READING PASSAGE 3
You should spend about 20 minutes on Questions 28-40, which are based on Reading Passage 3 below.
CLINICAL TRIALS
A. The benefits of vitamins to our well-being are now familiar to most; however, when the link between diets lacking in citrus fruits and the development of the affliction ‘scurvy’ in sailors was first discovered by James Lind in 1747, the concept of vitamins was yet to be discovered. Scurvy, which causes softening of the gums, oral bleeding and, in extreme cases, tooth loss, is now known to present as a result of lack of Vitamin C in the diet. Additional symptoms include depression, liver spots on the skin – particularly arms and legs – loss of colour in the face and partial immobility; high incidence of the ailment aboard ships took an enormous toll on the crew’s ability to complete essential tasks while at sea.
B. Suggestions that citrus fruit may lower the incidence or indeed prevent scurvy had been made as early as 1600. It was Lind, however, who would conduct the first clinical trial by studying the effect within scientific experimental parameters. However, while the correlation between consuming citrus fruit and avoidance of scurvy was established, the preventative properties were attributed to the presence of acids in the fruit and not what would later be identified as vitamin content.
C. Lind’s subjects for his trial consisted of twelve sailors already exhibiting symptoms of scurvy. These individuals were split into six groups; each pair common diet. Pair 1 were rationed a daily quart of cider, pair 2 elixir of vitriol, pair 3 a given quantity of vinegar, pair 4 seawater, pair 5 oranges and a lemon and pair 6 barley water. Despite the trial having to be aborted after day five, when supplies of fruit were depleted, the findings of the interventional study showed that only the control group who were given fruit supplements showed any significant improvement in their condition (one had, in fact, recovered to the extent that he was fit enough to return to work). The immediate impact on sailors’ health and incidence of scurvy on board ship was, however, limited as Lind and other physicians remained convinced that the curative effect was acid based. Therefore, while consumption of citrus fruit was recommended, it was often replaced by cheaper acid supplements. The preventative Qualities of citrus fruit against scurvy were not truly recognised until 1800, though throughout the latter part of the 1700s, lemon juice was increasingly administered as a cure for sailors already afflicted.
D. Nowadays, the implementation of findings discovered in clinical trials into mainstream medicine remains an arduous and lengthy process and the clinical trials themselves represent only a small stage of the process of developing a new drug from research stage to launch in the marketplace. On average, for every thousand drugs conceived, only one of the thousand actually makes it to the stage of clinical trial, other projects being abandoned for a variety of reasons. Stages which need to be fulfilled prior to clinical trial – where the treatment is actually tested on human subjects -include discovery, purification, characterisation and laboratory testing.
E. A new pharmaceutical for treatment of a disease such as cancer typically takes a period of 6 years or more before reaching the stage of clinical trial. Since legislation requires subjects participating in such trials to be monitored for a considerable period of time so that side-effects and benefits can be assessed correctly, a further eight years typically passes between the stage of a drug entering clinical trial and being approved for general use. One of the greatest barriers to clinical trial procedures is availability of subjects willing to participate, Criteria for selection is rigorous and trials where subjects are required to be suffering from the disease in question, experience tremendous recruitment difficulties as individuals already vulnerable due to the effects of their condition, are often reluctant to potentially put their health at higher levels of risk.
F. Clinical trials are conducted in line with a strict protocol and the stages of a trial are generally defined by five distinct phases. A drug that is deemed safe and effective enough to reach the end of stage three is most often, at that point, approved for use in mainstream medicine. Phase 0 involves a first-in-human trial (usually conducted using a small population often to fifteen subjects) with the purpose of ascertaining that the drug’s effect is, in fact, the same as predicted in pre-clinical studies. If no concerns are raised, the drug then enters Phase 1 of trial where a modest selection (usually between twenty and eighty subjects) of usually healthy volunteers, is exposed to the drug. However, for HIV and cancer drugs, this stage is conducted using patients suffering from the condition in question. There are two main variations of Phase I testing, these being SAD (single ascending dose) and MAD (multiple ascending dose). The former involves a single administration of a drug at a pre-determined level to one group of subjects, and the second involves administration of a pre-determined sequence of dosages.
G. Phases 0 and 1 are geared towards establishing the safety of a pharmaceutical and once this has been confirmed, drugs pass into Phase II testing where, while safety continues to be monitored, the drug’s effectiveness is also assessed using a larger group of subjects, ranging from twenty up to three hundred. In some trials, Phase II is regarded as involving two sub-stages, in that Phase 11(a) may be concerned with establishing optimum dosage levels and Phase 11(b) to evaluate effectiveness. Phase III is the most expensive, time-consuming and complex stage of the trial process, often involving as many as 3000 patients. At this stage, a new drug’s effectiveness is rigorously tested and compared to that of the best of the existing alternatives already approved and in common use. Where research indicates that a pharmaceutical has passed all requirements of Phases 0, I, II and III, submissions to relevant regulatory and licensing bodies are then made.
H. The final phase of clinical testing, Phase IV, is conducted over a lengthy period of time post-launch for general usage. This stage is, in essence, a safety net which involves continued monitoring of the drug, its properties and side-effects through which any long term adverse reactions, which remained undetected in the pre-launch clinical testing time frame can be discovered. Identification of harmful effects at this stage, on occasion, has led to withdrawal of a drug from the market; for example, as was the case with cerivastin, a cholesterol-lowering drug, which was later found to have an adverse effect on muscle reaction which, on occasion, had fatal consequences.
