Genericos, presentaci

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Strengthening national drug regulatory capacity
Valerio Reggi, Eshetu Wondemagegnehu, HTP/EDM/QSM
28 September 2004
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Regulation in medicine is 4000 years old

• Hammurabi's Code of Laws ( 2000 BCE)
• physician fees adapted to patients status
• 215. a physician shall receive ten shekels
  in money.
• 216. If the patient be a freed man, he receives
  five shekels.
• 217. If the patient be the slave two shekels.

• sanctions for malpractice
• 218. If a physician make a large incision with
  the operating knife and kill the patient or .
  cut out the eye, his hands shall be cut off.

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The three key statements on DRAs

• health system counts on DRA for good, safe, and
  effective medicines, as well as fair rules and
  control on drug trade, information, and use
• any strategy to improve anything in the
  pharmaceutical area involves DRA
• any problem encountered in the pharmaceutical
  area has something to do with the DRA

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Drug regulation is a multi- faceted activity at
the centre of complex interactions
Government
Experts
Manufacturers
Regulatory authority
Prescribers
Products
Medicines
Patients/Consumers
Importers/Wholesalers/Retailers
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Drug regulation is a multi- faceted activity at
the centre of complex interactions
Government
Experts
Manufacturers
Regulatory authority
Prescribers
Products
Medicines
Patients/Consumers
Importers/Wholesalers/Retailers
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Drug regulation is a multi- faceted activity at
the centre of complex interactions
Government
Experts
Manufacturers
Regulatory authority
Prescribers
Products
Medicines
Patients/Consumers
Importers/Wholesalers/Retailers
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Drug regulation is a multi- faceted activity at
the centre of complex interactions
Government
Experts
Manufacturers
Regulatory authority
Prescribers
Products
Medicines
Patients/Consumers
Importers/Wholesalers/Retailers
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Drug regulation is a multi- faceted activity at
the centre of complex interactions
Government
Experts
Manufacturers
Regulatory authority
Prescribers
Products
Medicines
Patients/Consumers
Importers/Wholesalers/Retailers
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Regulation is an essential state function

• Essential means that if the public sector is
  unable to perform these functions, public health
  goals cannot be achieved and the least privileged
  part of the population will suffer.

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Market failure

• Equity does market care for the poor?
• Information imbalance unequal access to
  information, incapacity to assess quality,
  safety, efficacy, value for money,
  appropriateness
• External benefits immunizations and treatment
  of contagious diseases benefit all, if left to
  market laws alone many will not be immunized or
  treated
• Failure of competition competition based on
  product differentiation rather than price
• Market asymmetry who pays does not choose, who
  chooses does not pay

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• Market access is a two-step process
• 1- market approval of a product on the basis of
  efficacy, safety and quality. This regulatory
  decision results in the availability of the drug
  on the market.
• 2- public private drug schemes limit
  procurement or reimbursements to certain drugs.
  For these decisions an evaluation is made, based
  on a comparison between various drug products and
  on considerations of value for money.

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• The reality (and the paradox)
• - only richer countries use both steps and enact
  effective mechanisms to rationalise consumption
  and keep expenditure under control,
• - in poorer countries, where health insurance
  mechanisms are not fully developed and people pay
  most drugs out of pocket, there are no adequate
  mechanisms to protect consumers

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This puts special responsibility and burden on
decision makers and regulatory officials of
developing countries
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WHO Expert Committee on Specifications for
Pharmaceutical Preparations, TSR 790, 1990
...approach to regulation must be attuned to
available resources... ...problems in
establishing regulatory control have too often
resulted from the introduction of provisions
successful elsewhere but of a complexity that
precludes their effective implementation in the
country of adoption...
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No importable models
Need for review of national regulatory situation
and definition of country-specific strategy and
priorities
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Effective drug regulationA multi-country
study
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Rationale for the study

• 20 of WHO Member States have well-developed drug
  regulation 50 have varying capacity and
  level of implementation 30 have limited
  capacity or have no DRA at all
• WHO has never undertaken a systematic assessment
  of drug regulation to know how DRAs function,
  what strategies they use, why regulation is weak
  in most Member States, etc.

