E speranza I . C abral, MD S ecretary of H ealth Keynote Address at

1. “. . . now is the time to stop butting heads and start linking arms. It is not impossible to work out a united plan that will be acceptable for all, and in the end will benefit those who need it most.” Esperanza I. Cabral, MD Secretary of Health Keynote Address at The 3rd MeTA Philippines Forum

2. Initiatives to Address Access Issue Diamond Hotel Manila, Philippines January 27, 2010

3. Bioequivalence – Is It The Gold Standard In The Philippines? Rita Grace Y. Alvero, M.D. Chair, Department of Pharmacology Director, Research Support and Extension Services Head, Bioavailability Unit De La Salle Health Sciences Institute

4. Philippine Health Statistics Total population: 86,264,000 Gross national income per capita (PPP international $): 3,430 Life expectancy at birth m/f (years): 64/71 Healthy life expectancy at birth m/f (years, 2003): 57/62 Probability of dying under five (per 1 000 live births): 32 Probability of dying between 15 and 60 years m/f (per 1 000 population): 277/157 Total expenditure on health per capita (Intl $, 2006): 223 Total expenditure on health as % of GDP (2006): 3.3 Figures are for 2006 unless indicated. Source: World Health Statistics 2008

5. National Expenditure on Health 2002 • Total expenditure on health as 2.9 % of Gross Domestic Product • Government expenditure on health as 39.1 % of Total expenditure on health • Private sector expenditure on health as 60.9 % of Total expenditure on health • Private household's out-of-pocket payment 77.9 as % of Private sector expenditure On health

6. Philippine Health StatisticsLeading Causes of Morbidity and Mortality Morbidity, per 100,000 - 2006 Mortality, per 100,000 - 2004 1. ALRI and pneumonia 828.80 2. Acute watery diarrhoea 707.70 3. Bronchitis/bronchiolitis 689.90 4. Hypertension 522.80 5. Influenza 435.00 6. TB respiratory 169.90 7. Diseases of the heart 49.30 8. Acute febrile iIlness 32.50 9. Malaria 27.60 10. Dengue fever 19.60 1. Heart diseases 85.72 2. Vascular system diseases 62.52 3. Malignant neoplasm 49.02 4. Accidents 41.30 5. Pneumonia 38.83 6. Tuberculosis, all forms 31.30 7. Ill-defined and unknown 25.74 causes of mortality 8. Chronic lower respiratory 22.95 diseases 9. Diabetes mellitus 20.02 10. Certain conditions 15.94 originating in the perinatal period

7. Philippine Health StatisticsLeading Causes of Morbidity and Mortality Morbidity, per 100,000 - 2006 Mortality, per 100,000 - 2004 1. ALRI and pneumonia 828.80 2. Acute watery diarrhoea 707.70 3. Bronchitis/bronchiolitis 689.90 4. Hypertension 522.80 5. Influenza 435.00 6. TB respiratory 169.90 7. Diseases of the heart 49.30 8. Acute febrile iIlness32.50 9. Malaria 27.60 10. Dengue fever 19.60 1. Heart diseases 85.72 2. Vascular system diseases 62.52 3. Malignant neoplasm 49.02 4. Accidents 41.30 5. Pneumonia 38.83 6. Tuberculosis, all forms 31.30 7. Ill-defined and unknown 25.74 causes of mortality 8. Chronic lower respiratory 22.95 diseases 9. Diabetes mellitus 20.02 10. Certain conditions 15.94 originating in the perinatal period

8. Impediments to AccessWHO – HAI, 2006 • medicine prices were between 3.4 and 184 times higher than the international reference index • allocation for medicines of the total health budget was only 0.08% in a 6th class municipality and 10% in one of the biggest cities • availability of core essential medicines was only 11.5% and 15% in the public and private sectors, respectively. • irrational drug use due to inappropriate drug promotion

