2 Clinical Trials At this point a decision is needed as to whether to take the candidate forward into clinical development , where the costs will again rapidly escalate still further. Although informed by advice from the scientific team, this is primarily a commercial decision. In parallel with the scientific activities, a considerable amount of additional work will have been undertaken to assess the commercial potential of the candidate. Have any negative indications appeared during the pre-clinical development? How good is the drug at meeting the medical criteria? Are there any significant remaining challenges in formulation or manufacturing? How secure is the intellectual property? What is the current competitive situation? What is known about future competition? How large is the target market? And crucially, what is the likely sale price, etc. etc .? Provided that these questions can be answered satisfactorily, the candidate then moves on to the first phase of clinical trials. Clinical trials take place in four distinct phases, the first three before the drug is marketed and the fourth phase begins when the pharmaceutical is prescribed for the first time and continues for the lifetime of the product. Clinical trials are intended to provide answers to two essential questions in the development of a new drug: (a) does the drug work? and (b) if it does, is it safe for the patent to take? However, in many cases, even at the large scale that some of these trials are undertaken, the answer to these questions may not be clear-cut. Many people assume that in a clinical trial all (or at least a majority) of the patients given the treatment will get better, but this is a rare occurrence. We know that not all patients react in the same way to a drug, although we rarely know precisely why. One example where we do know the reason is the breast cancer drug trastuzumab (marketed as herceptin), 58 which only has beneficial effects in those patients with a specific gene; it is of no benefit to all the other s. Fortunately, this fact is known and there is a diagnostic test to identify those patients who will benefit. Otherwise we would be in the situation that pertains for many pharmaceuticals that they only work in some patients. For this reason, amongst many others, the results of a clinical trial usually require advanced statistical techniques for their interpretation. Clinical trials are also beset with a wide range of practical 59 and ethical 60 problems. Every trial must be approved by an ethics committee and all patients must give their prior informed consent to participate. In order to eliminate observer bias, in patients, administrators and doctors, all trials will be blinded ( i.e . the patients receiving medication will be unaware of whether they are part of the trial group or the control group ) and many trials are now double blind ( i.e . neither patient, nurse nor physician will be aware of this information). All clinical trials undertaken for the purpose of drug registration must be subject to good clinical practice (GCP) guidelines. 61 A candidate drug will take from six to ten years to complete the first three phases of clinical trials. The time taken is determined by the duration of the disease that is being treated and by the extended time that it can sometimes take to assemble sufficient patients for the trial. Phase 1 trials are to confirm that the results derived from the in silico , in vitro and in vivo trials in experimental animals are replicated in human subjects . Small numbers (10–15) of healthy human volunteers are exposed to very low amounts of the candidate drug for short periods under carefully controlled and monitored conditions. Data from the trial are compared with data from the pre-clinical studies to ensure that the drug is working as anticipated. These studies are “first time in man” experiments and, despite the care and preparation taken, the unexpected can happen. One of the best-known examples is the recognition that sildenafil, a drug under development by Pfizer to treat hypertension , subsequently marketed as viagra, had a notable impact on male erectile dysfunction . 62 However, in some rare cases the consequences can also be severely adverse. 63 If all has gone according to plan in Phase 1, Phase 2 trials can begin, the primary purpose of which is to establish whether the drug works, i.e. is it effective against the target disease? In addition, further information on pharmacodynamics and safety is collected. These trials are larger (100–300) and now involve patients with the illness concerned. In Phase 3 trials, the treatment is then given to much larger groups of patients (1000–3000) in order to confirm its effectiveness, monitor any side effects, compare it to commonly used treatments and collect information that will allow it to be used safely. Despite the vast amount of information that has been generated on the candidate drug before it enters its Phase 3 trials, many drugs fail at this point, with some analysts estimating the failure rate to be as high as 30%. This is the first time that the drug will have been given to a large number of patients and only now will low-frequency side effects begin to appear. Even a serious, potentially life-threatening, side effect that appears in less than 1 in 100 people will not have been identified previously. 64 In addition, the higher level of statistical power in the Phase 3 trial may also demonstrate that the drug has, in fact, little if any efficacy. 65 In fact, frequently the drug doesn’t work or works much less effectively than originally predicted or only works on a sub-set of the population. This information is itself immensely valuable in furthering our knowledge and without this detailed empirical evidence pharmacology would revert to merely anecdotal observation which, in turn, would ensure that future developments in pharmacology would be delayed. Failures of drug candidates at this late stage in the process are, of course, bad news for the business; by this point a very large amount of money, time and research effort will have been invested, all of which will have been to no avail. The impact on the morale of the research team should also not be forgotten; it is not unusual for a medicinal chemist , for example, to have spent his/her whole career in the industry and to have never worked on a successful product. As a consequence, the industry has devoted considerable efforts in the last few decades to address this problem of late-stage attrition. 66 The result is that more and more promising drug candidates are terminated early in the process, at the first sign of any potential problem, which history tells us may have led to the unnecessary elimination of many potentially successful drugs. For example, neither aspirin nor penicillin would have made it to the market under today's industry drug-development regimes. People are frequently surprised that drug development takes such a long time. Approximately 10 years is likely to elapse between the news media articles that “scientists have discovered a cure for X” and patients actually receiving the medication, even if the development is successful. The reason is that it actually takes this amount of time and the extensive clinical trial procedures involved to discover if the treatment will actually work. However, this raises ethical issues, particularly with life-threatening diseases where patients and their doctors are desperate to try any new treatment as soon as possible. This becomes a challenge when it seems clear from early trial data that the drug may have significant beneficial outcomes, but by the time a marketing authorisation is approved many potential patients will be dead. Consequently a number of regulatory programmes 67 now exist to provide “expanded access” or “compassionate access” to patients with serious or life-threatening conditions who do not meet the enrolment criteria for the clinical trial in progress when it is clear that patients may benefit from the treatment, that the therapy can be given safely outside the clinical trial setting, that no other alternative therapy is available, and the drug developer agrees to provide access to the drug. These programmes are, however, carefully managed so that the body of clinical trial data itself is not compromised. However, there is increasing demand for wider and more rapid access to unproven therapies where the need is severe. 68 A successful conclusion of the phase 3 trials enables the innovating company to assemble all the relevant data on the candidate drug for submission as an application for a marketing authorisation to the appropriate regulatory body, e.g . the Federal Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in the European Union. Assuming that the application is successful, the pharmaceutical, with its trade name, will be launched on the market and start to be prescribed to patients. It is at this point that phase 4 of the clinical trial process begins. Phase 4 relates to the on-going safety surveillance and technical support of the pharmaceutical. The safety surveillance, usually known as pharmacovigilance, is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the phase 1–3 clinical trials. In some instances pharmacovigilance regimes will be required by the regulator as part of the marketing authorisation; in other cases they will be being undertaken by the innovating company for further research into new applications for the pharmaceutical. It is relatively unusual for serious harmful effects to be discovered during these phase 4 trials but in some cases the data may result in a pharmaceutical being no longer sold, or restricted to certain uses. 69 The product will then continue to be sold at a high price until the innovator's patent expires, usually somewhere betw