Abstract and Introduction

Abstract

The development of new drugs for cancer is extremely complex and expensive, and poses ethical problems. In this article we will review issues in clinical trials for cancer drugs that will cast new light on the doctor-patient relationship and their interaction with industry, the health service, academic and administrative organizations. We show that the Declaration of Helsinki cannot be applied to cancer trials as it is currently written, that patients do not and perhaps cannot give fully informed consent to participate, and that the results of clinical trials do not translate into daily practice in a way that patients might expect.

Introduction

The choice of participants in clinical trials, particularly cancer trials, goes far beyond the confines of a simple relationship between doctor and patient, or investigator and trial subject. Drug development has become highly complex and regulated and, driven by the huge expense, has taken on a political, social and moral significance that transcends the rather simple, although often misunderstood, rules concerning confidentiality, informed consent and the protection of human subjects.

Clinical Trials in Cancer

The standard treatment modalities for patients with cancer include surgery, radiotherapy and cytotoxic chemotherapy. Cytotoxic agents have been supplemented by hormonal agents and in recent years by the newer biological therapies. However, conventional cytotoxic agents remain the mainstay of medical treatment. Cytotoxic drugs have significant toxicities, which chiefly affect proliferating cells such as those in the bone marrow, bowel and hair follicles. Therefore, the prevalent side effects of chemotherapy include myelosuppression, mucositis and alopecia, respectively. As some of the drugs in this class have mutagenic effects in addition to these acute toxicities, it would be inappropriate to test drugs in early clinical development in normal volunteers, as would be the case with novel drugs in other diseases. So, trials of new anticancer agents are normally carried out in patients with cancer. This fact highlights ethical and practical difficulties, and dilemmas that are of special interest.

Phase I Clinical Trials

Clinical trials in patients with cancer aim to evaluate and develop new treatments. The conventional strategy when taking a drug (or a combination of drugs) into patients for the first time is to conduct a phase I study to define the maximum tolerated dose, dose-limiting toxicity, other toxicities and the pharmacokinetics of the agent (Fig. 1). Conventionally this means that a group of patients who have no other therapeutic option is enrolled and treated with a low dose of a drug. After all, it would only be ethically acceptable and legally prudent to expose patients to the risks involved in trials of new cancer drugs if it is clear that they have literally nothing to lose in terms of both toxicity and low efficacy^[1,2].

Figure 1. 

Structure of phase I, II and III clinical trials.

Typically, patients entering phase I trials have to be fit, and entry criteria dictate that their vital organs function within or close to normal parameters. Although these patients are often desperate to enter clinical trials despite any risks to themselves, the aim of the trial is to establish the toxicity of the drug, not to test its efficacy; hence the requirement for normal organ function. These very strict eligibility criteria for phase I trials can therefore be very frustrating for patients who have no other treatments but who might be found to have an abnormal blood test result that precludes entry into the trial.

If the first cohort of patients tolerates the dose, then a further cohort is recruited and treated with a higher dose^[3] and so on until a toxicity occurs that precludes further dose escalation. This strategy identifies the maximum tolerated dose and the schedule that can then be used for further studies. Therefore, the aim of a phase I trial is to identify the best initial dose of the new compound, not to assess the efficacy of the drug. In principle, decisions to proceed with further drug development should not be made on the basis of the anti-tumour activity seen in phase I clinical trials, as the main purpose of the trial is to identify a suitable regimen for testing in phase II trials. Of course, if worrying toxicity is seen this would impact on further development.

The ethical challenges that arise in phase I trials stem from the lack of experience with the trial drug. As neither the correct dose nor the optimum schedule of a new drug are known, most patients in a phase I clinical trial will not benefit from taking part as they will be treated with sub-therapeutic doses of the drug. In keeping with this, recent data have indicated that only 4.4% of patients who participate in single-drug phase I clinical trials achieve a partial response, whereas 17.8% of those taking part in phase I trials of combinations of drugs attain a partial response^[2]. So, of all therapeutic clinical trials in cancer medicine, phase I trials require the greatest altruism from the patient. Although the information sheet explains that the patient is unlikely to benefit from the treatment, there is nearly always disappointment when the post-treatment scan shows that their disease has not responded. This raises issues about the genuineness of consent and also about the basis of the 'contract' between patient and researcher^[4,5]. In short, are researchers trading on the real but unrealistic hopes of patients?

