1 PAR Seminar 28 September 2004 WHO - HTP
Strengthening national drug regulatory capacity
Valerio Reggi, Eshetu Wondemagegnehu, HTP/EDM/QSM 28 September 2004
2 PAR Seminar 28 September 2004 WHO - HTP
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.
3 PAR Seminar 28 September 2004 WHO - HTP
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
4 PAR Seminar 28 September 2004 WHO - HTP
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
5 PAR Seminar 28 September 2004 WHO - HTP
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
6 PAR Seminar 28 September 2004 WHO - HTP
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
7 PAR Seminar 28 September 2004 WHO - HTP
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
8 PAR Seminar 28 September 2004 WHO - HTP
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
9 PAR Seminar 28 September 2004 WHO - HTP
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.
10 PAR Seminar 28 September 2004 WHO - HTP
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
11 PAR Seminar 28 September 2004 WHO - HTP
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”.
12 PAR Seminar 28 September 2004 WHO - HTP
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
13 PAR Seminar 28 September 2004 WHO - HTP
APPLICATIONS APPLICATIONS
Nr of drugs that can achieve important prescription
NRANRA Assessment of QS&E
REIMBURSEMENT
Assessment of ‘value for money’
MAs MAs
14 PAR Seminar 28 September 2004 WHO - HTP
This puts special responsibility and burden on decision
makers and regulatory officials of developing countries
15 PAR Seminar 28 September 2004 WHO - HTP
...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:
16 PAR Seminar 28 September 2004 WHO - HTP
No importable models
Need for review of national regulatory situation and
definition of country-specific strategy and priorities
17 PAR Seminar 28 September 2004 WHO - HTP
Effective drug regulation
A multi-country study
18 PAR Seminar 28 September 2004 WHO - HTP
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.
19 PAR Seminar 28 September 2004 WHO - HTP
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
20 PAR Seminar 28 September 2004 WHO - HTP
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
21 PAR Seminar 28 September 2004 WHO - HTP
Framework for the study
Product assessment
& registration Inspection of manufacturers
& distributors
Monitoring quality of
drugs
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
22 PAR Seminar 28 September 2004 WHO - HTP
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
23 PAR Seminar 28 September 2004 WHO - HTP
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
24 PAR Seminar 28 September 2004 WHO - HTP
Per capita GNP in US$
0 5000 10000 15000 20000 25000
Malaysia
Australia
Netherlands
Estonia
Cyprus
Uganda
Zimbabwe
Tunisia
Cuba
Venezuela
25 PAR Seminar 28 September 2004 WHO - HTP
IMR per 1000 live births
0 20 40 60 80 100 120
Malaysia
Australia
Netherlands
Estonia
Cyprus
Uganda
Zimbabwe
Tunisia
Cuba
Venezuela
26 PAR Seminar 28 September 2004 WHO - HTP
Number of pharmaceutical manufacturers
0 100 200 300 400
Malaysia
Australia
Netherlands
Estonia
Cyprus
Uganda
Zimbabwe
Tunisia
Cuba
Venezuela
27 PAR Seminar 28 September 2004 WHO - HTP
Number of registered pharmaceuticals for human use
0 5000 10000 15000 20000 25000 30000 35000
Malaysia
Australia*
Netherlands
Estonia
Cyprus
Uganda
Zimbabwe
Tunisia
Cuba
Venezuela
28 PAR Seminar 28 September 2004 WHO - HTP
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
Cuba
Venezuela
Staff per million population
29 PAR Seminar 28 September 2004 WHO - HTP
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
Cuba
Venezuela
30 PAR Seminar 28 September 2004 WHO - HTP
DRA budget as a % national drug expenditure
0% 1% 2% 3% 4% 5% 6%
Malaysia
Australia
Netherland
Estonia
Cyprus
Uganda
Zimbabwe
Tunisia
Cuba
Venezuela
31 PAR Seminar 28 September 2004 WHO - HTP
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
Cuba
Venezuela
GMP inspector Production head Product release person
32 PAR Seminar 28 September 2004 WHO - HTP
Big gap in registration fees for new drugs
120,000
700
120
785
15,000
1200
300
1270
1000
100
0 20,000 40,000 60,000 80,000 100,000 120,000
Australia
Cuba
Cyprus
Estonia
Malaysia
Netherlands
Tunisia
Uganda
Venezuela
Zimbabwe
Fees US$
33 PAR Seminar 28 September 2004 WHO - HTP
Time taken to register new and generic products
0
2
4
6
8
10
12
14
16
18
New product Generic product Fast track product
34 PAR Seminar 28 September 2004 WHO - HTP
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)
35 PAR Seminar 28 September 2004 WHO - HTP
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)
36 PAR Seminar 28 September 2004 WHO - HTP
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
37 PAR Seminar 28 September 2004 WHO - HTP
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
38 PAR Seminar 28 September 2004 WHO - HTP
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
39 PAR Seminar 28 September 2004 WHO - HTP
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
40 PAR Seminar 28 September 2004 WHO - HTP
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
41 PAR Seminar 28 September 2004 WHO - HTP
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
42 PAR Seminar 28 September 2004 WHO - HTP
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
43 PAR Seminar 28 September 2004 WHO - HTP
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
Some recommendations:
44 PAR Seminar 28 September 2004 WHO - HTP
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
Some recommendations:
45 PAR Seminar 28 September 2004 WHO - HTP
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
Some recommendations:
46 PAR Seminar 28 September 2004 WHO - HTP
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
Some recommendations:
47 PAR Seminar 28 September 2004 WHO - HTP
International Comparative Study on Drug Information
48 PAR Seminar 28 September 2004 WHO - HTP
26 countries
http://link.springer.de/link/service/journals/00228/contents/03/00607/paper/s00228-003-0607-1ch000.html
49 PAR Seminar 28 September 2004 WHO - HTP
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
50 PAR Seminar 28 September 2004 WHO - HTP
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
51 PAR Seminar 28 September 2004 WHO - HTP
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)
52 PAR Seminar 28 September 2004 WHO - HTP
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)
53 PAR Seminar 28 September 2004 WHO - HTP
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)
54 PAR Seminar 28 September 2004 WHO - HTP
For each analysed material:
How many checklist elements found
Elements not found in checklist were ignored
Proportion of agreement
Elements found
Elements in checklist=
55 PAR Seminar 28 September 2004 WHO - HTP
For each variable (except dose) mean and 95% confidence intervals
Degree of agreementIndic., side eff., prec.
Value >= high CI
=
1
0
-1 =
=
Value within CI
Value <= low CI
Degree of agreement for dose range
1
0
56 PAR Seminar 28 September 2004 WHO - HTP
For each material, the sum of the 4 parameters can be:
Maximum agreement4
-3 =
=
Maximum disagreement
57 PAR Seminar 28 September 2004 WHO - HTP
Overall results
Low -
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
High
High
CIPROFLOXACIN
FLUOXETINE
58 PAR Seminar 28 September 2004 WHO - HTP
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
59 PAR Seminar 28 September 2004 WHO - HTP
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
60 PAR Seminar 28 September 2004 WHO - HTP
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
61 PAR Seminar 28 September 2004 WHO - HTP
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
62 PAR Seminar 28 September 2004 WHO - HTP
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
63 PAR Seminar 28 September 2004 WHO - HTP
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
64 PAR Seminar 28 September 2004 WHO - HTP
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
65 PAR Seminar 28 September 2004 WHO - HTP
Thank you