1 par seminar 28 september 2004 who - htp strengthening national drug regulatory capacity valerio...

1 PAR Seminar 28 September 2004 WHO - HTP

Strengthening national drug regulatory capacity

Valerio Reggi, Eshetu Wondemagegnehu, HTP/EDM/QSM 28 September 2004

Regulation in medicine is 4000 years old

Hammurabi's Code of Laws (~ 2000 BCE):

physician fees adapted to patient’s 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.

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

Drug regulation is a multi- faceted activity at the centre of complex interactions

Regulatory authority

Manufacturers

Prescribers

Importers/Wholesalers/Retailers

Patients/Consumers

Products

ExpertsGovernment

Medicines

Manufacturers

Prescribers

Patients/Consumers

Products

ExpertsGovernment

Medicines

Manufacturers

Prescribers

Patients/Consumers

Products

ExpertsGovernment

Medicines

Manufacturers

Prescribers

Patients/Consumers

Products

ExpertsGovernment

Medicines

Manufacturers

Prescribers

Patients/Consumers

Products

ExpertsGovernment

Medicines

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.

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

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”.

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

APPLICATIONS APPLICATIONS

Nr of drugs that can achieve important prescription

NRANRA Assessment of QS&E

REIMBURSEMENT

Assessment of ‘value for money’

MAs MAs

This puts special responsibility and burden on decision

makers and regulatory officials of developing countries

...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...

WHO Expert Committee on Specifications for Pharmaceutical Preparations, TSR 790, 1990:

No importable models

Need for review of national regulatory situation and

definition of country-specific strategy and priorities

Effective drug regulation

A multi-country study

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.

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

Study objectives

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

Framework for the study

Product assessment

& registration Inspection of manufacturers

& distributors

Monitoring quality of

Control of drug

promotion & advertising

Standards Specifications Guidelines Procedures

Technical elements

Regulatory functions

Administrative elements

Licensing of premises,

practices & persons

Central State/province District Community

Policy, legislation, regulations Organizational structure Human resources Finance Planing, monitoring &

evaluation

Adverse drug reaction

monitoring

Regulation level

Multi-country study on effective drug regulation

Australia, Cuba, Cyprus, Estonia, The Netherlands,

Malaysia, Tunisia, Uganda, Venezuela, Zimbabwe

All WHO Regions includedType of governmentDeveloped, middle income, low income Newly independentWillingness to participate

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

Regulatory functions assessed

Per capita GNP in US$

0 5000 10000 15000 20000 25000

Malaysia

Australia

Netherlands

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

IMR per 1000 live births

0 20 40 60 80 100 120

Malaysia

Australia

Netherlands

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

Number of pharmaceutical manufacturers

0 100 200 300 400

Malaysia

Australia

Netherlands

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

Number of registered pharmaceuticals for human use

0 5000 10000 15000 20000 25000 30000 35000

Malaysia

Australia*

Netherlands

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

Number of DRA staff per million population

0.00 5.00 10.00 15.00 20.00 25.00

Malaysia

Australia

Netherland

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

Staff per million population

Per capita drug regulation expenditure

0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60

Malaysia

Australia

Netherland

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

DRA budget as a % national drug expenditure

0% 1% 2% 3% 4% 5% 6%

Malaysia

Australia

Netherland

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

Salaries of GMP inspectors: lower than their counterparts in private sector

0 500 1000 1500 2000 2500 3000 3500 4000 4500

Malaysia

Australia

Netherlands

Estonia

Cyprus

Uganda

Zimbabwe

Tunisia

Venezuela

GMP inspector Production head Product release person

Big gap in registration fees for new drugs

120,000

15,000

0 20,000 40,000 60,000 80,000 100,000 120,000

Australia

Cyprus

Estonia

Malaysia

Netherlands

Tunisia

Uganda

Venezuela

Zimbabwe

Fees US$

Time taken to register new and generic products

New product Generic product Fast track product

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)

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)

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

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

Human resources: different strategies

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

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

Regulatory tools: scarcity in most cases

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

Domains of control: vary among countries

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

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

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

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

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

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

International Comparative Study on Drug Information

26 countries

http://link.springer.de/link/service/journals/00228/contents/03/00607/paper/s00228-003-0607-1ch000.html

Objective: To document differences in information on indications, adverse effects and precautions

Materials: 683 documents approved by NRA or, if non existent, published by company

Drugs: ciprofloxacin, fluoxetine, nifedipinecelecoxib, cisapride, montelukast

Methods:

4 variables: indications, dose range for adults, side effects, precautions

Checklist based on BNF 40

Side effectsFrequent: >=1% patients (AHFS 2001)Severe: criteria defined by WHO CC, Uppsala

Indications respiratory tract infections, urinary tract infections, chronic prostatitis, gonorrhea, pseudomonal lower respiratory tract infection in cystic fibrosis, gastrointestinal infection (including typhoid fever), septicemia caused by sensitive organisms, surgical prophylaxis, corneal ulcers, skin and soft- tissue infections