Changes in clinical trial design have been proposed to minimize the number of patients receiving sub-therapeutic doses of drugs. For instance, investigators have either accelerated the dose-escalation strategy or recruited a single patient in each dose level^[1] until toxicity occurs, following which larger numbers are entered at each dose level. Other proposals include extending the dose-optimization process into subsequent phase II and III trials, as a less-heavily pre-treated population take part in the latter^[6]. In a more extreme situation, encountered when evaluating classes of drugs that have been extensively studied in the past (for example, monoclonal antibodies), the first patient could be treated at a dose that is likely to be at or near the finally accepted dose^[7]. However, the disadvantage of these accelerated approaches is that the phase I trial is the principal arena for studying the relationship between the dose of a drug and its pharmacokinetics, and this opportunity might be lost if only one patient is entered in each dose level.

Many modern anticancer drugs are being developed with a defined molecular target in mind — for instance, receptor-kinase inhibitors. It would therefore be logical to focus early clinical trial design on biomarker endpoints — for instance, either by measuring the impact that the drug has on the target mechanism or selecting patients on the basis of a molecular pathology of the tumour and then using that as the endpoint in phase I trials. However, to date, these pharmaco-dynamic endpoints remain unproven in comparison with traditional endpoints because of laboratory methodological issues^[8], a lack of crucial reagents (for example, specific and validated anti-phospho-VEGFR2 (vascular endothelial growth factor receptor 2) antibodies) and because of our lack of understanding of the relationship between the measured parameter (for example, phosphorylated VEGFR2) and clinical outcome. These are clearly crucial issues that are of great importance and need to be addressed in the next few years^[9]. Nevertheless, toxicity will remain as a primary endpoint even with biological or targeted agents, as emphasized, for instance, by the cardiac toxicity observed with trastuzumab (Herceptin).

Phase II Clinical Trials

Once a suitable dose and schedule have been identified, the efficacy of the drug is investigated in a phase II clinical trial in which a cohort of approximately 25-50 patients is treated with the new drug. The aim of this trial is to assess the anti-tumour activity of the new compound or combination of drugs. This is normally achieved by using clinical and radiological assessments to determine if there has been tumour shrinkage in at least a small proportion of patients.

A different group of patients enter phase II trials. Whereas the principal aims of phase I trials are to determine the toxi-cities and pharmacokinetics so that an optimum dose and schedule can be chosen for a new drug, phase II trials are designed to assess anti-tumour activity. In view of this, patients entering phase I trials have no other therapeutic options and can have a variety of different diagnoses, so long as vital organ function is preserved. In a phase II trial the patients will have a specific disease — for example, breast cancer — and will have received only one or two previous treatments for advanced disease before entering the trial; the rationale being that if the patients have had a large amount of treatment, no anti-tumour activity will be seen.

Phase III Trials

The main endpoint of a phase II trial is response rate. Arguably, however, this is not a useful endpoint for a patient, who is most interested in whether he or she is going to live longer as a result of the new treatment. This can only be assessed in an adequately powered phase III randomized clinical trial, in which standard treatments are compared with a new regimen. Usually, these trials involve many hundreds of patients and are therefore extremely expensive. The most common endpoints in phase III trials are either the progression-free interval — the time from starting the treatment until the point of disease progression — or the overall survival, which is measured from the start of treatment. Phase III trials are the principal method by which a new treatment's efficacy can be assessed and are the basis on which regulatory authorities approve drugs and health services around the world adopt new treatments ( Box 1 ).

The entry criteria for phase III studies will be relatively more relaxed than those for a phase II trial and much more relaxed than the criteria for entering a phase I study. So, the progression of a drug from phase I to phase III clinical trial reflects the increasing use of a particular drug in a more usual clinical setting. Patients who enter phase III clinical trials have received a lot less treatment than patients entering phase II trials. Phase III clinical trials usually enroll patients who require first- or second-line (therapy for recurrent disease) treatment. This is because the treatments have already demonstrated some anti-tumour activity in earlier phase II clinical trials and it is therefore deemed acceptable to allocate a patient randomly to either conventional treatment or the new treatment. Nevertheless, entry criteria are still required for phase III trials such that survival statistics for patients treated outside of a clinical trial, in which selection criteria are not applied, are likely to be worse than those presented as the results of the phase III trial. One of the principal explanations for this is that patients entering clinical trials are generally fit, whereas outside of a clinical trial all patients, including those who are very unwell, will be treated. This difference in survival between patients who enter phase III clinical trials and the entire clinical population might account for the frequently cited advantage in terms of survival for patients entering clinical trials^[10].

