1. 1 PAR Seminar 28 September 2004 WHO - HTP Strengthening national drug regulatory capacity Valerio Reggi, Eshetu Wondemagegnehu, HTP/EDM/QSM 28 September 2004

2. 2 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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 PAR Seminar 28 September 2004 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

9. 9 PAR Seminar 28 September 2004 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.

10. 10 PAR Seminar 28 September 2004 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

11. 11 PAR Seminar 28 September 2004 WHO - HTP Market access is a two-step process: 1- market approval of a product on the basis of efficacy, safety and quality. This regulatory decision results in the availability of the drug on the market. 2- public & private drug schemes limit procurement or reimbursements to certain drugs. For these decisions an evaluation is made, based on a comparison between various drug products and on considerations of “value for money”.

12. 12 PAR Seminar 28 September 2004 WHO - HTP The reality (and the paradox) : - only richer countries use both steps and enact effective mechanisms to rationalise consumption and keep expenditure under control, - in poorer countries, where health insurance mechanisms are not fully developed and people pay most drugs out of pocket, there are no adequate mechanisms to protect consumers

13. 13 PAR Seminar 28 September 2004 WHO - HTP APPLICATIONS Nr of drugs that can achieve important prescription NRA Assessment of QS&E REIMBURSEMENT Assessment of ‘value for money’ MAs

14. 14 PAR Seminar 28 September 2004 WHO - HTP This puts special responsibility and burden on decision makers and regulatory officials of developing countries

15. 15 PAR Seminar 28 September 2004 WHO - HTP...approach to regulation must be attuned to available resources......problems in establishing regulatory control have too often resulted from the introduction of provisions successful elsewhere but of a complexity that precludes their effective implementation in the country of adoption... WHO Expert Committee on Specifications for Pharmaceutical Preparations, TSR 790, 1990:

16. 16 PAR Seminar 28 September 2004 WHO - HTP No importable models Need for review of national regulatory situation and definition of country-specific strategy and priorities

17. 17 PAR Seminar 28 September 2004 WHO - HTP Effective drug regulation A multi-country study

18. 18 PAR Seminar 28 September 2004 WHO - HTP Rationale for the study n 20% of WHO Member States have well-developed drug regulation; 50% have varying capacity and level of implementation; 30% have limited capacity or have no DRA at all n WHO has never undertaken a systematic assessment of drug regulation to know how DRAs function, what strategies they use, why regulation is weak in most Member States, etc.

19. 19 PAR Seminar 28 September 2004 WHO - HTP nTo map the legal and organisational structures of drug regulation in selected countries nTo collect information on how regulatory functions operate nTo identify strengths & weaknesses, and factors contributing to them nTo document the results of the assessment so that other countries may learn from them nTo propose strategies that can help decision-makers to improve drug regulation Study objectives

20. 20 PAR Seminar 28 September 2004 WHO - HTP Method of study n Collection of data by national partners n interview of key informants-regulators, industry, associations n review of existing reports and documents n Writing a report on the country drug regulation by each partner n Preparing a synthesis report

21. 21 PAR Seminar 28 September 2004 WHO - HTP Framework for the study

22. 22 PAR Seminar 28 September 2004 WHO - HTP Multi-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

23. 23 PAR Seminar 28 September 2004 WHO - HTP n Licensing of persons, premises and practices n Product assessment and registration n Inspection n Control of promotion & advertising n Drug quality testing (QC laboratory) n ADR monitoring n Clinical trials oversight Regulatory functions assessed

24. 24 PAR Seminar 28 September 2004 WHO - HTP Per capita GNP in US$

25. 25 PAR Seminar 28 September 2004 WHO - HTP IMR per 1000 live births

26. 26 PAR Seminar 28 September 2004 WHO - HTP Number of pharmaceutical manufacturers

27. 27 PAR Seminar 28 September 2004 WHO - HTP Number of registered pharmaceuticals for human use

28. 28 PAR Seminar 28 September 2004 WHO - HTP Number of DRA staff per million population

29. 29 PAR Seminar 28 September 2004 WHO - HTP Per capita drug regulation expenditure

30. 30 PAR Seminar 28 September 2004 WHO - HTP DRA budget as a % national drug expenditure

31. 31 PAR Seminar 28 September 2004 WHO - HTP Salaries of GMP inspectors: lower than their counterparts in private sector

32. 32 PAR Seminar 28 September 2004 WHO - HTP Big gap in registration fees for new drugs

33. 33 PAR Seminar 28 September 2004 WHO - HTP Time taken to register new and generic products

34. 34 PAR Seminar 28 September 2004 WHO - HTP Organizational structure can vary nSingle, autonomous (Zimbabwe & Uganda) nSeveral authorities/agencies, some autonomous, no functional link (The Netherlands) nDepartment under the Ministry of Health (MoH) & no independence (Tunisia) nDepartment under MoH with statutory independence (Australia) nDepartments under MoH but with additional structure, a central committee, having decision-making power (Cyprus & Malaysia)

35. 35 PAR Seminar 28 September 2004 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 (Cyprus, Tunisia, Zimbabwe & Uganda) nDistribution of responsibilities between federal and state levels with little or no co-ordination (Australia & Malaysia) nDelegation of functions without legal power and accountability (Uganda) nMultiple and conflicting responsibilities assigned (Cyprus & Malaysia)

36. 36 PAR Seminar 28 September 2004 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

