Planning and Design of Clinical Trials

Planning and Design of Clinical Trials: 1st Articulation

Clinical trials may be prophylactic or therapeutic. Prophylactic trials are performed in preventive medicine. The aim of a prophylactic trial is to assess the impact of a preventive treatment. A therapeutic trial is represented to compare a new treatment with the best of the current treatments. In a typical therapeutic trial, victims with indistinguishable characteristics are divided into 2 groups; first group is given the new treatment and the other, usually called the control, is given the current treatment. These patients are then observed over the same period of time to see which group does better. In a prophylactic trial, first group is given the prophylactic and the other is not. At the end of the study period, we investigate if the protected group has a lower incidence of the study period, we scrutinize if the protected group has a lower incidence of the specific disease than the unprotected. Thus, basic principles for prophylactic and therapeutic trials are resembling.

Before a clinical trial is conducted, the clinician must have in mind a main objective, to know how to prepare the plans, usually called a protocol outlining the design and methods of conducting the clinical try-outs, and know how many patients (sample size) are needed and how to allocate them to dissimilar treatments. The clinician should have an understanding of what randomisation is, what is the need for it, and how to use it as well as some knowledge of the statistical concepts used in the design and analysis of clinical trials. In the following sections, we attempt to provide such standard procedures.

History of Clinical Trials

1. From limited records, it is believed that typical ancient Egyptian treatments were a combination of ritual encouragement and mixtures of herbs and natural products. The Greeks believed that the therapy was intended to assist the natural powers of healing by exercises and diet. In the Middle Ages, when Arab tradesmen dominated the spice and drug trade, there were numerous pharmacologic demonstrations. Avicenna (980-1037) suggested, in his encyclopaedic Cannon, that in the trial of a remedy, it should be used in its natural state upon unexacting disease, that the two opposed cases should be observed, and that the time of action and of the reproducibility of the effects should be cautiously examined. He further suggested that the experiments must be done on a human body. These protocols imply the very modern approach of clinical trials but there seems to be no record of their detailed application.
2. During the sixteenth century, although Leonardo da Vinci (1451-1519) had developed the theory and practice of modern scientific experiments, therapeutic experiments were performed only unexpectedly. One such trial was forced upon Ambroise Pare (1510-1590) in 1537 after the capture of the castle of Villaine.  He treated the wound with boiling oil until he ran out of it. He then applied in its place a digestive made of egg yolks, oil of rose and turpentine: “I raised myself to visit them, when beyond my hope I found those to whom I had applied the digestive medicament feeling but little pain, their wounds were neither swollen nor inflamed, and having slept through the night. The others were very feverish with much pain and swelling on and around their wounds. Then I determined never again to burn thus so cruelly the poor wounded by arquebases” (Bull 1959, Packard 1925). During the seventeenth century there was a great growth of the application of scientific methods in physics, chemistry and biology. However, small-scale development was made in therapeutic trials except that practical men did learn from comparative observations. A well-known story was the first voyage of four ships to India by the East India Company in 1600. Only one of those ships, that of General James Lancaster, provided lemonade for its sailors. These sailors were almost free of scurvy while the others were very ill. Lemon juice was subsequently supplied to all their ships.
3. It was in the eighteenth century that the therapeutic trials began to be developed. An important early trial concerned the use of small pox inoculation. Maitland (1668-1748) and Lady Wartley-Montague persuaded King George I to permit a trial of six Newgate convicts in 1721. Their results were considered conclusive in favour of inoculation, and it became widely practiced. In 1747, a comparative trial of scurvy was conducted by a ship’s surgeon, James Lind (1716-1794). He randomly selected 12 patients with scurvy. The cases were as homogeneous as possible. They lay together in one place and had the same diet. Two of them had two oranges and one lemon every day, two a quarter of cider, two vinegar, two the tincture of vitriol, two a course of sea water and the remaining two an electuary. After six days, the two who had oranges and lemons were well enough to take care of the sick. The cider seemed to be of help; however, the other restoratives were not effective at all. Forty-eight years later, the British Navy began to supply lemon juice to all its ships.
4. Many medical schools and hospitals were founded in the eighteenth century. These institutes then carried out many therapeutic experiments. For example, William Withering (1741-1799), First Physician at the Birmingham General Hospital, conducted a comparatively large-scale study, involving 163 cases, of digitalis as a remedy for dropsy. In addition to the effectiveness of the drug, he also tried to establish the correct dosage. Other famous studies included those conducted by Jenner on vaccination and Pearson on syphilis treatment.
5. Statistical evaluation of clinical trials began in the nineteenth century. P.C.A. Louis (1787-1872) was one of the trailblazers in the application of statistics in the field of medicine. Experiment on animals also began in this century. The rapid growth of bacteriology led to trials of immunisation against rabies, therapeutic serum for diphtheria, and inoculation for typhoid fever. The population of patients involved in these trials increased considerably, for example, a test of diphtheria included 300 patients in France and a trial of typhoid fever had more than 11,000 fighters in India.
6. In the present century, the scientific study of therapeutic procedures has been greatly intensified by the two world wars, the increased number of facilities for their study in hospital, laboratory and research organisations and the great advances in bacteriology, organic chemistry, pharmacology, statistics, computer science and many other related fields. Numerous trials have been carried out for syphilis, diabetes, pneumonia, chronic cardiac disease, malaria, contagious hepatitis, cancer, AIDS and so on. Large-scale prophylactic trials of tetanus anti-serum, anti-typhoid and anti-cholera inoculations and so on, have been successful. One of the most well-known trials is that of penicillin by Abraham and associates. The many trials conducted by different investigators with and without control in infectious diseases and wounds with large and small group of patients confirmed the effectiveness of the drug. Another well-known trial was set up by the British Medical Research Council under the leadership of Sir Austin Bradford Hill in 1946 to evaluate streptomycin in the treatment of pulmonary tuberculosis. This was the first large-scale randomised clinical trial, and Hill was largely responsible for introducing modern statistics into medicine. Since then, clinical trials have become a common practice in medical research. Well-known clinical trials include those for Salk polio vaccine, the University Group Diabetes Program, the Beta Block Heart Attack Trial, the Hypertension Detection Program and Follow-up Program, the National Surgical Adjuvant Breast Project and many recent trials on AIDS. Today the planning, design and analysis of clinical trials often involve multiple disciplines, for example, medicine, biochemistry, immunology and biostatistics.

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