In early phase III clinical trials that test a new treatment we ask patients with a particular disease to enter the study and, in general, we recruit patients with advanced disease to these trials so that we can identify efficacy (progression-free and overall survival) within a few years of starting the trial. Once a new regimen has been proven in patients with advanced disease, the same treatment will be tested in early cancer — for example, in patients who undergo breast surgery followed by the systemic (in this situation called adjuvant) drug therapy for a small breast cancer — in which endpoints such as an increase in overall survival will take many more years to become apparent.

One of the most significant changes in oncology is the understanding of the molecular basis of cancer and the way that these molecular differences determine whether a patient's disease will respond to a particular therapy. This has been elegantly exemplified in chronic myeloid leukaemia, which is characterized by a genetic mutation that can be targeted specifically^[11], and in breast cancer in which the cell-surface expression of the ERBB2 protein correlates with response to trastuzumab^[12]. However, the relationship between molecular pathology and response to treatment is not always clear cut. Had we assumed that expression of the EGF receptor (EGFR) would predict response to EGFR-tyrosine-kinase inhibitors in patients with lung cancer, this would have been incorrect. Recent data have indicated that a combination of patient demographic details, receptor mutations and receptor copy number are associated with response to this class of drug^[13].

These issues are of huge importance for clinical trials: unless the molecular pathophysiology is understood, the entry criteria for a clinical trial might be so broad — for example, recruiting all patients with lung cancer when only a distinct subset of patients' tumours expressed the molecular mutations that predicted response — that the phase III trial results are negative. This raises several problems, such as the false rejection of an effective drug; the massive physical, emotional and financial expense involved in phase III clinical trials; or, conversely, the exclusion of patients who consent to enter a trial but who are subsequently rejected because their tumours do not harbour the correct molecular abnormalities.

Deciding Whether to Participate

Consent

A principle of modern cancer research (indeed, all medical research) is that patients should give informed consent to enter into clinical trials^[14,15,16], a process that is designed to limit deception and coercion and to protect the liberty and autonomy of the subject. When we test new compounds in phase I clinical trials, particularly when we take compounds into patients for the first time, there are often large numbers of monitoring tests to assess eligibility and progress throughout the trial and during follow-up. These include the traditional measures of medical history and physical examination, but in addition we often take multiple blood tests and perform multiple scans, including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. In some protocols, patients also undergo multiple biopsies as well. Because of the complexity of these investigations, the need to explain why we are performing the tests and the potential complications of each test, the information sheets for these trials can be several pages long and we know that there is a limit to the amount of information that a patient entering a phase I clinical trial can retain^[17]. The problems with informed consent arise for a number of reasons, including an overestimation of the patient's reading skills^[18] or because of assumed understanding of concepts that are familiar to healthcare workers, such as percentage figures^[19]. Difficulties with understanding increase anxiety and regret^[20] that can be alleviated through simpler information sheets^[21]. As current data indicate that most participants in clinical trials do not appreciate the unproven nature of the experimental treatment and the increased risk incurred, whereas a quarter of participants do not appreciate the altruistic nature of trial participation, we clearly need to improve standard consent procedures^[22]. This raises issues both about the adequacy of information and indeed as to whether informed consent remains the appropriate 'gold standard' for consent.

Abandoning Informed Consent

We are so used to talking about 'informed' consent that we forget it is a highly artificial, technical term arising from a combination of ethical argument and concern over legal liability. Informed consent is required when the validity of consent is conditional on the prior provision of full disclosure of anything that might be considered material to the patient's decision. There is however also the possibility of 'simple consent' in which the patient agrees in an open ended way to a set of procedures, possibly on the basis of trust and/or self interest rather than full information. For instance, a patient might agree to take part in a trial agreeing that multiple scans are required but not necessarily being informed of or understanding the differences between CT, MRI and PET scans. Often, what is called informed consent is in reality a more or less simple consent^[23]. Arguably this fact alone would not vitiate the consent so long as the patient was aware of the difference, with a real option to insist on full information if he or she chooses.

