Strengthening national drug regulatory capacity

1 TB Seminar September 2006 WHO - HTP

Strengthening national drug regulatory capacity

Valerio Reggi19 September 2006


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


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:


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……...


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


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


Effective drug regulation:

a multi-country study

Assessment of national regulatory systems


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


Assessment of regulatory systems (24 countries)


Organizational structure can vary

Single, autonomous Several authorities/agencies, some

autonomous, no functional link Department under the Ministry of Health


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)


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

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


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


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


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


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 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


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

Maximum agreement4

-3 =

=

Maximum disagreement


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


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 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


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


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 side effects still need to be developed

In the meantime, the impression is that side effect information is listed only to limit liability


What is quality?


Background• 2000, Nepal: school children mass-treatment campaign • Locally procured albendazole• QC tested after treatment completed, result: failed• Campaign outcome: success


Wrong sample?

Wrong results?

NoWrong method?

Wrong children?

No, USP and IPNo

Questions


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


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


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


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


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%


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.


What is quality?

It is suitability for purpose!


No importable models

Need for review of national situation and definition of

country-specific strategy and priorities

How to strengthen national drug regulatory capacity?




Thank you

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