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Study objectives

• To map the legal and organisational structures of
  drug regulation in selected countries
• To collect information on how regulatory
  functions operate
• To identify strengths weaknesses, and factors
  contributing to them
• To document the results of the assessment so that
  other countries may learn from them
• To propose strategies that can help
  decision-makers to improve drug regulation

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Method of study

• Collection of data by national partners
• interview of key informants-regulators, industry,
  associations
• review of existing reports and documents
• Writing a report on the country drug regulation
  by each partner
• Preparing a synthesis report

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Framework for the study
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Multi-country study on effective drug regulation

• All WHO Regions included
• Type of government
• Developed, middle income, low income
• Newly independent
• Willingness to participate

Australia, Cuba, Cyprus, Estonia, The
Netherlands, Malaysia, Tunisia, Uganda,
Venezuela, Zimbabwe
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Regulatory functions assessed

• Licensing of persons, premises and practices
• Product assessment and registration
• Inspection
• Control of promotion advertising
• Drug quality testing (QC laboratory)
• ADR monitoring
• Clinical trials oversight

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Per capita GNP in US
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IMR per 1000 live births
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Number of pharmaceutical manufacturers

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Number of registered pharmaceuticals for human use
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Number of DRA staff per million population
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Per capita drug regulation expenditure
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DRA budget as a national drug expenditure
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Salaries of GMP inspectors lower than
their counterparts in private sector
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Big gap in registration fees for new drugs
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Time taken to register new and generic products
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Organizational structure can vary

• Single, autonomous (Zimbabwe Uganda)
• Several authorities/agencies, some autonomous, no
  functional link (The Netherlands)
• Department under the Ministry of Health (MoH)
  no independence (Tunisia)
• Department under MoH with statutory independence
  (Australia)
• Departments under MoH but with additional
  structure, a central committee, having
  decision-making power (Cyprus Malaysia)

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Diverse mission distribution of responsibilities

• Ensuring the safety, efficacy and quality of
  drugs is the mission of most countries - but
  some include price control ensuring
  availability as their goals (Cyprus, Tunisia,
  Zimbabwe Uganda)
• Distribution of responsibilities between federal
  and state levels with little or no co-ordination
  (Australia Malaysia)
• Delegation of functions without legal power and
  accountability (Uganda)
• Multiple and conflicting responsibilities
  assigned (Cyprus Malaysia)

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Human resources shortage everywhere

• Some DRAs have power to recruit and dismiss staff
• Shortage and high turnover of staff is universal
• Salaries of DRA staff lower than those of their
  counterparts in the private sector
• Lack of career structure and incentive
• Few trained people available, lack of training
  institution, recruitment system not flexible
  brain-drain
• All DRAs train staff on ad-hoc basis- very few
  have human resources development plan

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Human resources different strategies

• All DRAs employ advisory boards, committees
  experts to assist in regulatory functions
• Some DRAs apply different strategies to address
  human resources problem
• self-regulation co-regulation, streamlining of
  work process and risk management (Australia, The
  Netherlands)
• prioritization and multi-skilling (Zimbabwe)
• Most countries do not require staff experts to
  declare conflict of interest and respect for
  confidentiality of information

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Financing different mechanisms

• All the DRAs have a fee system but only
  Australia, Uganda, Zimbabwe are empowered to use
  the revenues generated
• Australia depends 100 on revenues collected,
  Uganda Zimbabwe also receive government
  allocation
• Most countries depend on government budget- part
  of MoH budget
• Fees charged by most DRAs do not reflect the
  actual costs/values of services provided
• In most countries the fee systems do not cover
  all the services provided by the DRAs

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Regulatory tools scarcity in most cases

• Inadequate regulatory tools-guidelines, SOPs, job
  descriptions, code of conduct. etc.
• Tools not accessible to stakeholders and in
  most cases stakeholders are not consulted during
  the development stage

