1 tuberculosis drug issues: fixed dose combination products second line drugs, and prices, richard...
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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)
4
Fixed Dose Combinations (FDC’s)
WHO and IUATLD now recommend FDC’s for treatment of all new cases of TB
JustificationSimplicity of treatmentImproved complianceLogistic easePrevent MDR
“FDC s will facilitate and support DOTS programs. They are not an alternative!”
5
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
6
Prices of Two Drug FDC over time
INH + Rifampicin 150-300mg
0.59
0
0.5
1
1.5
2
2.5
3
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r ta
ble
t
INH + RifadinRed Book 150-300mg INH + Rifadin Massachusetts 150-300mg
inh + Rifadin MSH 150-300mg Inh + Rif Singapore
$0.06
$0.58
$2.43
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Drugs for Multiple Drug Resistant TB - A global problem
8
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 doneBUT this approach if combined with
effective DOTS will inevitably lead to an increase in MDRTB resistant to five or more drugs
9
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
10
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/tbres/drugres1.pdf
Concern that no new drugs in pipeline
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TB Drug Prices
Drug Prices are determined by many factors:Company PricesRegistration feesCustoms dutiesTaxes National and localMarkups wholesaler to retailer & retailer to
patientOther charges
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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%
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Time seriesRifampicin 300mg
0.87
0.5
0
0.5
1
1.5
2
2.5
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r ta
ble
t
Rifampicin Red Book 300mg Rifampicin Massachusettes 300mg
Rifampicin Intl 300mg Rifampicin Japan 300mg
Rifampicin Singapore 300mg
$0.06
$2.15
$0.50
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Time seriesEthambutol 400mg
0.40
0.62
0
0.5
1
1.5
2
2.5
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r ta
ble
t
Ethambutol Red Book 400mg Ethambutol Massachusetts 400mg
Ethambutol MSH 400mg Ethambutol List Price, Japan
Ethambutol Singapore 400mg
$0.04
$1.00
$1.91
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Time seriesPyrazinamide 500mg
0.63
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r T
ab
let
Pyrazinamide Red Book 500mg Pyrazinamide Massachusetts 500mgPyrazinamide MSH 500mg Pyrazinamide List Price, JapanPyrazinamide Singapore 500mg
$0.58
$0.04
$1.03
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Time series - Second Line Drugs
Smaller Numbers of suppliersAverage 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 seriesCapreomycin 1 gram Injectable
4.38
0
5
10
15
20
25
30
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r In
jec
tio
n
Capreomycin Red Book 1gm, inj Capreomycin Massachusetts 1gm, inj
Capreomycin List Price, Japan
$16.71
$24.33
20
Times seriesKanamycin 1gm Injection
2.96
0
5
10
15
20
25
1980 1985 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Year
Do
llar
Co
st
pe
r in
jec
tio
n
Kanamycin Red Book 1gm/3ml Kanamycin Massachusetts 1gm/3ml
Kanamycin List Price, Japan
$0.88
$6.25
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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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TB Drug Prices ComparisonEthambutol, 400mg
0.024 0.0400.0170.0330.028
1.000
1.910
0.000
0.200
0.400
0.600
0.800
1.000
1.200
1.400
1.600
1.800
2.000
USA Pub '9
9
USA Pvt
'99
Singapore
Pub '9
8
Japan P
ub 99
South A
frica
Pub '9
9
Ukrain
e Pub '9
9
Russia
Pub '9
9
Russia
Pvt
'99
Kazaks
tan P
vt n
'99
India
Pvt
'99
IDA P
ub 99
Pakista
n '00
Thailand P
ub '99
Camero
on Pub '9
9
Zim
babwe P
ub 98
Cote D
'Ivoire
Pub '9
8
Burkin
o Faso
Pub '9
8
Afro T
ender Pub '9
8
USA MSH In
tl Pub '9
8
Country
Co
st
pe
r ta
ble
t U
SD
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TB Drug Prices ComparisonIsoniazid, 100mg
0.003 0.004 0.0040.002 0.004
0.050
0.020
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
0.100
USA Pub '9
9
USA Pvt
'99
Japan P
ub 99
South A
frica
Pub '9
9
Ukrain
e Pub '9
9
Kazaks
tan P
vt n
'99
India
Pvt
'99
India
Pub '9
9
IDA P
ub 99
Pakista
n '00
Zim
babwe P
ub 98
Burkin
o Faso
Pub '9
8
Mala
wi P
ub '98
Afro T
ender Pub '9
8
USA MSH In
tl Pub '9
8
Country
Co
st
pe
r ta
ble
t, U
SD
24
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
TB Drug Prices Comparison - Second Line Drugs
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TB Drug Prices ComparisonStreptomycin, 1gm
0.083 0.0770.178
0.065
5.500
0.000
1.000
2.000
3.000
4.000
5.000
6.000
USA Pvt
'99
Japan P
ub 99
Ukrain
e Pub '9
9
Russia
Pub '9
9
Kazaks
tan P
vt n
'99
India
Pvt
'99
IDA P
ub 99
Thailand P
ub '99
Camero
on Pub '9
9
Cote D
'Ivoire
Pub '9
8
Angola P
ub '98
Kenya P
ub '98
Afro T
ender Pub '9
8
USA MSH In
tl Pub '9
8
Country
Co
st
pe
r v
ial,
US
D
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TB Drug Prices ComparisonEthionamide, 250mg
0.89
2.2
0.89
0.172
0.3059
0.15
0
0.5
1
1.5
2
2.5
USA Pub '99 USA Pvt '99 Singapore Pub '98 Russia Pub '99 Kazakstan Pvt n'99 International Pub 00
Country
Co
st
pe
r u
nit
US
D
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Tuberculin PPD
Though not strictly a drug tuberculin is procured like a drug
Dramatic recent increase in price
PPD Cost over time
0
2
4
6
8
10
12
14
16
18
20
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
Year
Unit c
ost U
SD
PPD tubersol Aplisol
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Discussion
Free market works for first line drugs outside US
Barrier to access is high registration feesSecond line drugs not a free market
because of limited number of suppliersDuring 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’sProcurement 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 support