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

2. 2 TB Seminar September 2006 WHO - HTP Regulation in medicine is 4000 years old Hammurabi's Code of Laws (~ 2000 BCE): n 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. n 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. 3 TB Seminar September 2006 WHO - HTP The three key statements on DRAs: n health system counts on DRA for good, safe, and effective medicines, as well as fair rules and control on drug trade, information, and use n any strategy to improve anything in the pharmaceutical area involves DRA n any problem encountered in the pharmaceutical area has something to do with the DRA

4. 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 Experts Government Medicines

5. 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 Experts Government Medicines

6. 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 Experts Government Medicines

7. 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 Experts Government Medicines

8. 8 TB Seminar September 2006 WHO - HTP n 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 n drug products are safe, effective and of acceptable quality n product information is unbiased, accurate and appropriate n drugs are available n drugs are used rationally Drug regulation comprises all the legal, administrative & technical arrangements meant to ensure that:

9. 9 TB Seminar September 2006 WHO - HTP Basic functions in drug regulation (1) n Licensing of manufacturers, importers, distributors, wholesale and retail outlets (premises, persons and practices) n Marketing authorization for drug products n Sampling and quality control laboratory testing n Provision of drug information and monitoring of drug promotion and advertising Continues……...

10. 10 TB Seminar September 2006 WHO - HTP n Inspection of manufacturing and distribution channel premises n Adverse drug reaction monitoring n Authorization of clinical trials n Monitoring of drug dispensing and prescribing practices n Monitoring of drug utilization and promotion of rational drug use n Application of sanctions Basic functions in drug regulation (2) ….continued

11. 11 TB Seminar September 2006 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.

12. 12 TB Seminar September 2006 WHO - HTP Market failure: n Equity: does market care for the poor? n Information imbalance: unequal access to information, incapacity to assess quality, safety, efficacy, value for money, appropriateness n External benefits: immunizations and treatment of contagious diseases benefit all, if left to market laws alone many will not be immunized or treated n Failure of competition: competition based on product differentiation rather than price n Market asymmetry: who pays does not choose, who chooses does not pay

13. 13 TB Seminar September 2006 WHO - HTP Effective drug regulation: a multi-country study Assessment of national regulatory systems

14. 14 TB Seminar September 2006 WHO - HTP 10-country study on effective drug regulation Australia, Cuba, Cyprus, Estonia, The Netherlands, Malaysia, Tunisia, Uganda, Venezuela, Zimbabwe ä All WHO Regions included ä Type of government ä Developed, middle income, low income ä Newly independent ä Willingness to participate

15. 15 TB Seminar September 2006 WHO - HTP Assessment of regulatory systems (24 countries)

16. 16 TB Seminar September 2006 WHO - HTP Organizational structure can vary nSingle, autonomous nSeveral authorities/agencies, some autonomous, no functional link nDepartment under the Ministry of Health

17. 17 TB Seminar September 2006 WHO - HTP Diverse mission & distribution of responsibilities nEnsuring the safety, efficacy and quality of drugs is the mission of most countries - but some include price control & ensuring availability as their goals nDistribution of responsibilities between central and peripheral levels with little or no co-ordination nDelegation of functions without legal power and accountability nMultiple and conflicting responsibilities assigned (e.g. regulation and procurement)

18. 18 TB Seminar September 2006 WHO - HTP Human resources: shortage everywhere nSome DRAs have power to recruit and dismiss staff nShortage and high turnover of staff is universal nSalaries of DRA staff lower than those of their counterparts in the private sector nLack of career structure and incentive nFew trained people available, lack of training institution, recruitment system not flexible & brain-drain nAll DRAs train staff on ad-hoc basis- very few have human resources development plan

19. 19 TB Seminar September 2006 WHO - HTP nAll DRAs employ advisory boards, committees & experts to assist in regulatory functions nDifferent strategies to address HR problem: self-regulation & co-regulation, streamlining of work process and risk management prioritization and ‘multi-skilling’ nMost countries do not require staff & experts to declare conflicts of interest and to respect confidentiality of information Human resources: different strategies

20. 20 TB Seminar September 2006 WHO - HTP Financing: different mechanisms nAll the DRAs have a fee system but only a few are empowered to use the revenues generated n Some depend 100 % on revenues collected, most depend on government budget n Fees charged by most DRAs do not reflect the actual costs/value of services provided n In most countries fee systems do not cover all the services provided by the DRAs

21. 21 TB Seminar September 2006 WHO - HTP nInadequate regulatory tools: guidelines, SOPs, job descriptions, code of conduct, etc. nTools not accessible to stakeholders & and in most cases stakeholders are not consulted during the development stage Regulatory tools: scarcity in most cases

22. 22 TB Seminar September 2006 WHO - HTP Imbalance in implementation of regulatory functions nBetween pre-marketing & post-marketing assessment nBetween product registration & regulation of drug distribution and information nGMP inspection and distribution channels inspection nInformation/data not readily available and often not computerized

