Efficacy, safety, and cost of new anticancer drugs -- = Garattini and Bertele' 325 (7358): 269 -- BMJ

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Home > Education > = BMJ=20 2002;325(7358):269 (3 August), = doi:10.1136/bmj.325.7358.269

BMJ 2002;325:269-271 = ( 3 August )

Education and debate

Efficacy, safety, and cost of new anticancer drugs

Silvio Garattini,=20 director, Vittorio Bertele',=20 head, regulatory policy laboratory.

Mario Negri Institute for Pharmacological Research, 20157 Milan, = Italy

Correspondence to: S Garattini sgarattini{at}marionegri.it

Italian pharmacologists Silvio Garattini and Vittorio Bertele' note = that new=20 anticancer drugs reaching the European marketin=20 1995-2000 offered few or no substantial advantages over = existing⁼²⁰preparations, yet cost several times $3D---=20$ in one=20 case 350 times $3D---=20$ asmuch

Though only an imperfect indicator of progress in cancer control,¹= age=20 standardised mortality in the European Union, forboth sexes=20 combined, had been increasing up to 1988; since thenit has = decreased=20 from 147 to 136 per 100 000 inhabitants.²= ⁼²⁰Prevention is probably one of the main reasons for this drop,⁼particularly the decrease in tobacco smoking; another reason = is⁼²⁰the use of screening for early diagnosis of cancers of the = cervix⁼²⁰and breast and possibly also of the colon and rectum..

The greatest changes have been 4500 fewer deaths from childhood = tumours=20 and 4000 fewer from lymphomas (Hodgkin's disease)each = year over=20 the past four decades. Among solid tumours, advanceshave = been made=20 in treating breast cancer, in which tamoxifen increases⁼10 year=20 survival by 6% for node negative and 11% for node positive⁼tumours,³= and=20 chemotherapy increases survival by 7% and 11%,⁼respectively.⁴= For=20 most other common solid tumours such asthose of lung, = oesophagus,=20 stomach, or pancreas, only limitedsurvival gains have been = achieved.=20 ²= =20 ⁵= =20 ⁶= =20

On the whole, pharmacological treatments are credited with only a = very small=20 proportion of cures.⁷= =20 However, some kind ofpharmacological intervention is often=20 considered as a last resort,particularly when cancer has = already=20 disseminated. We evaluatedthe progress made over the past = few years=20 in terms of new drugsapproved for prescription in order to = judge=20 their likely impacton cancer mortality in the near future. =

Summary=20 points=20

: Drugs approved in Europe in the first six years of activity of = the=20 European Medicines Evaluation Agency do not meet the = expectations=20 generated by the gains in basic knowledge on cancer cell = proliferation=20 and dissemination=20
: To reach the market swiftly new drugs are often candidates for = second or=20 third line treatment of rare cancers, and they are evaluated in = small=20 phase II studies which assess their equivalence or = non-inferiority=20 (rather than superiority) to standard treatments=20
: In spite of not improving survival, quality of life, or safety, = these=20 new drugs cost much more than the standard treatments=20
: Clinical investigation must seek substantial advantages for = patients in=20 order to gain real benefit from future anticancer drugs =

	Methods

The European Medicines Evaluation Agency, set up in January = 1995, has=20 led to Europe-wide approval of the most important drugs,⁼including=20 anticancer medicines. Drugs approved by the agency are⁼automatically=20 marketable in 15 European countries. Despite theircost, = new=20 anticancer drugs will probably be used in a large proportion⁼of⁼²⁰patients.

We identified 12 anticancer drugs approved in the six years from = 1995-2000 which contain new chemical entities or known active⁼²⁰principles with new indications (table). The information on = the⁼²⁰new drugs was collected from several documents (available on www.emea.eu.int/index/i= ndexh1.htm),⁼²⁰including the European public assessment report, which = describe⁼²⁰the steps, reasons, and commitments for the approval of a = given⁼²⁰drug, and the summaries of product characteristics, the = technical⁼²⁰documents that report indications and adverse reactions for = each⁼²⁰drug. We calculated the costs of treatments on the basis of = cost⁼²⁰per cycle of therapy and compared costs, where possible, with⁼those of reference drugs. Prices of drugs are those = pertaining⁼²⁰in Italy when available, converting the Italian lira at a = rate⁼²⁰of 1936.27 to the euro (=A31.58, $1).=20

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Features of the 12 new = anticancer drugs=20 approved for marketing in the European Union from January=20 1995 to December=20 2000

What defines a = response to=20 a drug?=20

To be of clinical interest a drug must provide measurable = advantages=20 to patients or to national health services

It should be more effective than placebo or any other = available=20 treatment; if there is no advantage in terms of efficacy, it = should be=20 at least safer, more tolerable, easier to use, or cheaper than = active=20 comparators

Outcome measures used should be objective, assessing = survival or=20 quality of life

Subjective end points such as the "time to progression" are = liable=20 to bias and should be avoided

New approvals
Analysis of the clinical trials = reported=20 inthe European public assessment reports or summaries of=20 productcharacteristics shows that anticancer agents are = often=20 approvedon the basis of phase II trials. Few attempts are = made to=20 establishthe value of the new drugs in relation to the = reference=20 drugs.The trials often look for "non-inferiority," which = entails=20 recruitingonly few patients and relatively short periods of=20 observation.The end points tend to be subjective, such as = the "time=20 to progression";seldom is there an evaluation of survival or = quality=20 of life.There is a tendency to seek the first approval for = an=20 indicationfor second or third line treatment in a relatively = rare=20 cancerin Europe: in three cases the indication was for = Kaposi's=20 sarcomain patients with AIDS. There seem to be few = innovative=20 treatmentsfor cancers of such sites as the colon and rectum, = prostate, orpancreas.