9. Initiatives to Address Access Issue AO 1 series of 2005 • AO 1 series of 2005 was passed to revise policies and guidelines governing patent and trade secret rights in relation to the registration of pharmaceutical products • Consistent with RA 6675 otherwise know as the Generics Act, it sought to make medicines available at more affordable prices

10. Initiatives to Address Access Issue RA 9502 Universally Accessible Cheaper and Quality Medicine Act of 2008 • Strengthened competition by amending the IP Code • Gave the President the power to set price ceilings on various drugs as recommended by DOH Secretary • Strengthened the Bureau of Food and Drugs to ensure safety of medicines • Ensured the availability of affordable medicines by requiring drug outlets to carry a variety of brands for each drug

11. Initiatives to Address Access Issue RA 9711 • Act strengthening and rationalizing the regulatory capacity of BFAD... renaming it the Food And Drugs Administration • Enabled FDA to establish testing laboratories and field offices, upgrade equipment and augment manpower

12. Immediate Impact of RA 9502 With the issuance of the Maximum Drug Retail Price List, the price of 5 leading medicines were cut in half • amlodipine, • atorvastatin, • azythromycin, • cytarabine and • doxorubicin The Goverment Mediated Access Price List followed soon reducing the price of an additional 16 leading drugs • telmisartan, • irbesartan, • clopidogrel, • gliclazide, • piperacillin+tazobactam, • ciprofloxacin, • metronidazole, • co-amoxiclav, • bleomycin, • carboplatin, • cisplatin, • cyclophosphamide, • etoposide, • mercaptopurine, • methotrexate and • mesna

13. Immediate Impact of RA 9502 • Inflow of generic or multisource products • Total applications in 2008 – 3279 • Total applications in 2nd half of 2009 – 1202 • Increase in the number of branches of drug outlets particularly those catering to multisource drugs • Increase in the market share of multisource drugs

14. With greater access, there was a multitude of branded generic drugs to choose from…..

15. Substitution considerations Before substituting a generic product, physicians and other decisions makers should consider the potential clinical and pharmaco-economic consequences • Overtreatment • Undertreatment • Adverse effects • Additional expenses • Cost savings

16. Substitution considerations • Health care decision makers encourage physicians to prescribe generic medications • Pharmaceutical companies actively promote the use of their innovator drugs harping on proven efficacy and safety • PMA policy: physicians should have the freedom to prescribe generic or brand-name drugs • What then should be the guideline in determining interchangeability or in substitution of an innovator drug with a generic drug?

17. Interchangeability or Therapeutic Equivalence

18. Pharmaceutical Equivalents • Drug products are considered pharmaceutical equivalents if they contain the same activeingredient(s), have the same dosage form and route of administration, and are identical in strength or concentration • Equivalent products contain the same amount of ingredient in the same dosage form but may differ in characteristics, such as shape, release mechanisms, and packaging Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed September 29, 2003.

19. Pharmaceutical Equivalents Test Reference Could lead to differences in product performance in vivo Possible Differences Drug particle size Excipients Manufacturing Equipment or Process Site of manufacture 19

20. Therapeutic Equivalents • Drug products are considered therapeutic equivalents if they are all of the following • Pharmaceutical equivalents • Bioequivalent • Approved as safe and effective • Adequately labeled • Manufactured in compliance with current Good Manufacturing Practice regulations • Drugs must be pharmaceutical equivalents and be bioequivalent to be considered interchangeable!

21. Review of Bioavailability

22. Bioavailability “The rate and extent to which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation.”

23. Bioequivalence the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

24. Important Pharmacokinetic Parameters • AUC: area under the concentration-time curve   measure of the extent of bioavailability • Cmax: the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability • tmax: the time after administration of drug at which Cmax is observed  measure of the rate of absorption

25. Pharmacokinetic Studies Key Measurements Study Compound Reference Compound • AUC • Area under the concentration- time curve • Cmax • Maximum concentration • A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds • Tmax • Time to maximum concentration Cmax Concentration AUC Tmax Time

