Tuberculosis Drug Issues: Fixed Dose Combination Products Second Line Drugs, and Prices,

1. Tuberculosis Drug Issues: Fixed Dose Combination Products Second Line Drugs, and Prices, Richard Laing, Kelly McGoldrick Boston University School of Public Health

2. Overview of TB Drug Issues • Since streptomycin became available in 1948 drugs have become the mainstay of TB control • But low cure rates occur because of poor access or compliance • Leading to the emergence of Multiple drug resistant Tuberculosis (MDRTB)

3. Fixed Dose Combinations (FDC’s) • WHO and IUATLD now recommend FDC’s for treatment of all new cases of TB Justification • Simplicity of treatment • Improved compliance • Logistic ease • Prevent MDR “FDC s will facilitate and support DOTS programs. They are not an alternative!”

4. Fixed Dose Combinations (FDC’s) continued • Not Combo packs but 2,3 or 4 drugs in a single tablet • Problem of bioavailability of rifampicin in some formulations identified by Acocella • WHO have defined a standard formulation and abbreviated protocol for bioavailability standards, also reference laboratories • Concern about cost but 2 drug FDC stable or decreased in price

5. Prices of Two Drug FDC over time

6. Drugs for Multiple Drug Resistant TB - A global problem

7. MDRTB Drug Issues • In many countries treatment failures are treated with WHO Category 2 regimen (same four drugs plus one more) • If this fails nothing to be done • BUT this approach if combined with effective DOTS will inevitably lead to an increase in MDRTB resistant to five or more drugs

8. DOTS Plus as a response to MDRTB • WHO have included MDRTB drugs in next Model Drug List but not in main list! • Selected Drugs- • capreomycin kanamycin cycloserine ciprofloxacin para-aminosalicylic acid (PAS) ethionamide l evofloxacin • ofloxacin amikacin

9. Components of a DOTS + Program • Political Will and support of relevant government bodies • Access to adequate laboratory facilities for smear microscopy, culture and drug susceptibility testing • Directly observed therapy • Uninterrupted supply of first and second line drugs • Use of reliable monitoring system to assess outcomes • Operational research to identify constraints to implementation

10. Drug Issues in DOTS Plus • Standardized or Customized regimens? • Peru did very well with customized regimens • South Africa did better with standardized but overall cure rates lower Treatment manual available on Web at URL http://www.pharmweb.net/pwmirror/library/tbres/drugres1.pdf • Concern that no new drugs in pipeline

11. TB Drug Prices Drug Prices are determined by many factors: • Company Prices • Registration fees • Customs duties • Taxes National and local • Markups wholesaler to retailer & retailer to patient • Other charges

12. Survey of TB Drug Prices -Results Time series First Line Drugs • Rate of Price Increase per year • US Private 10.66% • US Public 4.1% • International -2%

13. Time series

14. Time series

15. Time series

16. Time series - Second Line Drugs • Smaller Numbers of suppliers Average annual Rate of Increase: • US Private 6.5% year • US Public 2% year • Exception is Kannamycin which has fallen in price

17. Time series

18. Times series

19. Comparison of TB Drug Prices by Country and Sector For first line max:min drug price ratio varies from 115 to 27 times US Private sector the most expensive except for Isoniazid where Japan most expensive US Public sector nearly always more expensive that public or private sector in other countries

20. TB Drug Prices Comparison

21. TB Drug Prices Comparison

22. TB Drug Prices Comparison - Second Line Drugs • Differences not so marked because no international tenders or non profit suppliers • Max:Min ratio from 2.2 to 6.6 times for various drugs

23. TB Drug Prices Comparison

24. TB Drug Prices Comparison

25. Tuberculin PPD • Though not strictly a drug tuberculin is procured like a drug • Dramatic recent increase in price

26. Discussion • Free market works for first line drugs outside US • Barrier to access is high registration fees • Second line drugs not a free market because of limited number of suppliers • During 2000 likely to see non-profit suppliers and pooled procurement bring prices down

27. Managing TB Drug Supply • Selection limited list based on FDC’s • Procurement Restricted tender with prequalification and performance monitoring • Distribution Use private sector or NTP store • Rational Use Basis of DOT, prevent misuse of TB drugs for other diseases such as chlamydae

28. Global Drug Facility • Provides a grant and purchasing facility • Can purchase TB drugs using Global Fund money directly from GDF • Accessible Web Site http://www.stoptb.org/GDF/default.asp

29. Conclusion • Ensuring reliable supply of quality assured TB drugs at best possible price is aim of any TB program • TB managers will need to become more aware of TB drug supply issues • Outlook is promising - • FDC’s coming • MDRTB drugs as part of DOTS + likely at better prices Will require international support