23. 23 TB Seminar September 2006 WHO - HTP International Comparative Study on Drug Information

24. 24 TB Seminar September 2006 WHO - HTP 26 countries http://link.springer.de/link/service/journals/00228/contents/03/00607/paper/s00228-003-0607-1ch000.html

25. 25 TB Seminar September 2006 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, nifedipine celecoxib, cisapride, montelukast

26. 26 TB Seminar September 2006 WHO - HTP 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

27. 27 TB Seminar September 2006 WHO - HTP Indicationsrespiratory 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 Dose500-1500 mg Side effectsnausea, 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)

28. 28 TB Seminar September 2006 WHO - HTP Indicationsdepressive illness, bulimia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder Dose20 – 60 mg Side effectshypersensitivity 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 Cautionsmaniac 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)

29. 29 TB Seminar September 2006 WHO - HTP Indicationsprophylaxis of angina, hypertension, Raynaud’s phenomenon Dose15-80 mg Side effectsheadache, 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 Cautionsadvanced 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)

30. 30 TB Seminar September 2006 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 =

31. 31 TB Seminar September 2006 WHO - HTP For each variable (except dose) mean and 95% confidence intervals Degree of agreement for indic., side effects, precaut. Value >= high CI = 1 0 = = Value within CI Value <= low CI Degree of agreement for dose range 1 0

32. 32 TB Seminar September 2006 WHO - HTP For each material, the sum of the 4 parameters can be: Maximum agreement4 -3 = = Maximum disagreement

33. 33 TB Seminar September 2006 WHO - HTP Overall results

34. 34 TB Seminar September 2006 WHO - HTP Source of materials analysed

35. 35 TB Seminar September 2006 WHO - HTP Results for ciprofloxacin

36. 36 TB Seminar September 2006 WHO - HTP Results for fluoxetine

37. 37 TB Seminar September 2006 WHO - HTP Results for nifedipine

38. 38 TB Seminar September 2006 WHO - HTP Data from one of the 26 countries

39. 39 TB Seminar September 2006 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

40. 40 TB Seminar September 2006 WHO - HTP 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

41. 41 TB Seminar September 2006 WHO - HTP What is quality?

42. 42 TB Seminar September 2006 WHO - HTP Background 2000, Nepal: school children mass-treatment campaign Locally procured albendazole QC tested after treatment completed, result: failed Campaign outcome: success

43. 43 TB Seminar September 2006 WHO - HTP Wrong sample? Wrong results? No Wrong method? Wrong children ? No, USP and IP No Questions

44. 44 TB Seminar September 2006 WHO - HTP 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

45. 45 TB Seminar September 2006 WHO - HTP 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

46. 46 TB Seminar September 2006 WHO - HTP Results Drug Albendazole 400 mg Batch NQuantity (mg/tablet) % Active Ingredient Disintegration time (minutes) % Dissolution 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-53401.3 (USP) 394.0 (IP) 100.4 (USP) 98.7 (IP) 11.8 (IP) 10.3 (USP) Failed Azol 400 (Curex Ltd Nepal) 61413.8 (USP) 415.8 (IP) 103.5 (USP) 103.9 (IP) > 1 hour (IP) 0.27 (USP) Failed

47. 47 TB Seminar September 2006 WHO - HTP Results Drug Albendazole 400 mg N Day 0 % Pos EPG a Day 21 % Pos EPG CR ERR (95%CI) AscarisGSK429 31.5 13 0.9 0.0 97.0 92.6 (89.2, 95.0) Royal Drug419 33.9 17 1.7 0.1 95.0 93.8 (90.9, 95.8) Curex429 36.1 19 6.3 0.6 82.6 b c 91.9 (88.0, 94.4) TrichurisGSK429 80.7 79 62.2 22 28.6 71.7 (64.4, 77.5) Royal Drug419 80.0 75 61.6 21 26.6 71.4 (64.6, 77.1) Curex429 78.3 60 60.6 21 28.0 63.2 (53.7, 70.8) d e HookwormsGSK429 49.0 13 14.2 0.9 74.3 87.1 (83.3, 90.1) Royal Drug419 50.1 15 24.6 2.0 53.3 b 80.8 (75.6, 84.9) d Curex429 47.8 12 25.9 2.4 50.7 b 73.1 (66.2, 78.6) b c

48. 48 TB Seminar September 2006 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$) Curex81,600100% Royal Drug115,600141% GSK136,000166%

49. 49 TB Seminar September 2006 WHO - HTP 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.

50. 50 TB Seminar September 2006 WHO - HTP What is quality? It is suitability for purpose!

51. 51 TB Seminar September 2006 WHO - HTP No importable models Need for review of national situation and definition of country- specific strategy and priorities How to strengthen national drug regulatory capacity?

52. 52 TB Seminar September 2006 WHO - HTP

53. 53 TB Seminar September 2006 WHO - HTP

54. 54 TB Seminar September 2006 WHO - HTP Thank you