Transcript Tuberculosis Drug Issues: Fixed Dose Combination Products

Tuberculosis Drug Issues: Fixed
Dose Combination Products
Second Line Drugs, and Prices,
Richard Laing,
Kelly McGoldrick
Boston University
School of Public
Health
1
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)
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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
INH + Rifampicin 150-300mg
3
Dollar Cost per tablet
2.5
$2.43
2
1.5
1
$0.58
0.5
0.59
$0.06
0
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
INH + RifadinRed Book 150-300mg
INH + Rifadin Massachusetts 150-300mg
inh + Rifadin MSH 150-300mg
Inh + Rif Singapore
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Drugs for Multiple Drug
Resistant TB - A global problem
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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
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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
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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/t
bres/drugres1.pdf
Concern that no new drugs in pipeline
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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
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Survey of TB Drug Prices -Results
Time series First Line Drugs
Rate of Price Increase per year
US Private
US Public
International
10.66%
4.1%
-2%
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Time series
Rifampicin 300mg
2.5
Dollar Cost per tablet
$2.15
2
1.5
1
0.87
$0.50
0.5
0.5
$0.06
0
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Rifampicin Red Book 300mg
Rifampicin Intl 300mg
Rifampicin Singapore 300mg
Rifampicin Massachusettes 300mg
Rifampicin Japan 300mg
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Time seriesEthambutol 400mg
2.5
Dollar Cost per tablet
2
$1.91
1.5
1
$1.00
0.62
0.5
0.40
$0.04
0
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Ethambutol Red Book 400mg
Ethambutol Massachusetts 400mg
Ethambutol MSH 400mg
Ethambutol List Price, Japan
Ethambutol Singapore 400mg
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Time series
Pyrazinamide 500mg
1.60
Dollar Cost per Tablet
1.40
1.20
$1.03
1.00
0.80
$0.58
0.60
0.63
0.40
0.20
$0.04
0.00
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Pyrazinamide Red Book 500mg
Pyrazinamide MSH 500mg
Pyrazinamide Singapore 500mg
Pyrazinamide Massachusetts 500mg
Pyrazinamide List Price, Japan
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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
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Time series
Capreomycin 1 gram Injectable
30
$24.33
Dollar Cost per Injection
25
20
$16.71
15
10
4.38
5
0
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Capreomycin Red Book 1gm, inj
Capreomycin List Price, Japan
Capreomycin Massachusetts 1gm, inj
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Times series
Kanamycin 1gm Injection
Dollar Cost per injection
25
20
15
10
$6.25
5
2.96
$0.88
0
1980
1985
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Year
Kanamycin Red Book 1gm/3ml
Kanamycin List Price, Japan
Kanamycin Massachusetts 1gm/3ml
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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
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Cost per tablet USD
TB Drug Prices Comparison
Ethambutol, 400mg
2.000
1.910
1.800
1.600
1.400
1.200
1.000
1.000
0.800
0.600
0.400
0.200
0.028
0.033
Country
0.017
0.024 0.040
0.000
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Cost per tablet, USD
TB Drug Prices Comparison
Isoniazid, 100mg
0.100
0.090
0.080
0.070
0.060
0.050
0.050
0.040
0.030
0.020
0.020
0.004
Country
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0.004
0.000
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
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Cost per vial, USD
TB Drug Prices Comparison
Streptomycin, 1gm
6.000
5.500
5.000
4.000
3.000
2.000
1.000
0.065
0.178
0.000
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TB Drug Prices Comparison
Ethionamide, 250mg
2.5
2.2
Cost per unit USD
2
1.5
1
0.89
0.89
0.5
0.3059
0.172
0.15
0
USA Pub '99
USA Pvt '99
Singapore Pub '98
Russia Pub '99
Kazakstan Pvt n'99 International Pub 00
Country
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Tuberculin PPD
PPD Cost over time
20
18
16
14
Unit cost USD
Though not strictly a
drug tuberculin is
procured like a drug
Dramatic recent
increase in price
12
10
8
6
4
2
0
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
Year
PPD tubersol
Aplisol
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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
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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
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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
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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 support31