As for safety, most drugs caused the usual signs of cytotoxicity, = including=20 neutropenia, thrombocytopenia, fever, infections,and=20 gastrointestinal toxicity. In no instance did comparisons⁼show a=20 clear cut advantage, in terms of adverse reactions, overthe=20 reference drugs or analogousagents.

New approvals lead to expectations, fuelled by the pharmaceutical = companies'=20 direct and indirect promotion through the media,on the part = of=20 patients, their families, and their doctors, butthese = expectations=20 may not be justified by the results of trials.⁷= ⁼²⁰At the time of approval the medicines agency may ask a = company⁼²⁰to carry out additional studies. The company may plead that = off⁼²⁰label use makes these difficult "for ethical reasons." But it⁼is for these ethical reasons that new drugs should be = compared⁼²⁰with existing drugs.

View = larger=20 version (16K):
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Comparison of some new drugs = with existing=20 drugs

Costs
The approval of new drugs that offer no = substantialadvantages puts further burdens on national = health=20 services, insurers,and patients. The costs of the new = preparations=20 are several times $3D---=20$ sometimesan order of magnitude $3D---=20$ higher=20 than those of existing drugs. Thisincrease is difficult to = justify,=20 considering that the newer drugsare usually largely = equivalent to=20 the standard treatments in efficacyand safety. The lack of=20 differences in activity makes any pharmacoeconomicevaluation = virtually useless: it is difficult to explain why toremifene⁼should=20 cost more than twice as much as tamoxifen. Similarly, one⁼²⁰temozolomide cycle costs about 350 times as much as a cycle = of⁼²⁰procarbazine, although there are serious doubts about the = real⁼²⁰efficacy of either treatment.⁹= In=20 ovarian cancer, one cycleof topotecan costs over = 10 times more=20 than a cycle of cisplatin.The new drugs for advanced breast = cancer=20 cost 3-13 times as muchas doxorubicin. Just to = complicate=20 matters further, pharmacoeconomicassessments of new = anticancer drugs=20 tend to be biased in theirfavour.¹⁰

None of the 12 drugs included in this list offers any = significant=20 improvement in activity. The liposomal preparation of doxorubicin⁼may=20 be less cardiotoxic, although cardiotoxicity does not seemto = be an=20 important limiting factor in the efficacy of doxorubicin.^{11⁼²⁰It has also been claimed that epirubicin is less cardiotoxic =
than⁼²⁰doxorubicin.¹²}

The monoclonal antibodies are completely new anticancer agents but = their=20 efficacy has yet to be confirmed by appropriate studies,⁼while their=20 safety seems unfavourable, contrary to all expectations.^{13⁼²⁰Perhaps the results will be better when some of these drugs =
are⁼²⁰combined in new therapeuticschemes.}

From these results over the past six years there is little to justify = some of=20 the promises made to the public. ⁷= It=20 iswidely expected that the general population of cancer=20 patientsnot involved in clinical trials will gain no benefit = from=20 newanticancer drugs. It is to be hoped, however, that some = new=20 anticancerdrugs, including resistant revertants, = anti-angiogenic=20 agents,pro-apoptotic drugs, and chemopreventive products, = will soon=20 undergoadequate clinical testing and show substantial = benefits over=20 currenttherapies.

	Acknowledgments

SG and VB act as member and expert of the Committee for Proprietary = Medical=20 Products. The views presented here are those ofthe authors = and=20 should not be understood or quoted as being madeon behalf of = the=20 European Medicines Evaluation Agency or its scientific⁼committees.

Footnotes

	Footnotes

Funding:None.=20

Competing interests: In the last five years VB has received fees for = speaking=20 from Schwarz Italia SpA and InstrumentationLaboratory, and = for=20 scientific advice from SmithKline Beechamand Aventis⁼²⁰Pharma.=20

