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1 TB Seminar September 2006 WHO - HTP
Strengthening national drug regulatory capacity
Valerio Reggi19 September 2006
2 TB Seminar September 2006 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 TB Seminar September 2006 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 TB Seminar September 2006 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 TB Seminar September 2006 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 TB Seminar September 2006 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 TB Seminar September 2006 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 TB Seminar September 2006 WHO - HTP
all premises, persons & practices engaged in the development, manufacture, importation, exportation, wholesale, supply, dispensing & promotion of drugs comply with approved standards, norms, procedures and requirements
drug products are safe, effective and of acceptable quality product information is unbiased, accurate and appropriate drugs are available drugs are used rationally
Drug regulation comprises all the legal, administrative & technical arrangements meant to ensure that:
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Basic functions in drug regulation (1)
Licensing of manufacturers, importers, distributors, wholesale and retail outlets (premises, persons and practices)
Marketing authorization for drug products Sampling and quality control laboratory
testing Provision of drug information and monitoring
of drug promotion and advertising
Continues……...
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Inspection of manufacturing and distribution channel premises
Adverse drug reaction monitoring Authorization of clinical trials Monitoring of drug dispensing and
prescribing practices Monitoring of drug utilization and
promotion of rational drug use Application of sanctions
Basic functions in drug regulation (2)
….continued
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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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Effective drug regulation:
a multi-country study
Assessment of national regulatory systems
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10-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
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Assessment of regulatory systems (24 countries)
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Organizational structure can vary
Single, autonomous Several authorities/agencies, some
autonomous, no functional link Department under the Ministry of Health
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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
Distribution of responsibilities between central and peripheral levels with little or no co-ordination
Delegation of functions without legal power and accountability
Multiple and conflicting responsibilities assigned (e.g. regulation and procurement)
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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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All DRAs employ advisory boards, committees & experts to assist in regulatory functions
Different strategies to address HR problem:• self-regulation & co-regulation, streamlining of work
process and risk management • prioritization and ‘multi-skilling’
Most countries do not require staff & experts to declare conflicts of interest and to respect confidentiality of information
Human resources: different strategies
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Financing: different mechanisms
All the DRAs have a fee system but only a few are empowered to use the revenues generated
Some depend 100 % on revenues collected, most depend on government budget
Fees charged by most DRAs do not reflect the actual costs/value of services provided
In most countries fee systems do not cover all the services provided by the DRAs
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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
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Imbalance in implementation of regulatory functions
Between pre-marketing & post-marketing assessment
Between product registration & regulation of drug distribution and information
GMP inspection and distribution channels inspection
Information/data not readily available and often not computerized
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International Comparative Study on Drug Information
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26 countries
http://link.springer.de/link/service/journals/00228/contents/03/00607/paper/s00228-003-0607-1ch000.html
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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
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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
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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)
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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)
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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)
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For each analysed material:
How many checklist elements found
Elements not found in checklist were ignored
Proportion of agreement
Elements found
Elements in checklist=
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For each variable (except dose) mean and 95% confidence intervals
Degree of agreement forindic., side effects, precaut.
Value >= high CI
=
1
0
-1 =
=Value within CI
Value <= low CI
Degree of agreement for dose range
1
0
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For each material, the sum of the 4 parameters can be:
Maximum agreement4
-3 =
=
Maximum disagreement
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Overall results
Low -
Low Argentina, Egypt, India, TunisiaHigh Australia, Italy, Mexico, Spain, UK
Low Philippines, VenezuelaHigh: agreement ≥ 3, Low: agreement ≤ - 2
India, Switzerland, UK, USA
Colombia, Estonia, Italy, Philippines, Thailand, UK, USA
NIFEDIPINE
High
High
CIPROFLOXACIN
FLUOXETINE
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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
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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
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Drug Indications Dose (adult) Side effects CautionsNumber 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
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Drug Indications Dose (adult) Side effects CautionsNumber 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
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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
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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
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Side effects simply listed…. not a guide to rational prescribing
Effective models for rational information on side effects still need to be developed
In the meantime, the impression is that side effect information is listed only to limit liability
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What is quality?
