Efficacy, safety, and cost of new anticancer drugsBMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7358.269 (Published 03 August 2002) Cite this as: BMJ 2002;325:269
All rapid responses
The intention of our article was to show the evidence available when
a new drug is approved. Calvert et al. criticized this approach, which
aimed at reflecting the general perception of what innovation must mean by
relying on the documentation accompanying EMEA approval, while not
overlooking the current literature. The fact that we are usually dealing
with few patients, phase II trials, open label studies, and lack of
comparison, makes it difficult to establish how new anticancer drugs
should be placed in the existing therapeutic armamentarium. We agree with
Manfredini and Jirillo that any advantage for patients is valuable and
worth considering, but we believe it is so if (a) it is proved, not
merely suggested by uncontrolled findings in patients in whom other
treatments failed; and (b) the benefit is not counterbalanced by poor
safety or tolerability.
It is true, as Barton and Salsbury argue, that many drugs approved as
second or third-line treatments undergo further development post-
marketing. We only note that the additional studies the companies commit
themselves to do so as to have the tag “under exceptional circumstances”
removed from a marketing authorization are rarely done (1).
Contrary to Manfredini’s interpretation, our paper does not intend
patients, families and even less so doctors to be excluded from decisions
on treatment but they should be enabled to decide on treatments of known
impact, with all their pros and cons. Any other approach means either
denying people potential benefits or exposing them to potential risks,
both by chance. Calvert and coll. may not endorse it, but this is the
favour we believe has to be done to cancer patients. The reference they
made to show an increase in survival refers to the period 1986-90 which
reflects - if treatment is the most important factor - previously
developed effective drugs, which are not pertinent to the period we
analyzed. Increases in survival can be ascribed to more frequent early
diagnosis rather than to new drugs. The taxane issue Calvert et al. raise
is also not valid as paclitaxel was already on the market and docetaxel
did not provide any documented advantage to justify the difference in
price. The superiority of temozolomide over procarbazine also remains to
be demonstrated, as referenced in our article.
We acknowledge that there are advantages other than better efficacy
that are worth considering. As Calvert et al., Barton and Salsbury point
to the better tolerability of liposome doxorubicin. The two papers they
mentioned (2,3) suggest its lower cardiotoxicity. Notwithstanding, there
was a trend towards shorter survival in the liposome doxorubicin group
than in the conventional doxorubicin group (3). This is surprising
considering the imbalances in baseline characteristics (more older
patients, more disease sites, more previous adjuvant therapy, etc. in the
conventional doxorubicin group) that, though small, could have favored the
liposome group. Consequently, the better benefit-risk profile of liposome
formulations is still far from proved.
With regard to outcome measures, we concur with Lawson that the time
to progression per se is not necessarily a subjective endpoint, but can
easily be affected simply by scheduling assessment at different intervals.
As for the costs, the analysis by Messori et al. supports our view
that innovative treatments in oncology are too expensive, although their
cost-effectiveness may be regarded as not "unreasonable" as in other
areas. The premium price allowed to new products - Barton and Salsbury say
- will partly be routed back into research and development but - we add -
it will mainly be invested in marketing to convince people of a value that
should be self-evident if it were true. We agree with Lawson (and Calvert
and colleagues) that direct comparison of the costs of tamoxifen and
chemotherapy, which was intended as a provocative example of the size of
the difference between previous and current treatments, turned out to be
misleading. However, the table also allows a comparison of the costs of
docetaxel and paclitaxel.
Besides tamoxifen, Calvert et al. also object to the choice of other
cost comparators: we recognise that, for instance, fludarabine is not a
therapeutic alternative to rituximab, which is indicated in patients
resistant to chemotherapy, but still do not understand why the latter
should cost so much more than fludarabine while providing a similar
effect, though in patients unsuitable for chemotherapy. As for the alleged
economic advantages we must remind readers that most of the economic
analyses of new drugs used in oncology have been criticized (4) on the
basis of conflict of interests of the authors.