Moving to Simple Consent in the Presence of Full Information

It is important that clear and full information is supplied and that patients have the opportunity to consider that information and ask questions about it if they choose to do so before they give consent. It is perhaps less important that the consent is actually informed (based on full consideration and understanding of the information). After all, how much information an individual chooses to consider is a personal decision, and it is a matter of individual difference how much any particular person can actually consider and comprehend. There is a middle way between fully informed consent and simple consent. Rather than continuing with what is increasingly obvious to be a fiction — that fully informed consent has been obtained — we should perhaps move to a consent protocol that is basically simple consent in the presence of full information. This is effectively what happens at the moment, but recognizing and accepting this fact, as with most other open and honest admissions of the truth, would be an improvement on existing practice. We recommend a constructive addition to the consent protocol — the addition of a summary paragraph to each information sheet, which would allow the patient to focus on that alone if they choose.

The development of new drugs is now an international business. Drugs that have been developed in one country are often being tested in another. This issue highlights cultural differences in the consent process. For example, patients are often unaware that all compounds have been tested on animals before the clinical trial, and some might not wish to be party to animal testing. Similarly, some administrations will require patient information sheets to describe all possible toxicities, including, in some cases, acceptance by the patient that they might die as a result of taking part in the clinical trial. Although some research ethics committees have found this unacceptable, most patients do not decline to participate on this basis. Nevertheless, it raises profound issues about the authenticity of consent and the degree of risk to which it is reasonable to subject patients or to which they might reasonably consent. In normal circumstances it would rightly be considered unacceptable to ask a patient to risk death to further medical research, and any consent to such a proposal would be highly suspect ( Box 2 ). However, these cancer trials are far from normal because of the toxicity of the agents concerned and the short life-expectancy of the trial subjects.

Consent and Confidentiality

A large number of individuals and organizations are involved in drug development. Such wide involvement raises issues for confidentiality and privacy as well as possible conflicts of interest that affect research subjects.

The development of new compounds is now particularly complex, with large numbers of regulatory bodies overseeing the process. Whereas the traditional management of cancer treatment fell to the doctor, nurses and the patient, we now involve governmental agencies that can be national or international, local ethics committees, pharmaceutical companies and hospital research-management committees, creating close relationships that have been heavily criticized^[24]. The involvement of industry is particularly common now in early phase I clinical trials, as pharmaceutical and biotech companies are very anxious that a new drug is not associated with a toxicity that occurred because the patient was unwell at the time of entry into the study. Patients usually expect that their personal information will be confined to a small group of professionals committed to their personal care. Because this cannot be the case in trials of this complexity, it is important to make clear to patients that these expectations cannot be met in trials such as these, although all parties are bound by confidentiality agreements. This fact itself constitutes an important legal and ethical dimension of cancer trials.

Consent and Cooperative Groups

The aim of clinical trials is to improve the treatment of patients. Because of the numbers of patients needed for clinical trials, particularly phase III trials, large cooperative groups have been formed that regulate national or international trials. These have greatly increased the numbers of patients taking part in clinical cancer trials by encouraging multiple centres to participate, particularly in phase III randomized studies, thereby identifying effective treatments earlier.

There are additional benefits for the organization and its staff who run the studies. From the principal investigator through to the national and/or disease-centric organizations, their career progression and indeed their jobs are supported by the completion and reporting of successful clinical trials. This might result in a conflict of interest in that an investigator has an interest in a positive result that will be published in a higher-impact journal. Because the doctors and nurses who are informing a patient about a trial have a vested interest in recruitment and a successful trial, they cannot be considered impartial or as necessarily the best advocates for their patients. Hence the importance of phase III randomized trials that should remove a physician's bias. Because of the nature of the drugs and side-effects involved, placebo-controlled studies are difficult to conduct in cancer medicine. So, even if they don't officially know, investigators can often make an educated guess as to which drug a patient is taking, based on what they know about the side effects of the standard treatment with which the new drug is being compared. A worrying consequence of this has been highlighted recently in a report^[25] that describes physicians acting in some cases as paid advisers to investment companies, increasing the chances that confidential and premature clinical trial information is released to investors. It must be stressed that whatever the chosen method, clinicians have a clear obligation of transparency over pertinent conflicts of interest both to the patient and to the professional community.