26. Methods to Determine Bioequivalence In order of preference, methods used to determine bioequivalence: • Pharmacokinetic studies • Pharmacodynamic studies • Comparative clinical trials • In vitro studies

27. Why are pharmacokinetic studies the preferred approach in establishing bioequivalence? • There is a strong correlation between single-dose pharmacokinetics and therapeutic effects • Single-dose pharmacokinetics are similar to steady-state pharmacokinetics • Patients have a pharmacokinetic profile comparable to that of healthy volunteers • A –20% to +25% difference in absorption (Cmax, AUC) has no effect on therapeutic outcomes

28. Rationale for Requiring Bioequivalence Study

29. Why is bioequivalence needed? • Pharmaceutical equivalence does not necessarily mean therapeutic equivalence • Multisource drug products should conform to the same standards of quality, safety and efficacy required of the reference product and must be interchangeable  • Differences in excipients or manufacturing process may lead to differences in product performance. • Also, in vitro dissolution does not necessarily reflect in vivo bioavailability.

30. Acceptance Guidelines

31. Bioequivalence standards (acceptance ranges) • The 90% confidence interval of the relative mean AUC of the test to reference product should be between 80-125%. • The 90% confidence interval of the relative mean CMAX of the test to reference product should be between 80-125%. Since CMAX is recognized as being more variable than the AUC ratio, a wider acceptance range may be justifiable.   • These standards must be met on log-transformed parameters calculated from the measured data   • TMAX may be important for some drugs

32. Requirements for Bioequivalence • Product A is bioequivalent to the reference drug; its 90% confidence interval of the AUC falls within 80% to 125% of the reference drug • Product B is not bioequivalent to the reference drug; its 90% confidence interval of the AUC falls outside of 80% to 125% of the reference drug 125% Pharmacokinetic Reference Range 100% 80% Product ABioequivalent Reference Drug Product BNot Bioequivalent

33. Implementation of Bioequivalence Testing in the Philippines

34. Bioequivalence as a Requirement for Registration • To help avoid complications arising from product substitution, the BFAD established a list of generic drugs that require bioavailability testing using the pharmacokinetic approach • These products are enumerated in the List B’ under DOH AO 67 series of 1989

35. BFAD Circular 01 series of 1997

36. BFAD Circular 13A s 1999

37. BFAD Circular 08 series of 2006

38. Drugs that Require Bioequivalence Studies As per Bureau Circular No. 13A s. 1999 • Rifampicin As per Bureau Circular No. 8 s 2006 • Atenolol • Diltiazem • Gliclazide • Metformin • Metoprolol • Nicardipine • Nifedipine • Phenytoin • Propranolol • Pyrazinamide • Theophylline

39. Assessment of FDA’s Policy on Bioequivalence • This is the gold standard in the Philippines • The use of pharmacokinetic approach in establishing bioequivalence is consistent with the position of EMEA, US FDA and other major regulatory bodies

40. Recommendations: Requirement for bioequivalence studies should be expanded to include all of the following: • The rest of 64 drugs identified in List B’ • Drugs known to have narrow therapeutic index • Drugs classified as Type 2, 3 or 4 based on the Biopharmaceutics Classification System

41. Recommendations: Requirement for bioequivalence, however, may be waived for the following: • Drugs classified as BCS Type 2 if a weak acid and highly soluble at pH 6.8 • Drugs classified as BCS Type 3 if rapidly dissolving

42. Recommendations: Disseminate results of bioequivalence studies to stakeholders by: • Publishing list of drugs proven to be bioequivalent much like the Orange Book of the US FDA • Indicating in the label and packaging if multisource product has been shown to be bioequivalent with innovator

43. Primum non nocere! Drug safety and efficacy should come before any cost considerations

44. THANK YOU! Thank you!

45. “. . . now is the time to stop butting heads and start linking arms. It is not impossible to work out a united plan that will be acceptable for all, and in the end will benefit those who need it most.” Esperanza I. Cabral, MD Secretary of Health Keynote Address at The 3rd MeTA Philippines Forum