We all hope that the future will be brighter but we must be honest in our
promises to patients. We must also not forget that any undue burden for
drug expenditure will always be at the expense of other measures that
might contribute to better care.
Silvio Garattini, MD, Vittorio Bertele’, MD
“Mario Negri” Institute, Milan, Italy
Competing interests: SG: none. VB has received fees for speaking from
Schwarz Italia SpA and Instrumentation Laboratory, and for scientific
advice from SmithKline Beecham and Aventis Pharma.
1. Garattini S, and Bertele’ V. Adjusting Europe’s drug regulation to
public health needs. Lancet 2001;358:64-7
2. Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and
preserved antitumour efficacy of liposome encapsulated doxorubicin and
cyclophosphamide compared with conventional doxorubicin and
cyclophosphamide in a randomised multicentre trial of metastatic breast
cancer. J Clin Oncol 2001; 19:1444-1454
3. Harris L, Batist G, Belt R et al. Liposome encapsulated doxorubicin
compared with conventional doxorubicin in a randomized multicentre trial
as first line therapy of metastatic breast cancer. Cancer 2002; 94:25-36
4. Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL. Evaluation of
conflict of interest in economic analyses of new drugs used in oncology.
JAMA 1999; 282:1453-1457
Competing interests: No competing interests
Garratini and Bertele1 conclude that new anticancer drugs introduced
during the last 6 years have not increased survival or quality of life in
cancer patients - a surprising conclusion to be made at the end of a
decade which has seen unprecedented advances in the treatment of common
tumours, both in survival and quality of life. Perhaps if they had
examined the contemporary literature and taken account of oncology
practice they might have reached a less pessimistic conclusion.
To take some of the drugs in question: Docetaxel and paclitaxel have
been extensively evaluated in large randomised trials, many of which have
associated quality of life studies. Both have been shown to significantly
enhance survival in randomised trials in both adjuvant and metastatic
breast cancer treatment2. In addition, data are presented in the article
showing enhanced survival in second-line lung cancer. Paclitaxel has also
been shown to significantly increase survival in ovarian cancer3. Taken
together, the introduction of taxanes has substantially impacted on
survival in breast and ovarian cancer as well as making a contribution to
lung cancer. The registration of paclitaxel for soft tissue sarcoma is
clearly a niche indication presumably being used to license a generic
version of paclitaxel and so is hardly relevant to the discussion. The
use of tamoxifen as a cost comparator for docetaxel is also irrelevant
since the survival advantage for taxanes is conferred in patients who are
either oestrogen-receptor negative or are resistant to hormonal agents.
A direct comparison of drug costs for oral compounds vs standard i.v.
treatments does not take into account savings made on in-patient
treatment. Phase III randomised trials have demonstrated that capecitabine
is at least as active as a standard regimen of 5-FU in combination with
folinic acid (FUFA). Capecitabine was better tolerated, with fewer life
threatening toxicities than i.v. FUFA. In addition, when all the
administration costs are considered there are economic advantages and
strong patient preferences supporting oral administration of drugs.4A
similar situation exists with temozolomide, when compared with
procarbazine, in patients with recurrent glioblastoma multiforme.
Doxorubicin peg liposomes are used in ovarian cancer resistant to
platinum-containing regimens and do indeed reduce the significant problem
of anthracycline cardiotoxicity. An inappropriate cost comparator drug
(CCD), cisplatin, has been chosen, and this theme is continued with the
two antibodies, rituximab (CCD fludarabine) and trastuzamab (CCD
paclitaxel). Rituximab is indicated for patients resistant to
chemotherapy, so fludarabine is not an alternative treatment. Trastuzamab
prolongs survival in a HER-2 expressing subset of breast cancer patients,
is virtually without side effects and is recommended for use in
combination with paclitaxel. The discussion of the cardiotoxicity of
trastuzamab in combination with doxorubicin is spurious since these two
agents are not used in combination.
The authors make much of mutagenicity and carcinogenicity in their
safety notes. The former is an avoidable side effect which is seldom even
relevant in the population of patients concerned. The latter has been
remarkable by its rarity except in patients treated for lymphoma. The
predicted rash of drug-related leukaemias in, for example, the thousands
of long term survivors of breast cancer who have received adjuvant
chemotherapy, has simply not occurred.