Patients' Families

It is easily forgotten that participation by a patient in a clinical trial inevitably involves the patient's family and/or their carers. The involvement is not only physical, in that the family have to take the patient to and from their clinic appointments and investigations, but also emotional. How should a carer advise a patient taking part in the clinical trial? If a patient has run out of conventional therapeutic options, are they best served by taking part in a phase I clinical trial where they will be in or visiting a hospital for a significant proportion of their remaining time, or should they be at home with their families? Although these are pertinent questions, it is surely for the patient to decide whether or not both their interests and their autonomous choices are best served, for example, by spending their last days prioritizing the value of family and home or by equally altruistically prioritizing the possible help they might be to strangers in a similar plight to themselves. It is tempting to press the question: how much altruism is it reasonable to ask of or expect from patients? They surely do not take part in trials because it is expected of them, but rather because they choose to participate.

We should also ask how conflicts between the best interests of patients, the interests of science and the interests of relatives are to be resolved. This seems a complicated question, but the answer is straightforward. Although it is obvious that the interests of patients and those of science are often congruent, the only way that vulnerable patients can be protected is by ensuring that it is the patients who have the clear and final say. As the relatives of patients only get into the equation 'on the back' of their relationship with the patients, and because it is clearly unacceptable that they should pursue their own interests at the expense of their vulnerable relatives, ultimately family and carers have no privileged place in decision making unless they are granted that place by the patients.

Society

Patients participate in clinical trials not only for their own benefit but also for the benefit of others, both present and future, in society. Clearly, they would want the results of the trial to influence current practice as soon as possible, but this process can be protracted. In the United Kingdom, following the licensing of a drug by the licensing authority (the Medicines and Healthcare Products Regulatory Agency (MHRA)), the introduction of new treatments is overseen by the National Institute for Clinical Excellence (NICE). Typically, phase III results are presented at international conferences (for example, bevacizumab results were presented in 2003 (Ref. 26)) a year before they are published in peer-reviewed journals^[27] and these publications are reviewed by NICE a year or more later (bevacizumab appraisal in the United Kingdom expected November 2006: see the NICE bevacizumab & cetuximab appraisal web page). Bevacizumab (Avastin) was approved by the Food and Drug Administration (FDA) in the United States in February 2004, at which point it was generally available in the United States. Although already licensed in the United Kingdom, the crucial requirement for NICE approval means that, according to NICE's own forecast, the drug will, if approved, only be generally available through the National Health Service 2 and a half years later than the United States. So, if a patient participates in a clinical trial with the aim of benefiting society, the results of the study might be available within 2 years of the patient taking part, but there might be another 2-year interval before those results influence the standard of care. One of the principal purposes of NICE is to ensure the cost-effectiveness of treatments. However, if effective treatments are not made swiftly available, the costs of delayed effectiveness might be greater than the savings to society that accrue from delayed implementation of costly treatments. There are many sorts of costs here, and the cost of delay in terms of human misery and postponed benefit are borne by the patients and not by society or NICE. In the 2 years or so that it often takes for drugs that are available elsewhere in the world to be approved by NICE, patients continue to suffer and many die before treatments that might have helped them are approved. These are also real costs that must be taken into account, and they are also real measures of effectiveness. If one were to attempt to measure the cost-effectiveness of gatekeeping measures in healthcare systems worldwide, the effects and costs of delayed introduction of therapies are an important, but so far unrecorded, part of the overall cost-benefit equation.

Although it might be true that society cannot afford all new drugs that show small benefits, the question of how to ration healthcare is not a question of cost-effectiveness at all. It is a question of justice, of how to show equal concern, respect and protection in the provision of healthcare to all who can derive benefit from that care. There is no space here for a positive account of how to do justice in conditions of scarcity^[28]. However, when it is proposed to deny a patient access to a treatment that has been shown to have a small but significant benefit when the alternative is no treatment at all, then the justification of that denial cannot be a question of cost-effectiveness. In such circumstances, cost-effectiveness calculations that purport to apply to treatment actually apply to patients. What is effectively being said to the patient is that 'you are not worth treating at this cost', not 'this treatment is not cost-effective for society'. The circumstances in which it can be just or ethical to say to patients 'postponing your death for this amount of time or palliating your symptoms to this degree is just not worth it for society' are complex and depend on how the choice of which patients to treat is made and how the priority of their particular case is arrived at compared with others^[29,30].

What is clear is that such decisions are not a matter of cost-effectiveness. Also, because these are often life and death decisions, it is not a matter that can safely be left to bodies whose expertise lies principally in calculating cost-effectiveness^[31,32].