References

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2.=20 Levi F, Lucchini F, Negri E, La Vecchia C. The = decline in=20 cancer mortality in the European Union, 1988-1996. Eur J = Cancer=20 2000; 36:=20 1965-1968.
3.=20 Early breast cancer trialists' collaborative group. = Tamoxifen for early breast cancer: an overview of the randomised = trials.=20 Lancet 1998; 351: 1451-1467[CrossRef][ISI][Medline].=20
4.=20 Early breast cancer trialists' collaborative group. = Polychemotherapy for early breast cancer: an overview of the = randomised=20 trials. Lancet 1998; 352: 930-942[CrossRef][ISI][Medline].=20
5.=20 Berrino F, Gatta G, Chessa E, Valente F, Capocaccia = R, the=20 Eurocare Working Group. Introduction: the Eurocare II study. = Eur J=20 Cancer 1998; 34: 2139-2153.
6.=20 Coleman MP. Opinion: why the variation in breast = cancer=20 survival in Europe? Breast Cancer Res 1999; 1: 22-26[CrossRef][Medline].=20
7.=20 Bailar JC, Gornik HL. Cancer undefeated. N Engl = J=20 Med 1997; 336: 1569-1574[Abstract/Free Full Text].=20
8.=20 Garattini S, Bertele' V. Adjusting Europe's drug = regulation=20 to public health needs. Lancet 2001; 358: 64-67[CrossRef][Medline].=20
9.=20 Batchelor T. Temozolomide for malignant brain = tumours.=20 Lancet 2000; 355: 1115-1116[CrossRef][ISI][Medline].=20
10.=20 Friedberg M, Saffran B, Stinson TJ, Nelson W, = Bennett CL.=20 Evaluation of conflict of interest in economic analyses of new = drugs used=20 in oncology. JAMA 1999; 282: 1453-1457[Abstract/Free Full Text].=20
11.=20 Hortobagyi GN. Anthracyclines in the treatment of = cancer.=20 An overview. Drugs 1997; 54(suppl 4): S1-S7.
12.=20 Findlay BP, Walker-Dilks C. Epirubicin, alone or in = combination chemotherapy, for metastatic breast cancer. Provincial = breast=20 cancer disease site group and the Provincial systemic treatment = disease=20 site group. Cancer Prev Control 1998; 2: 140-146[Medline].=20
13.=20 White CA, Weaver RL, Grillo-Lopez AJ. = Antibody-targeted=20 immunotherapy for treatment of malignancy. Annu Rev Med = 2001; 52:=20 25-45.=20

	References

(Accepted 31 January 2002)

=A9 = BMJ=20 2002

Efficacy, safety, and cost of new anticancer drugs =: Hilary Calvert, Duncan I Jodrell, James Cassidy, Adrian L Harris, = Andrea=20 Messori, Sabrina Trippoli, Monica Vaiani, Silvio Garattini, and = Vittorio=20 Bertele'
BMJ 2002 325: 1302. [Extract]= [Full = Text]=20

New cancer drugs: little extra benefit, higher = price=20
BMJ 2002 325: 0. [Full = Text]=20

Western medicine: a confidence trick driven by the drug=20 industry?
BMJ 2002 325: 0. [Full = Text]=20

This article has been cited by other articles:

de Lemos, M. L (2006). Defining the clinical improvement in cancer = drug=20 therapy: implications for priority setting in healthcare. J Oncol = Pharm=20 Pract 12: 91-94 [Abstract]=20 =20
Maynard, A., Bloor, K., Freemantle, N. (2004). Challenges for the = National=20 Institute for Clinical Excellence. BMJ 329: 227-229 [Full = text]=20 =20
Garattini, S. (2003). New approaches to cancer therapy. Ann = Oncol=20 14: 813-816 [Full= =20 text] =20
Maynard, A., Bloor, K. (2003). Dilemmas In Regulation Of The = Market For=20 Pharmaceuticals. Health Aff (Millwood) 22: 31-41 [A= bstract]=20 [Full = text] =20
Calvert, H., Jodrell, D. I, Cassidy, J., Harris, A. L, Messori, = A.,=20 Trippoli, S., Vaiani, M., Garattini, S., Bertele', V. (2002). = Efficacy,=20 safety, and cost of new anticancer drugs. BMJ 325: 1302-1302 = [Full = text]=20 =20
Abraham, J., Bardelay, D., Kopp, C., Kleinke, J D, Bennion, E. = (2002).=20 Making regulation responsive to commercial interests: streamlining = drug=20 industry watchdogs * Commentary: Concern over drug industry's = influence on=20 regulatory policy in Europe * Commentary: Much ado about a good thing = *=20 Commentary: The freedom of informed choice. BMJ 325: = 1164-1169=20 [Full = text]=20

Rapid Responses:

Read all Rapid=20 Responses

Cost-effectiveness of anti-cancer drugs=20: Andrea Messori, et al.
bmj.com, 5 Aug 2002 [Full = text]=20
New anticancer drugs offer substantial advantage=20: Silvio Monfardini, et al.
bmj.com, 6 Aug 2002 [Full = text]=20
Anticancer drugs do benefit patients=20: Jeremy Barton, et al.
bmj.com, 13 Aug 2002 [Full = text]=20
New anticancer drugs for haematological and solid=20 malignancies.=20: Wendy L. Lawson
bmj.com, 14 Aug 2002 [Full = text]=20
Article has done no favours for cancer patients=20: Hilary Calvert, et al.
bmj.com, 23 Aug 2002 [Full = text]=20
Authors' reply=20: Silvio Garattini, et al.
bmj.com, 25 Sep 2002 [Full = text]=20

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