Transcript Strengthening national drug regulatory capacity Valerio Reggi 19 September 2006 1 TB Seminar September 2006 WHO - HTP.

Strengthening national drug
regulatory capacity
Valerio Reggi
19 September 2006
1 TB Seminar September 2006
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Regulation in medicine is 4000 years old
Hammurabi's Code of Laws (~ 2000 BCE):
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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.
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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:
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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
Manufacturers
Products
Government
Regulatory
authority
Importers/Wholesalers/Retailers
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Experts
Prescribers
Medicines
Patients/Consumers
WHO - HTP
Drug regulation is a multi- faceted activity at
the centre of complex interactions
Manufacturers
Products
Government
Regulatory
authority
Importers/Wholesalers/Retailers
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Experts
Prescribers
Medicines
Patients/Consumers
WHO - HTP
Drug regulation is a multi- faceted activity at
the centre of complex interactions
Manufacturers
Products
Government
Regulatory
authority
Importers/Wholesalers/Retailers
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Experts
Prescribers
Medicines
Patients/Consumers
WHO - HTP
Drug regulation is a multi- faceted activity at
the centre of complex interactions
Manufacturers
Products
Government
Regulatory
authority
Importers/Wholesalers/Retailers
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Experts
Prescribers
Medicines
Patients/Consumers
WHO - HTP
Drug regulation comprises all the legal, administrative
& technical arrangements meant to ensure that:
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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
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Basic functions in drug regulation (1)
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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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….continued
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Basic functions in drug regulation (2)
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
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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:
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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
All
WHO Regions included
Type of government
Developed, middle income, low income
Newly independent
Willingness to participate
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Australia, Cuba, Cyprus, Estonia,
The Netherlands,
Malaysia, Tunisia, Uganda, Venezuela,
Zimbabwe
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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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Human resources: different strategies
 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
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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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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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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
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: >=1% patients (AHFS 2001)
Severe: criteria defined by WHO CC, Uppsala
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Ciprofloxacin (500 mg)
Indications
Dose
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
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
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Fluoxetine (20 mg)
Indications
Dose
depressive illness, bulimia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder
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
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Nifedipine (20 mg)
Indications
Dose
prophylaxis of angina, hypertension, Raynaud’s phenomenon
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, breastfeeding , hepatic impairment, diabetes mellitus, ischaemic pain, avoid grapefruit juice
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For each analysed material:
How many checklist elements found
Elements not found in checklist were ignored
Proportion of
agreement
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Elements found
=
Elements in checklist
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For each variable (except dose) mean and 95%
confidence intervals
Degree of agreement for
indic., side effects, precaut.
1
=
Value >= high CI
0
=
Value within CI
-1
=
Value <= low CI
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Degree of
agreement for
dose range
1
0
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For each material, the sum of the 4 parameters
can be:
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4
=
Maximum agreement
-3
=
Maximum disagreement
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Overall results
CIPROFLOXACIN
High
Low
High
FLUOXETINE
Low
NIFEDIPINE
India, Switzerland, UK, USA
Colombia, Estonia, Italy, Philippines,
Thailand, UK, USA
High
Argentina, Egypt, India, Tunisia
Australia, Italy, Mexico, Spain, UK
Low
Philippines, Venezuela
High: agreement ≥ 3, Low: agreement ≤ -2
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Source of materials analysed
C iprofloxacin
C ompanie s
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5 different
(Bayer in
22 countries)
Fluoxe tine
Nife dipine
6 different
7 different
(Ely Lilly in
(Bayer in
21 countries) 20 countries)
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Results for ciprofloxacin
Drug
Number of
BNF
statements
Materials:
range
Ciprofloxacin
Materials:
median
Indications Dose (adult) Side effects
Cautions
200-1500
mg
17
9
4 - 10
5 - 16
1-7
8
12.5
5
none
none
10
Countries in 2 (Colombia,
full agreement
UK)
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23
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Results for fluoxetine
Dru g
In di cati on s Dose (adu l t) S i de e ffe cts
Number of
BNF
st at ement s
4
Mat erials:
1-4
Fl u oxe ti n e range
Mat erials:
median
3
Count ries in
3 (Canada,
full agreement Est onia, UK)
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20-60 mg
17
C au ti on s
32
11
0-31
0-9
14.5
5.5
none
none
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Results for nifedipine
Dru g
Number of
BNF
st at ement s
Mat erials:
Ni fe di pin e range
Mat erials:
median
Count ries in
full agreement
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In di cati on s Dose (adu l t) S i de e ffe cts
3
7
12
2-3
0-7
3 - 10
2
4.5
6
1 (Spain)
none
11
15-80 mg
C au ti on s
19
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Data from one of the 26 countries
Indications
No. of BNF statements
Found in the materials:
Side-effects
No. of BNF statements
Found in the materials:
Cautions
No. of BNF statements
Found in the materials:
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Ciprofloxacin
Fluoxetine
Nifedipine
(500 mg)
(20 mg)
(10-20 mg)
10
4-8
4
1-3
3
1-3
17
0 - 14
32
0 - 31
7
0-5
9
3-7
11
0-7
12
1 - 10
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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 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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Questions
Wrong sample?
No
Wrong method?
No, USP and IP
Wrong results?
No
Wrong
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children?
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Answer
Comparative study of quality and
efficacy of originator and
generic albendazole for the
mass treatment of soiltransmitted nematode infections
in Nepal*
* Transactions of the Royal Society of Tropical Medicine and Hygiene, accepted for publication September 2006
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The study
Two 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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Results
Drug
Albendazole 400 mg
Batch N
Quantity
(mg/tablet)
% Active
Ingredient
Disintegration
time (minutes)
%
Dissolution
Zentel 400
(GSK)
48907G10
0
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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Dissolution
Results
Drug
Albendazole
400 mg
Ascaris
Trichuris
Hookworms
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N
Day 0
% Pos
EPG a
Day 21
% Pos
EPG
CR
ERR (95%CI)
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)
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
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
WHO - HTP
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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How to strengthen national drug
regulatory capacity?
No importable models
Need for review of national
situation and definition of countryspecific strategy and priorities
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Thank you
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