Strengthening national drug regulatory capacity

Strengthening national drug regulatory capacity Valerio Reggi 19 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 Government Experts Manufacturers Regulatory authority Prescribers Products Medicines Patients/Consumers Importers/Wholesalers/Retailers

Drug regulation comprises all the legal, administrative & technical arrangements meant to ensure that: • 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

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……...

Basic functions in drug regulation (2) ….continued • 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

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 • All WHO Regions included • Type of government • Developed, middle income, low income • Newly independent • Willingness to participate Australia, Cuba, Cyprus, Estonia, The Netherlands, Malaysia, Tunisia, Uganda, Venezuela, Zimbabwe

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

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

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

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

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 Drugs: ciprofloxacin, fluoxetine, nifedipine celecoxib, cisapride, montelukast Materials: 683 documents approved by NRA or, if non existent, published by company

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

Ciprofloxacin (500 mg) 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 pregnancy, breast-feeding, children and adolescents, photosensitivity, renal impairment, history of epilepsy, avoid excessive alkalinity of urine, G6PD deficiency, myastenia gravis Cautions

Fluoxetine (20 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

Nifedipine (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

Elements found Proportion of agreement = Elements in checklist For each analysed material: How many checklist elements found Elements not found in checklist were ignored

= 1 Value >= high CI 1 = 0 Value within CI 0 = -1 Value <= low CI Degree of agreement for indic., side effects, precaut. Degree of agreement for dose range For each variable (except dose) mean and 95% confidence intervals

For each material, the sum of the 4 parameters can be: = 4 Maximum agreement = -3 Maximum disagreement

Overall results

Source of materials analysed

Results for ciprofloxacin

Results for fluoxetine

Results for nifedipine

Data from one of the 26 countries

Same company, i.e. same source of information in most cases • Same substance in same country Disagreement is high although: Disagreement difficult to explain but.... ... may have consequences on rational use and patient safety ... gives poor image of regulatory work

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?

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

Questions No Wrong sample? Wrong method? No, USP and IP Wrong results? No Wrong children?

Comparative study of quality and efficacy of originator and generic albendazole for the mass treatment of soil-transmitted nematode infections in Nepal* Answer * Transactions of the Royal Society of Tropical Medicine and Hygiene, accepted for publication September 2006

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). The study 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

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$) 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. Results

What is quality? It is suitability for purpose!

Strengthening national drug regulatory capacity