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Domains of control vary among countries

• Prescribing practice is regulated in six
  countries
• Promotion not allowed in Cuba
• Only seven countries make registration of herbal
  medicines mandatory
• Regulatory gaps exist in most countries
• not all categories of medicinal products are
  regulated
• Informal (unauthorized) sector receives little or
  no regulatory attention compared to the formal
  (licensed) sector
• There are regulatory double standards
• pubic vs. private sector (Cyprus)
• medicines for domestic use vs. medicines for
  export

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Imbalance in implementation of regulatory
functions

• Between pre-marketing post-marketing product
  assessment
• Between product registration regulation of drug
  distribution and information
• GMP inspection and distribution channels
  inspection
• Information/data on drug regulation performance
  not readily available and not computerized

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Some recommendations

• Review drug regulation
• Define the mission and objectives
• Update legislation and regulations to cover all
  areas involving drug products
• Create appropriate structure with a central
  authority which is accountable for the overall
  effectiveness of drug regulation
• Allocate adequate number of qualified personnel
  of integrity create human resources development
  programme and access to latest scientific and
  technological information

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Some recommendations

• Develop appropriate tools-standards, guidelines,
  SOPs, in consultation with stakeholders and
  disseminate to all interested parties
• Apply the same standard of regulation to all
  drugs-imported, exported, locally manufactured,
  private and public
• Set priorities (risk management) and streamline
  work
• Empower and create incentives for regulatory
  staff
• Apply multi-skills, rotation and team/group work

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Some recommendations

• Set fees for all services provided and ensure
  that fees reflect actual costs /values of
  services provided and review fees regularly
• DRA financing should strike a balance between
  revenue collected through fees and government
  support
• Control both the formal and informal
  sector/market
• Carry out regulatory functions in a balanced
  manner
• Ensure that decisions and services to be timely
  and evidence based and not compromising
  quality,safety and efficacy

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Some recommendations

• Ensure there is accountability to the government,
  those regulated and the public
• Create independent appeals mechanisms and a
  system for citizens complaints
• Ensure that communication with clients is
  formal-based on written guidelines
• Ensure staff and external experts participating
  in drug regulation declare conflict of interest
  and respect confidentiality of information

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Some recommendations

• Promote self-assessment, peer review, review by
  supervisory and external body
• Empower consumers and the public by providing
  accurate and appropriate information on drugs and
  educating

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• International Comparative Study on Drug
  Information

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• 26 countries

http//link.springer.de/link/service/journals/0022
8/contents/03/00607/paper/s00228-003-0607-1ch000.h
tml
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• Objective
• To document differences in information on
  indications, adverse effects and precautions

Drugs ciprofloxacin, fluoxetine,
nifedipine celecoxib, cisapride, montelukast
Materials 683 documents approved by NRA or, if
non existent, published by company
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• Methods
• 4 variables indications, dose range for adults,
  side effects, precautions

Checklist based on BNF 40
Side effects Frequent gt1 patients (AHFS
2001) Severe criteria defined by WHO CC, Uppsala
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• For each analysed material
• How many checklist elements found
• Elements not found in checklist were ignored

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• For each variable (except dose) mean and 95
  confidence intervals

Degree of agreement Indic., side eff., prec.
Degree of agreement for dose range
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• For each material, the sum of the 4 parameters
  can be

Maximum agreement
4

-3
Maximum disagreement
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• Overall results

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Source of materials analysed
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Results for ciprofloxacin
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Results for fluoxetine
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Results for nifedipine
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Data from one of the 26 countries
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• Disagreement is high although

• Same company, i.e. same source of information in
  most cases
• Same substance in same country

Disagreement difficult to explain but.... ... may
have consequences on rational use and patient
safety ... gives poor image of regulatory work
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Side effects simply listed. not a guide to
rational prescribing
Effective models for rational information on
safety still need to be developed In the
meantime, the impression is that safety
information is listed only to limit liability
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Thank you