37. 37 PAR Seminar 28 September 2004 WHO - HTP nAll DRAs employ advisory boards, committees & experts to assist in regulatory functions nSome DRAs apply different strategies to address human resources problem: äself-regulation & co-regulation, streamlining of work process and risk management (Australia, The Netherlands) äprioritization and multi-skilling (Zimbabwe) nMost countries do not require staff & experts to declare conflict of interest and respect for confidentiality of information Human resources: different strategies

38. 38 PAR Seminar 28 September 2004 WHO - HTP Financing: different mechanisms nAll the DRAs have a fee system but only Australia, Uganda, Zimbabwe are empowered to use the revenues generated n Australia depends 100 % on revenues collected, Uganda & Zimbabwe also receive government allocation n Most countries depend on government budget- part of MoH budget n Fees charged by most DRAs do not reflect the actual costs/values of services provided n In most countries the fee systems do not cover all the services provided by the DRAs

39. 39 PAR Seminar 28 September 2004 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

40. 40 PAR Seminar 28 September 2004 WHO - HTP nPrescribing practice is regulated in six countries nPromotion not allowed in Cuba nOnly seven countries make registration of herbal medicines mandatory nRegulatory gaps exist in most countries änot all categories of medicinal products are regulated äInformal (unauthorized) sector receives little or no regulatory attention compared to the formal (licensed) sector nThere are regulatory double standards npubic vs. private sector (Cyprus) nmedicines for domestic use vs. medicines for export Domains of control: vary among countries

41. 41 PAR Seminar 28 September 2004 WHO - HTP Imbalance in implementation of regulatory functions nBetween pre-marketing & post-marketing product assessment nBetween product registration & regulation of drug distribution and information nGMP inspection and distribution channels inspection nInformation/data on drug regulation performance not readily available and not computerized

42. 42 PAR Seminar 28 September 2004 WHO - HTP Some recommendations: nReview drug regulation äDefine the mission and objectives äUpdate legislation and regulations to cover all areas involving drug products nCreate appropriate structure with a central authority which is accountable for the overall effectiveness of drug regulation nAllocate adequate number of qualified personnel of integrity; create human resources development programme and access to latest scientific and technological information

43. 43 PAR Seminar 28 September 2004 WHO - HTP n Develop appropriate tools-standards, guidelines, SOPs, in consultation with stakeholders and disseminate to all interested parties n Apply the same standard of regulation to all drugs- imported, exported, locally manufactured, private and public n Set priorities (risk management) and streamline work n Empower and create incentives for regulatory staff n Apply multi-skills, rotation and team/group work Some recommendations:

44. 44 PAR Seminar 28 September 2004 WHO - HTP n Set fees for all services provided and ensure that fees reflect actual costs /values of services provided and review fees regularly n DRA financing should strike a balance between revenue collected through fees and government support n Control both the formal and informal sector/market n Carry out regulatory functions in a balanced manner n Ensure that decisions and services to be timely and evidence based and not compromising quality,safety and efficacy Some recommendations:

45. 45 PAR Seminar 28 September 2004 WHO - HTP n Ensure there is accountability to the government, those regulated and the public n Create independent appeals mechanisms and a system for citizens complaints n Ensure that communication with clients is formal-based on written guidelines n Ensure staff and external experts participating in drug regulation declare conflict of interest and respect confidentiality of information Some recommendations:

46. 46 PAR Seminar 28 September 2004 WHO - HTP n Promote self-assessment, peer review, review by supervisory and external body n Empower consumers and the public by providing accurate and appropriate information on drugs and educating Some recommendations:

47. 47 PAR Seminar 28 September 2004 WHO - HTP International Comparative Study on Drug Information

48. 48 PAR Seminar 28 September 2004 WHO - HTP 26 countries http://link.springer.de/link/service/journals/00228/contents/03/00607/paper/s00228-003-0607-1ch000.html

49. 49 PAR Seminar 28 September 2004 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

50. 50 PAR Seminar 28 September 2004 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

51. 51 PAR Seminar 28 September 2004 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 Cautionspregnancy, breast-feeding, children and adolescents, photosensitivity, renal impairment, history of epilepsy, avoid excessive alkalinity of urine, G6PD deficiency, myastenia gravis Ciprofloxacin (500 mg)

52. 52 PAR Seminar 28 September 2004 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)

53. 53 PAR Seminar 28 September 2004 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)

54. 54 PAR Seminar 28 September 2004 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 =

55. 55 PAR Seminar 28 September 2004 WHO - HTP For each variable (except dose) mean and 95% confidence intervals Degree of agreement Indic., side eff., prec. Value >= high CI = 1 0 = = Value within CI Value <= low CI Degree of agreement for dose range 1 0

56. 56 PAR Seminar 28 September 2004 WHO - HTP For each material, the sum of the 4 parameters can be: Maximum agreement4 -3 = = Maximum disagreement

57. 57 PAR Seminar 28 September 2004 WHO - HTP Overall results

58. 58 PAR Seminar 28 September 2004 WHO - HTP Source of materials analysed

59. 59 PAR Seminar 28 September 2004 WHO - HTP Results for ciprofloxacin

60. 60 PAR Seminar 28 September 2004 WHO - HTP Results for fluoxetine

61. 61 PAR Seminar 28 September 2004 WHO - HTP Results for nifedipine

62. 62 PAR Seminar 28 September 2004 WHO - HTP Data from one of the 26 countries

63. 63 PAR Seminar 28 September 2004 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

64. 64 PAR Seminar 28 September 2004 WHO - HTP Side effects simply listed…. not a guide to rational prescribing Effective models for rational information on safety still need to be developed In the meantime, the impression is that safety information is listed only to limit liability

65. 65 PAR Seminar 28 September 2004 WHO - HTP Thank you