The mainstays of cancer therapy remain surgery and radiotherapy, both of which date from the 19th century but which have undergone a process of continual technical improvement, which is still ongoing. Drug treatments for cancer are comparatively much more recent. The first successful cancer drug therapy was the use of synthetic female hormones to treat prostate cancer in the 1940s. Successful curative chemotherapy really dates from the 1970s with the development of treatments for leukaemias and lymphomas (cancers of the bone marrow and lymphatic system), although interestingly, the chemicals on which these treatments are based were previously developed for more nefarious purposes (as we have seen, mustine, one of the first successful drugs in this area, is based on the active ingredient of mustard gas). The development of new treatments and the improvement of existing ones clearly require a process of research. Here, some of the ways in which research happens, will be described, in particular the differences between the rules for drugs and those for devices (such as radiotherapy machines) or techniques (surgery). These contracts will be explored in some detail, as there are important differences, with significant anomalies resulting. Here it will be focused mostly on where new treatments come from, but similar trial structures apply to testing existing treatments against each other or for research into techniques of symptom control.
The development process for new surgical and radiotherapy techniques differs significantly from that applying to drugs. Typically, a surgical improvement will be a small technical change (for example, a better way to control bleeding) that does not fundamentally conceptually alter the underlying technique. Such improvements are often licensed essentially on a ‘fitness for purpose’ basis (that is, does it really help control bleeding?). Similar arguments apply to technical radiotherapy improvements (for example, better ways of targeting radiation to spare normal tissues). In general, it has been taken as self-evident that improvements of these sorts must be better and their implementation will follow. In fact, the improvements may be illusory and commercial pressure rather than any sound evidence base may drive their implementation. I will illustrate how and why this may arise, using robotic surgical techniques and intensity- modulated radiotherapy as examples.
Drug treatments, on the other hand, have to meet fundamentally different criteria. Generally, an improvement in survival rates compared to the previous standard of care is required by regulatory authorities such as the Food and Drug Administration (FDA) in the USA. This means a new drug treatment requires testing in a series of clinical trials involving large numbers of patients. Broadly, these can be divided into three categories termed phases 1 to 3.
Phase 1 trials establish the safety and side-effect profile of a drug. Typically, these will involve small numbers of patients, for cancer drugs usually those who have run out of standard options and who will have had multiple previous treatments. Drugs with less dramatic effects, for example blood pressure drugs, will often be tested first on healthy volunteers. Phase 2 trials are larger and will often involve patients earlier in the ‘cancer journey’ than phase 1 studies, and they aim to confirm that a drug has useful activity against the target cancer. For a drug that looks promising, the final phase 3 trial will compare it with whatever is considered the standard of care. A phase 3 trial will involve many hundreds or even thousands of patients. There are a range of problems inherent in this design, ranging from consent and cost to legislative burdens. Phase 3 licensing trials are now almost always international affairs and have to comply with legislative frameworks from multiple countries, in particular the USA. The costs of such trials are enormous and explain the very high costs of new drugs – around $1 billion from synthesis to registration of a new cancer drug. The licensing process – which gives a company the lucrative right to market a drug or product – is tightly regulated by national or transnational bodies such as the FDA. The high level of trial regulation protects the individual participant in a trial from possible harm at the expense of society at large by slowing the pace of improvement and driving up the costs of new drugs to the point when access is increasingly restricted, even in the wealthiest of economies.