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
- Silvio Garattini, director,
- Vittorio Bertele, head, regulatory policy laboratory
- Correspondence to: S Garattini
- Accepted 31 January 2002
Italian pharmacologists Silvio Garattini and Vittorio Bertele' note that new anticancer drugs reaching the European market in 1995-2000 offered few or no substantial advantages over existing preparations, yet cost several times—in one case 350 times—as much
Though only an imperfect indicator of progress in cancer control,1 age standardised mortality in the European Union, for both sexes combined, had been increasing up to 1988; since then it has decreased from 147 to 136 per 100 000 inhabitants.2 Prevention is probably one of the main reasons for this drop, particularly the decrease in tobacco smoking; another reason is the use of screening for early diagnosis of cancers of the cervix and breast and possibly also of the colon and rectum..
The greatest changes have been 4500 fewer deaths from childhood tumours and 4000 fewer from lymphomas (Hodgkin's disease) each year over the past four decades. Among solid tumours, advances have been made in treating breast cancer, in which tamoxifen increases 10 year survival by 6% for node negative and 11% for node positive tumours,3 and chemotherapy increases survival by 7% and 11%, respectively.4 For most other common solid tumours such as those of lung, oesophagus, stomach, or pancreas, only limited survival gains have been achieved. 256
On the whole, pharmacological treatments are credited with only a very small proportion of cures.7 However, some kind of pharmacological intervention is often considered as a last resort, particularly when cancer has already disseminated. We evaluated the progress made over the past few years in terms of new drugs approved for prescription in order to judge their likely impact on cancer mortality in the near future.
Drugs approved in Europe in the first six years of activity of the European Medicines Evaluation Agency do not meet the expectations generated by the gains in basic knowledge on cancer cell proliferation and dissemination
To reach the market swiftly new drugs are often candidates for second or third line treatment of rare cancers, and they are evaluated in small phase II studies which assess their equivalence or non-inferiority (rather than superiority) to standard treatments
In spite of not improving survival, quality of life, or safety, these new drugs cost much more than the standard treatments
Clinical investigation must seek substantial advantages for patients in order to gain real benefit from future anticancer drugs
The European Medicines Evaluation Agency, set up in January 1995, has led to Europe-wide approval of the most important drugs, including anticancer medicines. Drugs approved by the agency are automatically marketable in 15 European countries. Despite their cost, new anticancer drugs will probably be used in a large proportion of patients.
We identified 12 anticancer drugs approved in the six years from 1995-2000 which contain new chemical entities or known active principles with new indications (table). The information on the new drugs was collected from several documents (available on www.emea.eu.int/index/indexh1.htm), including the European public assessment report, which describe the steps, reasons, and commitments for the approval of a given drug, and the summaries of product characteristics, the technical documents that report indications and adverse reactions for each drug. We calculated the costs of treatments on the basis of cost per cycle of therapy and compared costs, where possible, with those of reference drugs. Prices of drugs are those pertaining in Italy when available, converting the Italian lira at a rate of 1936.27 to the euro (£1.58, $1).
What defines a response to a drug?
To be of clinical interest a drug must provide measurable advantages to patients or to national health services
It should be more effective than placebo or any other available treatment; if there is no advantage in terms of efficacy, it should be at least safer, more tolerable, easier to use, or cheaper than active comparators
Outcome measures used should be objective, assessing survival or quality of life
Subjective end points such as the “time to progression” are liable to bias and should be avoided
Analysis of the clinical trials reported in the European public assessment reports or summaries of product characteristics shows that anticancer agents are often approved on the basis of phase II trials. Few attempts are made to establish the value of the new drugs in relation to the reference drugs. The trials often look for “non-inferiority,” which entails recruiting only few patients and relatively short periods of observation. The end points tend to be subjective, such as the “time to progression”; seldom is there an evaluation of survival or quality of life. There is a tendency to seek the first approval for an indication for second or third line treatment in a relatively rare cancer in Europe: in three cases the indication was for Kaposi's sarcoma in patients with AIDS. There seem to be few innovative treatments for cancers of such sites as the colon and rectum, prostate, or pancreas.
As for safety, most drugs caused the usual signs of cytotoxicity, including neutropenia, thrombocytopenia, fever, infections, and gastrointestinal toxicity. In no instance did comparisons show a clear cut advantage, in terms of adverse reactions, over the reference drugs or analogous agents.
New approvals lead to expectations, fuelled by the pharmaceutical companies' direct and indirect promotion through the media, on the part of patients, their families, and their doctors, but these expectations may not be justified by the results of trials.7 At the time of approval the medicines agency may ask a company to carry out additional studies. The company may plead that off label use makes these difficult “for ethical reasons.” But it is for these ethical reasons that new drugs should be compared with existing drugs.
The approval of new drugs that offer no substantial advantages puts further burdens on national health services, insurers, and patients. The costs of the new preparations are several times—sometimes an order of magnitude—higher than those of existing drugs. This increase is difficult to justify, considering that the newer drugs are usually largely equivalent to the standard treatments in efficacy and safety. The lack of differences in activity makes any pharmacoeconomic evaluation virtually useless: it is difficult to explain why toremifene should cost more than twice as much as tamoxifen. Similarly, one temozolomide cycle costs about 350 times as much as a cycle of procarbazine, although there are serious doubts about the real efficacy of either treatment.9 In ovarian cancer, one cycle of topotecan costs over 10 times more than a cycle of cisplatin. The new drugs for advanced breast cancer cost 3-13 times as much as doxorubicin. Just to complicate matters further, pharmacoeconomic assessments of new anticancer drugs tend to be biased in their favour.10
None of the 12 drugs included in this list offers any significant improvement in activity. The liposomal preparation of doxorubicin may be less cardiotoxic, although cardiotoxicity does not seem to be an important limiting factor in the efficacy of doxorubicin.11 It has also been claimed that epirubicin is less cardiotoxic than doxorubicin.12
The monoclonal antibodies are completely new anticancer agents but their efficacy has yet to be confirmed by appropriate studies, while their safety seems unfavourable, contrary to all expectations.13 Perhaps the results will be better when some of these drugs are combined in new therapeutic schemes.
From these results over the past six years there is little to justify some of the promises made to the public. 7 It is widely expected that the general population of cancer patients not involved in clinical trials will gain no benefit from new anticancer drugs. It is to be hoped, however, that some new anticancer drugs, including resistant revertants, anti-angiogenic agents, pro-apoptotic drugs, and chemopreventive products, will soon undergo adequate clinical testing and show substantial benefits over current therapies.
SG and VB act as member and expert of the Committee for Proprietary Medical Products. The views presented here are those of the authors and should not be understood or quoted as being made on behalf of the European Medicines Evaluation Agency or its scientific committees.
Competing interests In the last five years VB has received fees for speaking from Schwarz Italia SpA and Instrumentation Laboratory, and for scientific advice from SmithKline Beecham and Aventis Pharma.