US FDA tentative approval process for ARVs
• EU Article 58 process

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WHO Prequalification

• The UN prequalification program is an action plan
  for expanding access to medicines for the hardest
  hit by
• HIV/AIDS
• Tuberculosis
• Malaria
• by ensuring quality, efficacy and safety of
  medicines procured using international funds

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Why the prequalification is needed?

• Problems
• Millions of people living with HIV/AIDS,
  tuberculosis and malaria, have no or limited
  access to treatment
• Substandard products widely available and in
  circulation
• Weak/absent QA systems of medicines supply chain
• Lot of money invested in procurement ?no
  harmonized quality assurance system available for
  procurement organizations/initiatives
• Risks
• Sourcing of poor quality products or even
  counterfeit medicines? risk to patients,
  treatment failure, resistance

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Prequalification basic principles

• Rigour regulatory approach to ensure quality,
  safety and efficacy
• Voluntary for participating manufacturers
• Legitimate - General procedure and standards
  approved through WHO Expert Committee system
  involving all WHO Member States and WHO Governing
  bodies
• Widely discussed
• FIP Congress, Nice 2002
• Supported by ICDRA in 2002 and 2004, representing
  more than 100 national drug regulatory
  authorities
• Transparent (all information available on the web
  site http//www.who.int/medicines/)
• Open to both innovators and multisource/generic
  manufacturers
• No cost for applicants (manufacturers) during
  pilot phase

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Prequalification misunderstandings and critics

• Too high standards increasing prices
• Too high and unnecessary standards for
  developing countries
• Too bureaucratic and slow, not proactive and
  not able to provide products
• Too low standards
• . " This leaves the impression with readers that
  the ARVs approved by WHO are in fact generic
  products that are interchangeable with their
  innovator cousins. From available documents,
  however, we conclude that they are copy products
  with unknown quality, safety and efficacy
  profiles".

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How prequalification is organized

• Role of WHO Managing and organizing the project
  on behalf of the United Nations.
• provide technical and scientific support and
  guarantee that international norms and standards
  are applied all through the process including
  assessment, inspection (GMP, GCP, GLP) and
  quality control
• Partners
• UNICEF, UN Population Fund (UNFPA), UNAIDS and
  with the support of the World Bank
• Anti-malarial and anti-TB products Roll Back
  Malaria and Stop TB (Global Drug Facility)
• Actors Mainly assessors and inspectors of
  National DRAs as well as National Quality Control
  Laboratories of PIC/S and ICH member countries

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Assessment procedure

• I. Assessment of products dossiers i.e. quality
  specifications, pharmaceutical development,
  bioequivalence etc.
• teams of professionals from national drug
  regulatory authorities (DRA) Brazil, Canada,
  Denmark, Estonia, Finland, France, Germany,
  Hungary, Indonesia, Malaysia, Philippines, Spain,
  South-Africa, Sweden, Switzerland, Tanzania, UK,
  Zimbabwe ...
• II. Inspections
• Manufacturing site (final product, packaging)
• Active pharmaceutical ingredient (API)
• Research laboratory or Contract Research
  Organization (CRO)
• Teamwork of inspectors
• WHO representative (qualified GMP inspector)
• Inspector from well-established inspectorate
  (Pharmaceutical Inspection Convention Scheme
  countries) Australia, Canada, UK, France, Italy,
  Switzerland,
• Quality control analysis - upon need but not
  always necessarily before prequalification and
  supply, increasingly as part of follow-up

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Current status 2005

• Started with HIV/AIDS products in 2001 malaria
  and TB products joined later
• Prequalified products Submitted
• 95 HIV related medicines - 289
• 8 anti-tuberculosis medicines - 153
• 2 anti-malarial medicines - 46
• 105 488
• Ongoing assessments and follow-up
• Products
• Manufacturing sites
• CROs

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Ongoing monitoring and requalification

• Samples taken after supply
• Routine inspections and additional inspections
• Changes and variations controlled
• Products and manufacturers
• Requalification (re-assessment) every 3 years
• World Health Assembly resolution WHA57.14 of May
  2004
• Public reports
• WHO Public Assessment Report (WHOPAR)
• WHO Public Inspection Report (WHOPIR)

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Prequalification

• Good news
• Relatively large number of products and suppliers
  indicated
• Many potential suppliers appreciating feedback
  and willing to improve
• Unique knowledge obtained about generic products
• De-listed products coming back to the
  prequalified products list
• Bad news
• Only limited number of products have met the
  required standards
• A number of de-listings from the prequalified
  products list in 2004
• Takes time to get into compliance
• Data to be generated, tests carried out
• GMP upgrade needed
• Bad quality generics may undermine the public
  confidence in generics
• Quality assurance has its price!

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Lessons to be learned

• Quality can not be assessed, tested or inspected
  into the product, BUT
• It has to be built into it!

