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Cost-effectiveness of anti-cancer drugs
- Andrea Messori, Sabrina Trippoli, and Monica Vaiani (5 August 2002)
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New anticancer drugs offer substantial advantage
- Silvio Monfardini, Antonio Jirillo - associate director (6 August 2002)
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Anticancer drugs do benefit patients
- Jeremy Barton, Jane Salsbury (13 August 2002)
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New anticancer drugs for haematological and solid malignancies.
- Wendy L. Lawson (14 August 2002)
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Article has done no favours for cancer patients
- Hilary Calvert, Duncan Jodrell, James Cassidy, Adrian Harris, Cancer Research UK (Robert Souhami) (23 August 2002)
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Authors' reply
- Silvio Garattini, Vittorio Bertele' (25 September 2002)
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Andrea Messori, Coordinator Lab.SIFO Farmacoeconomia, Drug Information Centre, Careggi Hospital, 50132 Firenze (Italy), Sabrina Trippoli, and Monica Vaiani
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Since
Garattini and Bertele’ address the problem of the cost of the newest
anticancer agents (BMJ, 3 August 2002 issue), we would like to provide further
data on this point. In
recent times, a large number of innovative anti-cancer agents have become
available in Europe. Consequently, the regulatory agencies of European
countries have faced the problem of defining the price or the reimbursement
level for these new agents. In Italy, the agency responsible for negotiating
the prices of innovative drugs is a joint Committee of the Ministry of Health
and of the Ministry of Economics (called CIPE Drug Negotiation Committee). In
this letter, we review the most recent decisions made by this Committee in the
area of innovative anti-cancer agents and we compare the prices approved for
these drugs with those suggested by a standard pharmacoeconomic algorithm. We
retrospectively reviewed the decisions made by the CIPE Committee from
February 1999 to August 2001 in the area of innovative anti-cancer agents and
we compared these decisions with a simple pricing algorithm based on standard
pharmacoeconomic principles. This algorithm has the aim to link the clinical
effectiveness of the drug to the price that can be recognized to it. More
precisely, the algorithm identifies a "negotiation window" which is
proposed as a reference to which the real price of the drug is eventually
compared. Briefly,
when the innovative drug determines a survival gain (SG) in the clinical trial
[1], the algorithm recognizes from EUR1,000 to EUR5,000 to each month of life
gained; when the new drug is instead equi-effective with the previous
treatment but reduces the days of hospitalization, the algorithm incorporates
the economic value of the reduced length of stay into its price. From
a practical point of view, when a survival gain is present, the pricing
negotiation window for the new drug is calculated as follows: 1.
The innovative drug
is valued between EUR1,000 and EUR5,000 per month of life gained (economic
value of a month gained, abbreviation EVMG); this value is in agreement with
the range of $10,000 to $50,000 per life year gained which has commonly been
cited in the pharmacoeconomic literature of the last five years [2]; 2.
The incremental
effectiveness (i.e. the SG expressed in months gained on average per patient,
abbreviation SG) is calculated from the survival information of the drug
(which is generally derived from one or more controlled clinical trials) [1]; 3.
An estimate is made
of the average cumulative dose per patient (CUMDOSE) for the innovative drug
and, when appropriate, also for the reference drug (i.e. the drug given to the
control group of the randomized trial); 4.
The price of the
CUMDOSE for the innovative drug (abbreviation Pcumdose_innovative) is calculated as: 5.