The authors rely heavily for their negative comments on the value of
cancer chemotherapy and chemotherapy trials on one reference. This is
cited 3 times and is a population mortality-based study (Bailar JC) using
data collected between 1970 and 1994, pre-dating by many years the period
being considered here.
Considerations of cost, while important, should not affect our
judgement on the data of the utility of a new agent. However, most of the
cost comparisons made here are clearly inappropriate, using comparators
that simply would not be used (or are ineffective) in the indication for
the new drug. The ephemeral nature of drug pricing as a result of generic
competition or the existence of more than one drug in the same class, has
also been overlooked.
We are living at a time when immense progress is being made in the
treatment of cancer. The survival rates and cure rates of several common
cancers such as breast, colon and lung cancer are being increased by the
use of anticancer drugs, including those listed in this article5.
Additional important drugs licensed during this period (eg irinotecan and
oxaliplatin) have not been included in this discussion presumably because
they were via a mutual recognition procedure and therefore did not come to
the attention of the EMEA.
The oncology community on an international basis now routinely
evaluates these drugs in large trials with hard endpoints such as survival
as well as softer ones such as quality of life. It is naïve, if not
disingenuous, to criticize current drugs on the basis of data available on
the EMEA web site alone.
We all hope that the outlook for future cancer patients will improve
further, and that the advent of newer classes of targeted agents will
contribute to that. However Garratini and Bertele have done these
patients no favours.
1. Garattini S, Bertele V. Efficacy, safety, and cost of new
anticancer drugs. BMJ 2002; 325:269-272.
2. Nabholz JM, Tonkin K et al Exp.Opin. Phamacother 2000;1(2):187-206.
3. Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of
cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with
advanced epithelial ovarian cancer: Three-year results. JNCI 2000; 92
(9):699-708 (3 May)
4. Van Cutsem E, Twelves C, Cassidy J, 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;
5. Richards MA, Stockton D, and Coleman P. How many deaths have been
avoided through improvements in cancer survival? BMJ 2000; 320: 895-898
Professor of Medical Oncology
University of Newcastle upon Tyne, NE2 4HH
Duncan I Jodrell
Senior Lecturer & Honorary Consultant in Medical Oncology
Western General Hospital, Edinburgh, EH4 2XU
Professor of Medical Oncology
Cancer Research UK Department of Medical Oncology
Glasgow, G61 1BD
Professor of Medical Oncology
Cancer Research UK Medical Oncology Unit
John Radcliffe Hospital, Oxford, OX3 9DS
Written with the support of Cancer Research UK
Professor Robert Souhami
Director of Clinical Research Development and Training
Cancer Research UK
44 Lincoln’s Inn Fields
Competing interests: Professor Calvert is a consultant to the
Competing interests: No competing interests
Garattini and Bertele's article regarding the cost of new anticancer
drugs (1) raises several points of discussion.
There appears to be misleading information in the comparitor drugs used,
for example tamoxifen hormone manipulation is not used for the same
indication as chemotherapy in breast cancer.
In defining a response to a drug it was stated that outcome measures
be objective,yet quality of life is a form of subjective analysis. In
contrast why is "time to progression" subjective? It may be a surrogate
for survival but this does not make it subjective.
A final comment relates to the fact that Garattini and Bertele' are
looking at the reduction of deaths to assess the efficacy of new
anticancer drugs. This method may miss increases in longevity in the short
Ref. Garattini S. Efficacy, saftey and cost of new anticancer drugs
Competing interests: No competing interests
The article by Garattini and Bertele on efficacy, safety and cost of
new anticancer drugs (1) raises many controversial issues and contains
factual inaccuracies relating to liposomal doxorubicin citrate.