Furthermore, it will be important to consider how organizations such as NICE will respond to the potential of pharmaco-genetics to identify patients within a currently identified tumour group (for example, colon cancer) who require higher doses of a new (and expensive) drug than others. Identifying these patients will create genetic subgroups whose quality-adjusted life years (QALYs)^[29] are considered too expensive to justify treatment, whereas other patients suffering from the same disease are considered eligible for treatment.

Industry and the Health Service

The development of new drugs has become very expensive, and recent estimates indicate that a marketed drug costs 1 billion US$ to develop. In view of this, drug development has become increasingly reliant on pharmaceutical companies. Although the aims of pharmaceutical companies are to develop successful products, they are businesses that have to make a profit that they can return to investors^[24]. For smaller biotech companies the aim will be to develop a drug sufficiently so that either the compound attracts further venture capital to the company or the drug/company is sold to a larger pharmaceutical company. The impact of this is crucial for clinical trials. For instance, clinical trials are usually conducted in diseases that present a large market potential, in countries that will buy significant amounts of the drug. This raises additional complexity, as new drugs such as gefitinib (Iressa) seem to have greater activity in Japanese women than in patients in the West^[33]. So, the effects of market potential might obscure efficacy if patients with less drug-sensitive disease or diseases that are less prevalent (which therefore have a lower financial return) are not recruited. Whether the advent of pharmacogenetics will provide further information on the efficacy of particular drugs in different ethnic groups remains to be seen.

One might assume that all clinical research will be a drain on a hospital's resources (Fig. 1; Box 1 ). However, clinical trials are costed very carefully so that all expenses are covered. In the case of phase II and III clinical trials, being involved in a clinical trial, in which treatment is usually supplied free of charge, might benefit the hospital. In some cases this 'trial drug funding' has become relied on so that annual drug budgets take into account the provision of free drugs for patients. Therefore, the implication is that national health services are profiting from the clinical trials in their hospitals. This has been compounded by the introduction of overhead charges in which a host institution charges the pharmaceutical company for use of their facilities in excess of the reimbursement charges incurred because of, for example, the cost of CT scans. Typically, however, patients do not receive remuneration or overheads other than travel expenses incurred through participation. This creates potential conflicts of interest and raises questions, if informed consent is to remain the gold standard, as to whether patients should be privy to these elements of their role as trial subjects. Perhaps these are interests that should be part of a 'declaration of interests' made to patients and families.

Recently in Europe, a clinical trials directive^[34] has been introduced that governs the conduct of all clinical trials. Although this has greatly improved clinical trials by raising standards in terms of trial construction, monitoring and review, it has also impacted on investigator-led studies, arguably limiting the effectiveness of British and European science. This is because the directive has mandated that all clinical trials require a sponsor, that full details of all drugs are submitted to regulatory authorities and that the trials are monitored up to the standards of company-sponsored clinical trials. This is a significant administrative and financial burden for investigators to bear. This could particularly hinder the conduction of trials in rare diseases, children or other vulnerable groups, which do not attract the attention of the pharmaceutical industry.

Conclusion

We have shown that drug development has become a complex, multi-organization based, financially orientated business. Recruitment of patients into cancer trials is exceptional because of the special features, vulnerabilities and needs of the population involved. Conflicts of interest are complicated and multilayered, making them difficult to resolve in ways that are easily understood by patients. It is difficult to apply conventionally understood standards of consent and confidentiality, and patients should be given the option for a simplified or full consent. Full compliance with the Declaration of Helsinki ( Box 2 ) and other international standards, particularly with regard to informed consent and with regard to the acceptable balance of risk and benefit, have become problematic. It is time to consider whether informed consent remains the gold standard, as at the moment it is difficult if not impossible to achieve. Finally, the cost and complexity of drug development mean that certain vulnerable groups that are defined genetically, pathologically, economically or geographically are excluded from clinical trials: this is unacceptable and is being addressed through national and international cooperative groups.

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Sidebar: Databases and Further Information

Databases

The following terms in this article are linked online to:

Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
EGFR | ERBB2 | VEGFR2

National Cancer Institute: http://www.cancer.gov
breast cancer | chronic myeloid leukaemia | colon cancer | lung cancer

Further Information

NICE bevacizumab & cetuximab appraisal: http://www.nice.org.uk/page.aspx?o=217702

WMA Declaration of Helsinki Policy: http://www.wma.net/e/policy/b3.htm

Correspondence to: G.J.
email: Gordon.Jayson@christie-tr.nwest.nhs.uk