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http//mednet3.who.int/prequal/
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US FDA tentative approvals

• Exactly the same standards for assessment as for
  US internal market
• The same inspection standards
• The same post approval surveillance
• When IP rights allow (patents and other
  exclusivity rights) can enter US market
• Limited to ARVs as linked to specific program
  does not cover other product groups

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Article 58 LEGAL BASIS AND SCOPE

• Article 58 of Regulation (EC) No 726/20041 (the
  Regulation) establishes a mechanism whereby the
  European Medicines Agency (EMEA) may give a
  scientific opinion, in the context of cooperation
  with the World Health Organization (WHO), for the
  evaluation of certain medicinal products for
  human use intended exclusively for markets
  outside the Community.
• The Committee for Medicinal Products for Human
  Use may, after consulting the World Health
  Organization, draw up a scientific opinion in
  accordance with Articles 6 to 9.

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Article 58 Why?

• Under new EU legislation the EU Commission will
  no longer license medicinal products unless they
  are to be placed on the market in the EU.
• Applicants were not able to get marketing
  authorization in the EU for products that had no
  market
• WHO CPPs not issued under such circumstances no
  basis for acceptance by other DRAs
• Commission did not intend to kill incentives from
  companies to address public health issues outside
  the EU

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How Article 58 will work?

• Strong cooperation with the WHO
• WHO gate keeper (determines if product is of high
  public health value)
• WHO can send observers to CHMP
• WHO can provide experts to EMEA
• Procedure resembles centralized procedure same
  standards
• Outcome not MA but "scientific opinion for WHO"
• WHO type CPP will be issued
• EPAR like document will be made public

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Specific non-EU medical needs

• Medicines for non-EU use only due to
• - Specific epidemiological situation
• - Specific socio-economical conditions
• - Specific logistical conditions
• Vaccine examples
• - Pneumococcal vaccines with adapted
• composition
• - Multidoses containing thiomersal etc.

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What type of medicines we have? 2. Generic
products

• The term generic product has somewhat different
  meanings in different jurisdictions. Therefore,
  term multisource pharmaceutical product is
  preferred by WHO.
• Where the term generic product is used, it means
  a pharmaceutical product, usually intended to be
  interchangeable with the innovator product, which
  is usually manufactured without a license from
  the innovator company and marketed after expiry
  of the patent or other (e.g. data) exclusivity
  rights.
• Multisource pharmaceutical (generic) products are
  pharmaceutically equivalent products that may or
  may not be therapeutically equivalent.
  Multisource pharmaceutical products that are
  therapeutically equivalent are interchangeable

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What standards are need for generic medicines?

• For generic medicines the manufacturer has to
  prove that the product meets all quality
  requirements
• In case of safety and efficacy it refers to the
  originator's research
• To prove the therapeutic interchangeability it
  has, as a rule, to carry out bioequivalence
  studies (small scale clinical trials in healthy
  volunteers to examine if the test drug has
  essentially the same blood concentration pattern
  of active ingredient as the originator.
• It is assumed that if the blood concentrations
  are essentially the same the safety and efficacy
  profile is also the same.

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Standards for generic drugs first priority

• WHO continues to issue Global standards for
  generic medicines and regulatory topics for
  public health importance

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39th WHO Expert Committee on Specifications for
Pharmaceutical Preparations, 25-29 October 2004
(I)

• Draft Guidelines
• FDC -WHO-QAS04_108 (Fixed Dose Combination
  guidelines)
• GMP_Herbal_RevJuly-04_QAS050
• Interchangeability-WHO-QAS_093Rev3_23Sept04
  (bioequivalence)
• QAS_055_Rev1_validation (supplementary to GMP)
• QAS_066_Rev3_sampling (to replace 1990 guideline)
• QAS_068_GDP see next slide for details
• QAS047_Rev1_Water (GMP)
• Guidelines on MP HVAC (Rev 4) (GMP Heating,
  ventilation and air conditioning for non-sterile
  dosage forms)
• http//www.who.int/medicines/organization/qsm/expe
  rt_committee/expertcomm.shtml

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What is WHO doing in order to reduce quality and
regulatory gaps?

• Assessing regulatory capacity upon request
• Supporting capacity building and training of
  regulators
• Issuing norms and standards and guidance
  materials
• Preparing training tools, organizing training
  seminars and workshops on variety of topics as
  requested by countries - GMP, MA of Generic
  Drugs, GCP, GLP, Pharmacovigilance etc.
• Facilitating information exchange
• Supporting regional harmonization initiatives
• Favoring networking and cooperation
• Providing technical assistance upon request

Ultimate goal improve access to quality drugs
for all citizens
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International Conference of Drug Regulatory
Authorities

• Biennial unique forum of regulators
• Brings together more than 100 countries

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Information exchange.WHO Drug Informationhttp//
www.who.int/druginformation/
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Unfinished agendas 1. In many countries ABC
recommendations of this document to implement
effective drug regulation of medicines are still
not implemented
S
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2.Unregulated online shopping threat for public
health
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3. Counterfeit medicines Global threat to public
health
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3. Counterfeit medicines no country is immune
Figure 1. The Number of Investigations of
possible counterfeit drugs by the FDA has been
rising (Figure Margaret Shear, Public Library of
Science, cited form Cockburn R, Newton PN,
Agyarko EK, Akunyili D, White NJ (2005) PLoS Med
2(4) e100.
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As health professionals, in public and private
sector, as an international community ...we have
a lot left to do all of us, together, things
that do matter, in right time and in right order
www.who.int/medicines