Although it is true to say that the initial licences for many drugs are
often as second or third line therapies the article ignores the continued
development of the marketed product. Classical management of the drug will
extend development from the initial licence in the metastatic setting
(usually with palliative intent) through to the adjuvant and neoadjuvant
settings where cure is a possibility (2). With this strategy the drug is
made available to patients in the most timely fashion given that adjuvant
studies are large and time consuming.
Randomised anticancer drug trials will usually be designed to show
improvement in efficacy over standard treatment. However an equally valid
endpoint, in a well designed protocol, is to show improved tolerability
and non inferior efficacy to conventional treatment. The authors are
misinformed both in their description of non-inferiority studies and the
validity of the endpoints and when they state that “in no instance did
comparisons show a clear cut advantage in terms of adverse reactions over
the reference drugs or analogous agents”.
The liposomal doxorubicin citrate to which they refer showed statistically
significant advantages over conventional doxorubicin in terms of
proportion of patients with cardiac events and cumulative dose of
doxorubicin given at the time of first cardiac event in a prospective
statistical design (3,4). The liposomal preparation also showed an
improved haematological and non haematological tolerability profile
Moreover in comparison against epirubicin there were advantages in terms
of time to progression and time to treatment failure (5).
Given that many patients receive doxorubicin in the adjuvant setting and
on relapse may benefit from further treatment with the same drug, the
cardiotoxicity of doxorubicin will become a limiting factor. Additionally
the combination of trastuzumab with doxorubicin or paclitaxel is limited
The premium prices charged for these drugs is justified by their activity
in combination with other agents and their potential for significant
survival advantages in all disease settings. NICE in the UK has approved
reimbursement of at least 4 of the agents using stringent pharmacoeconomic
criteria. It must not be forgotten that part of the costs will be routed
back into research and development for the novel therapies which may
provide the breakthrough needed in cancer therapy.
1.Garattini S, Bertele V
Efficacy, safety, and cost of new anticancer drugs
2.Jones SE, Savin M, Holmes FA et al
Preliminary results of a prospective randomised trial of adjuvant
chemotherapy for patients with stage I-III operable invasive breast cancer
comparing 4 courses of Adriamycin/Cyclophosphamide (AC) to 4 courses of
Proc Am Soc Clin Oncol 2001;20:33a Abstract 128
3.Batist G, Ramakrishnan G, Rao CS et al
Reduced cardiotoxicity and preserved antitumour efficacy of liposome
encapsulated doxorubicin and cyclophosphamide compared with conventional
doxorubicin and cyclophosphamide in a randomised multicentre trial of
metastatic breast cancer
JCO 2001; 19(No 5): 1444-1454
4. Harris L, Batist G, Belt R et al
Liposome encapsulated doxorubicin compared with conventional doxorubicin
in a randomized multicentre trial as first line therapy of metastatic
Cancer 2002;94 (1):25-36
5.Chan S, Davidson N, Juozaityte E et al
Randomised trial of liposome encapsulated doxorubicin and cyclophosphamide
compared with epirubicin and cyclophosphamide in first line therapy of
metastatic breast cancer
Submitted to JCO
Competing interests: No competing interests
we read with interest this article, since we have been engaged in the last
24 months in our Division of Medical Oncology in an attempt to reduce the
expenses for antitumor drugs.
Aging of the population has been the main factor leading to the increase
of the costs (1), also for cancer patients, together with the shift to new
anticancer drugs. To reduce costs in Europe several mechanism have been
adopted by the Third Payers such as fixed and indicative budget for
prescribers, budgeting for regions, price regulations, patient co-payment
and differential reimboursement.
Rumor has been raised by some newspapers on this "Europe prescription drug
war" among patients, prescribing physicians, pharmacist and Third Payers.
With this provocative article also pharmacologists are entering in this
We do not believe that few or no substantial advantage over the existing
preparations has been offered to patients with the new anticancer drugs
reaching the European market in the last 7 years.