The price of the
innovative drug per milligram (Pmg) is obtained as: Pmg = Pcumdose_innovative/CUMDOSE. From
this value, the price per package of the new drug can finally be determined
through simple algebraic calculations. When
an innovative drug does not prolong survival, but reduces the average
expenditure per patient in terms of number of hospitalizations per patient,
the price of the innovative drug (expressed with reference to its CUMDOSE and
normalized to 1 patient or to 1 cycle, i.e. Pcumdose_innovative)
is simply the sum of the price of the CUMDOSE of the reference treatment
(normalized to 1 patient or to 1 cycle, i.e. Pcumdose_standard) plus the saving resulting from the
reduced hospitalizations (normalized to 1 patient). Step 5 is then applied as
shown above. As
an algebraic example of the application of the first part of the algorithm, we
consider the drug paclitaxel that was approved several years ago (and was
therefore omitted from the present analysis): 1) an EVMG between EUR1,000 and
EUR5,000 per month gained is recognized to the drug; 2) from the clinical
trial by McGuire et al. [3] (that compared cyclophosphamide + cisplatin versus
paclitaxel + cisplatin in advanced ovarian cancer) an average SG of 5.5 months
per patient can be estimated for the paclitaxel group [4]; 3) a CUMDOSE value
of 1,250 mg per patient was calculated on the basis of the data reported in
the clinical trial; 4) The price for the cumulative dose of paclitaxel is
therefore: Pcumdose_paclitaxel
= (EUR1,000 to EUR5,000) x 5.5 = EUR5,500 to EUR27,500; in this case, the
price for the reference treatment (Pcumdose_cyclophosphamide)
is negligible with respect to price of paclitaxel and is not introduced as a
subtractive term in the equation; 5) Finally: Pmg = EUR4.4 to
EUR22.0 per mg and, therefore, the negotiation window for the vial of
paclitaxel 100 mg is comprised between EUR440 and EUR2,200. The current price
of this vial is EUR582.67. Table
1 shows the list of the innovative anti-cancer agents considered in our
analysis and the clinical information available about them. Irinotecan,
oxaliplatin, and trastuzumab were add-on treatments. Temozolomide and
oxaliplatin did not prolong survival at levels of statistical significance (p
= 0.33 and p = 0.12, respectively). Table
2 shows the negotiation window calculated by the pharmacoeconomic algorithm in
comparison with the real price negotiated by the Committee. All drugs (with
the exception of capecitabine) were handled using the part of the algorithm
that starts from the SG and incorporates each month of life gained into the
drug price. Since
capecitabine does not prolong survival as compared with folinate +
fluorouracil [12] but reduces the average number of days of hospitalization
[13], the part of the algorithm designed for equi-effective treatments was
applied to this drug. The calculation procedure was the following. Twelves
et al. [13] have
translated the reduction in hospitalization in the capecitabine group into a
saving of EUR2,000 to EUR5,000 per patient (assuming 7 cycles per patient, 60
g of capecitabine per cycle and a cost for the folinate + fluorouracil regimen
of EUR39 per cycle). Hence, the negotiation "window" (normalized to
1 cycle) was calculated from the price for the standard therapy with folinate
+ fluorouracil (EUR39 per cycle) plus the range of avoided hospitalizations
(EUR286 to EUR714 per cycle) giving a result of EUR325 to EUR753 for the
cumulative dose of 60 g. This was therefore the negotiation window for the 60
g package of capecitabine; the final price negotiated by the Committee was
EUR571.71 (as shown in Table 2). Most
of the prices approved by our Negotiation Committee were somewhat higher than
the reference window suggested by the pharmacoeconomic algorithm. Hence, at
least in Italy, modern innovative anti-cancer agents generally receive a
higher price than that suggested by current international standards of
pharmacoeconomics. One point of controversy is that the SG for oxaliplatin and
temozolomide was valued at high levels even though no significant survival
benefit was found in the clinical trials of these two drugs. Interestingly
enough, there were no cases valued at an "unreasonable" level of
cost effectiveness. In contrast, these exceedingly high levels of
(incremental) cost in comparison with (incremental) effectiveness have
occasionally been documented in areas other than oncology (e.g. preoperative
autologous blood donations [14], interferon beta-1b in secondary progressive
multiple sclerosis [15]). ACKNOWLEDGEMENT Although
one of the authors (AM) is a component of the CIPE Committee, this report is
entirely based on public information (i.e. published clinical trials and
public decisions of the Committee). We
thank Roche Spa, Italy, for giving us the permission to utilize the survival
data of trastuzumab which refer to a patient subgroup (see Table 1) which was
not published in the original article by Slamon et al. [11]; this permission
was granted upon the condition of mentioning the bias explained in the last
footnote to Table 1. The
data reported herein have been submitted in abstract form to the 31st
European Symposium on Clinical Pharmacy, 30 October 2 November 2002, Florence
(Italy). REFERENCES 1.
Wright JC, Weinstein
MC. Gains in life expectancy from medical interventions--standardizing data on
outcomes. N Engl J Med 1998;339(6):380-6. 2.
Weinstein MC, Siegel JE,
Gold MR, Kamlet MS, Russell LB. Recommendations
of the Panel on Cost-effectiveness in Health
and Medicine. JAMA 1996;276(15):1253-8. 3.
McGuire WP, Hoskins
WJ, Brady MF, Kucera PR, Partridge EE, Clarke-Pearson DL, et al.
Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in
patients with stage III and stage IV ovarian cancer. N Engl J Med
1996;334(1):1-6. 4.
Messori A, Trippoli
S, Becagli P, Tendi E. Pharmacoeconomic profile of paclitaxel as a first-line
treatment for patients with advanced ovarian carcinoma. A lifetime
cost-effectiveness analysis. Cancer 1996;78(11):2366-73. 5. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000;18(7):1399-411.
6.
Messori A, Cattel F,
Trippoli S, Vaiani M. Survival in patients with metastatic breast cancer:
analysis of randomized studies comparing oral aromatase inhibitors versus
megestrol. Anti-Cancer Drugs 2000;11(9):701-6. 7.
Saltz LB, Cox
JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus
fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study
Group. N Engl J Med 2000;343(13):905-14. 8.
Vaiani M, Trippoli
S, Messori A. Irinotecan plus fluorouracil and leucovorin for metastatic
colorectal cancer. N Engl J Med 2001;344(4):305-6. 9. De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18(16):2938-47.
10. Yung
WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al. A phase II
study of temozolomide vs. procarbazine in patients with glioblastoma
multiforme at first relapse. Br J Cancer 2000;83(5):588-93. 11. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V,
Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med
2001;344(11):783-92. 12. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta
E, Boyer M, et al. Oral Capecitabine Compared With Intravenous Fluorouracil
Plus Leucovorin in Patients With Metastatic Colorectal Cancer: Results of a
Large Phase III Study. J Clin Oncol
2001;19(21):4097-106. 13. Twelves C, Boyer M, Findlay M, Cassidy J, Weitzel C,
Barker C, et al. Capecitabine (Xeloda) improves medical resource use compared
with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients
with advanced colorectal carcinoma. Eur
J Cancer 2001;37(5):597-604. 14. Etchanson J, Petz L, Keeler E, Calhoun L, Kleinman S, Snider C, et al. The
cost effectiveness of preoperative autologous blood donations. N Engl J Med
1995;332(11):719-24. Table 1.
Information on the innovative anti-cancer agents examined by the Italian
Committee over the study period* (together with the data of paclitaxel that has
been used as an algebraic example of the algorithm).
*
The values of cumulative dose per patient used in our analysis were the
following: exemestane: 25,096 mg [6]; megestrol: 140,662 mg [6]; irinotecan:
4,284 mg [8]; oxaliplatin: 1,393 mg [9]; paclitaxel: 1,250 mg [6]; temozolomide:
6,000 mg (4 cycles at 1.5 g per cycle according to the Technical Annex);
trastuzumab: 4,000 mg (assuming prosecution of therapy until progression) [11]. †
In the absence a lifetime analysis, the SG was estimated from the difference of
the two medians. ‡
The clinical trial has not been published. For the
purpose of this study, we asked Boehringer Ingelheim Italy to provide us with
the survival data that they had submitted to the European Agency for the
Evaluation of Medicinal Products (EMEA) when the drug was discussed and then
approved, but the response from the manufacturer was negative. These data are in
part available on the EMEA website (at the Internet address http://www.eudra.org/humandocs/humans/EPAR/Beromun/Beromun.htm
consulted on December 26th, 2001); no survival curves are however reported, and
so the SG needed for our analysis could not be determined. The current price per
package of tasonermin (Beromun 4 vials 1 mg) is EUR11,813.54. § According
to the randomized design of Slamon’s study, the treatment group was given
trastuzumab + paclitaxel while the controls were given paclitaxel alone (data
for the subgroup included in our analysis); however, the majority of the control
patients received trastuzumab as a second-line open-label treatment; this
second-line regimen presumably improved the survival of the controls, and so the
SG estimated from the real curves and included in our analysis is probably an
underestimate of the true (but unknown) gain attributable to trastuzumab vs. no
trastuzumab. Roche SpA (with the help of a modelling
expert) has performed a study based on the "propensity scoring" method
to simulate the SG for the comparison of trastuzumab
vs. no trastuzumab (excluding trastuzumab as a second-line for the control
group); this study estimated a gain
up to 9.6 months per patient, which was however not considered in our analysis
because of its simulated nature. Table 2.
Innovative anti-cancer agents approved in Italy: comparison between the
negotiation window proposed by the algorithm (expressed as lower limit and upper
limit) and the final price approved by the Committee.
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