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Background• 2000, Nepal: school children mass-treatment campaign • Locally procured albendazole• QC tested after treatment completed, result: failed• Campaign outcome: success
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Wrong sample?
Wrong results?
NoWrong method?
Wrong children?
No, USP and IPNo
Questions
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Answer
Comparative study of quality and efficacy of originator and generic albendazole for the mass treatment of
soil-transmitted nematode infections in Nepal*
* Transactions of the Royal Society of Tropical Medicine and Hygiene, accepted for publication September 2006
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The studyTwo locally-manufactured generic albendazole (ABZ)
products (Curex and Royal Drug) used for de-worming children in Nepal since 1999
tested against originator product (GlaxoSmithKline-GSK).
API content, disintegration and dissolution testing and a randomised controlled clinical trial comparing cure rates (CR) and egg reduction rates (ERR) for Ascaris lumbricoides, Trichuris trichiura and hookworm infections
1277 children examined before and 21 days after treatment
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ResultsDrugAlbendazole 400 mg
Batch N Quantity (mg/tablet)
% Active Ingredient
Disintegration time (minutes)
% Dissolution
Dissolution
Zentel 400(GSK)
48907G100
397.6 (USP)394.5 (IP)
99.2 (USP)98.7 (IP)
6.7 (IP) 84.8 (USP)
Passed
RDZ-400 (Royal Drug Ltd Nepal)
T-53 401.3 (USP)394.0 (IP)
100.4 (USP)98.7 (IP)
11.8 (IP) 10.3 (USP)
Failed
Azol 400 (Curex Ltd Nepal)
61 413.8 (USP)415.8 (IP)
103.5 (USP)103.9 (IP)
> 1 hour (IP) 0.27 (USP)
Failed
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ResultsDrugAlbendazole 400 mg
N Day 0% Pos EPG a
Day 21% Pos EPG
CR ERR (95%CI)
Ascaris GSK 429 31.5 13 0.9 0.0 97.0 92.6 (89.2, 95.0)
Royal Drug 419 33.9 17 1.7 0.1 95.0 93.8 (90.9, 95.8)
Curex 429 36.1 19 6.3 0.6 82.6 b c 91.9 (88.0, 94.4)
Trichuris GSK 429 80.7 79 62.2 22 28.6 71.7 (64.4, 77.5)
Royal Drug 419 80.0 75 61.6 21 26.6 71.4 (64.6, 77.1)
Curex 429 78.3 60 60.6 21 28.0 63.2 (53.7, 70.8) d e
Hookworms GSK 429 49.0 13 14.2 0.9 74.3 87.1 (83.3, 90.1)
Royal Drug 419 50.1 15 24.6 2.0 53.3 b 80.8 (75.6, 84.9) d
Curex 429 47.8 12 25.9 2.4 50.7 b 73.1 (66.2, 78.6) b c
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Results•goal of mass treatment campaigns is to reduce the overall burden of infection within a population•6.8 million tablets of ABZ are procured every year in Nepal COSTS (US$)
Curex 81,600 100%
Royal Drug 115,600 141%
GSK 136,000 166%
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Results
… questions on the importance of certain criteria used for planning mass treatment campaigns with anthelminthic drugs. The extremely poor performance of Curex's ABZ in quality tests would lead to the conclusion that it is unsuitable for use in a campaign. Yet, it has shown a good degree of effectiveness that, although inferior to the other two drugs, challenges the relevance or reliability of quality testing, as currently done, as a major decision criterion for inclusion of a specific product in de-worming campaigns.
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What is quality?
It is suitability for purpose!
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No importable models
Need for review of national situation and definition of
country-specific strategy and priorities
How to strengthen national drug regulatory capacity?
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53 TB Seminar September 2006 WHO - HTP
54 TB Seminar September 2006 WHO - HTP
Thank you