Of course, cure is the best advantage we can offer to the patients, but
also increase of survival, increase of disease-free interval, even partial
responses of few months duration and improvement of the quality of life
after chemotherapy administration are valuable for the patients. Even, for
example taking only the case of temozolomide, the availability of this
new drug in patients with recurrent glioblastoma after nitrosoureas alone
or in combination may be valuable since partial responses plus stable
disease in around half of patients can be achieved (2). The Authors
compare the existing with the new drugs, but they miss the fact that the
new drug can be offered as a second or third line, when the conventional
drug has lost his activity.
We agree on the need of reducing costs of anticancer drugs. In our
Division of Medical Oncology which spent in 2001, only for antineoplastic
drugs, 3.459.000 Euro, a containment policy has been adopted especially
1. The appropriate indication of treatment for each patient
2. Avoiding over-treatment in the last months of life, since we are aware
that a relevant percentage of pre-terminally ill patients (14%) in USA
are actively treated with cancer chemotherapy (3).
We were able to reduce the costs for anticancer drugs in the second
trimester of 2002 in the range of 15-20 % as compared to those of the
preceding year. But this was achieved without necessarily cutting the use
of the new antitumor drugs.
We know that drug prescription in cancer patients is a complex procedure
(4) but do not agree that patients, doctors and family members should be
excluded from the decision, as suggested in the article of Garattini and
Bertele. The press has also the right and the task of properly informing
the public of the progress, even small, achieved with the newer drugs. Not
performing this task could again bring us into the fog of the miraculous
therapies. We in Italy unfortunately have had a recent experience of
unproven and costly therapies: we are quite sure that Prof. Garattini and
Bertele remember very well the "Di Bella story".
1. Belien P., "What Can Europe's Health Care Systems Tell Us About the
Market's Role," in W. McArthur et al, eds., Healthy Incentives: Canadian
Health Reform in an International Context (Fraser Institute: Vancouver,
2. Brandes AA, Pasetto LM, Vastola F, Monfardini S., Temozolomide in
patients with high grade gliomas. Ocology 2000, 59: 181-186
3. Emanuel E.J. ,Young-Xu Y., Ash A., Gazelle G., Levinsky N.,
Moscwitz M. How much chemotherapy are cancer Patient receiving at the end
of life? Proceeding of the American Society of Clinical Oncology, May 12-
15, 2001 S. Francisco, CA; abstr. 953
4. Monfardini S., Prescribing in elderly cancer patients, Eur J
Cancer 2002, in press.
Competing interests: No competing interests
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.
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.
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
when the innovative drug determines a survival gain (SG) in the clinical trial
, 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.
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. 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) ;
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:
= (EVMG) x (SG) - Pcumdose_standard
is the price of the CUMDOSE of the reference drug and SG is expressed in
is assumed to be zero when the innovative drug is an add-on treatment or when
the price of the standard treatment is negligible in comparison with that of
the new drug;
5. The price of the
innovative drug per milligram (Pmg) is obtained as:
Pmg = Pcumdose_innovative/CUMDOSE.
this value, the price per package of the new drug can finally be determined
through simple algebraic calculations.
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
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.  (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 ; 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
= (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.
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).
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
capecitabine does not prolong survival as compared with folinate +
fluorouracil  but reduces the average number of days of hospitalization
, the part of the algorithm designed for equi-effective treatments was
applied to this drug. The calculation procedure was the following. Twelves
et al.  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).
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.
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 , interferon beta-1b in secondary progressive
multiple sclerosis ).
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).
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. ; this permission
was granted upon the condition of mentioning the bias explained in the last
footnote to Table 1.
data reported herein have been submitted in abstract form to the 31st
European Symposium on Clinical Pharmacy, 30 October 2 November 2002, Florence
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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 ; megestrol: 140,662 mg ; irinotecan:
4,284 mg ; oxaliplatin: 1,393 mg ; paclitaxel: 1,250 mg ; 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) .
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
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.
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.
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.
Price approved by the Committee
(EUR per package)
The negotiation window for exemestane was calculated considering the price of
the reference therapy (PCUMDOSE_megestrol = EUR 2,621).
† In our
analysis of temozolomide, the price of the reference drug given to the controls
was negligible, and so the subtractive term PCUMDOSE_standard was
omitted from the calculation.