Dose 500-1500 mg

Side effects nausea, diarrhea, vomiting , abdominal pain, jaundice, hepatitis with necrosis, headache, restlessness, Stevens Johnson Syndrome, hemorrhagic bullae, toxic epidermal necrolysis, increase in blood urea and creatinine, hepatic dysfunction (increased serum concentrations of AST and ALT), renal failure, convulsions, hypersensitivity reactions, tendon inflammation and damage

Cautions pregnancy, breast-feeding, children and adolescents, photosensitivity, renal impairment, history of epilepsy, avoid excessive alkalinity of urine, G6PD deficiency, myastenia gravis

Ciprofloxacin (500 mg)

Indications depressive illness, bulimia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder

Dose 20 – 60 mg

Side effects hypersensitivity reactions (angioedema, urticaria, anaphylaxis, pharyngitis, pulmonary inflammation or fibrosis, arthralgia, myalgia, serum sickness), nausea, vomiting, dyspepsia, abdominal pain, diarrhea, constipation, sexual dysfunction, sweating, dry mouth, tremor, nervousness, insomnia, anxiety, headache, lightheadedness, dizziness, suicidal ideation, anorexia with weight loss, movement disorders and dyskinesias, fever, anemia, convulsion, neuroleptic malignant syndrome-like event, aplastic cerebrovascular accident, eosinophilic pneumonia, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, thrombocytopenic purpura, violent behavior

Cautions maniac phase, epilepsy, hepatic impairment, renal impairment, pregnancy, breast-feeding, concurrent electroconvulsive therapy, cardiac disease, history of bleeding disorders, skilled tasks (impairment), avoid abrupt withdrawal

Fluoxetine (20 mg)

Indications prophylaxis of angina, hypertension, Raynaud’s phenomenon

Dose 15-80 mg

Side effects headache, flushing, dizziness, gravitational edema, exaggerated fall in blood pressure and reflex tachycardia which may lead to myocardial ischaemia, or cerebrovascular ischaemia (short acting preparation), nausea

Cautions advanced aortic stenosis, myocardial infarction within 1 month, unstable or acute attacks of angina, porphyria, severe hypotension, pregnancy, heart failure, breast-feeding , hepatic impairment, diabetes mellitus, ischaemic pain, avoid grapefruit juice

Nifedipine (20 mg)

For each analysed material:

How many checklist elements found

Elements not found in checklist were ignored

Proportion of agreement

Elements found

Elements in checklist=

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

Degree of agreementIndic., side eff., prec.

Value >= high CI

Value within CI

Value <= low CI

Degree of agreement for dose range

For each material, the sum of the 4 parameters can be:

Maximum agreement4

Maximum disagreement

Overall results

Low Argentina, Egypt, India, TunisiaHigh Australia, Italy, Mexico, Spain, UK

Low Philippines, Venezuela

High: agreement ≥ 3, Low: agreement ≤ - 2

India, Switzerland, UK, USA

Colombia, Estonia, Italy, Philippines, Thailand, UK, USA

NIFEDIPINE

CIPROFLOXACIN

FLUOXETINE

Ciprofloxacin Fluoxetine Nifedipine

Companies 5 different 6 different 7 different(Bayer in (Ely Lilly in (Bayer in

22 countries) 21 countries) 20 countries)

Source of materials analysed

Drug Indications Dose (adult) Side effects CautionsNumber of BNF statements 10

200-1500 mg 17 9

Materials: range 4 - 10 5 - 16 1 - 7Materials: median 8 12.5 5

Countries in full agreement

2 (Colombia, UK) 23 none none

Ciprofloxacin

Results for ciprofloxacin

Drug Indications Dose (adult) Side effects Cautions

Number of BNF statements 4 20-60 mg 32 11Materials: range 1 - 4 0-31 0-9Materials: median 3 14.5 5.5Countries in full agreement

3 (Canada, Estonia, UK) 17 none none

Fluoxetine

Results for fluoxetine

Drug Indications Dose (adult) Side effects Cautions

Number of BNF statements 3 15-80 mg 7 12Materials: range 2 - 3 0-7 3 - 10Materials: median 2 4.5 6Countries in full agreement 11 19 1 (Spain) none

Nifedipine

Results for nifedipine

Ciprofloxacin Fluoxetine Nifedipine

(500 mg) (20 mg) (10-20 mg)

10 4 34 - 8 1 - 3 1 - 3

17 32 70 - 14 0 - 31 0 - 5

9 11 123 - 7 0 - 7 1 - 10

Indications

Found in the materials:

No. of BNF statementsFound in the materials:

No. of BNF statements

No. of BNF statementsFound in the materials:Cautions

Side-effects

Data from one of the 26 countries

Disagreement is high although:

Disagreement difficult to explain but....... may have consequences on rational use and patient safety... gives poor image of regulatory work

- Same company, i.e. same source of information in most cases

- Same substance in same country

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

Thank you

1 par seminar 28 september 2004 who - htp strengthening national drug regulatory capacity valerio...

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