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
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 %
US Public %
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

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