Clinical trials are formal medical tests of a drug in a clinical setting, such as a hospital, to monitor a drug’s safety profile and effects in humans. Performed under strict regulatory and ethical guidelines, clinical trials form the majority of a drug development program’s time and cost and can involve thousands of patients over many years. The goal of any clinical trial is to determine a drug’s effects on the human body, based on a set of scientific parameters determined prior to the trial, with specific goals established for each ‘phase’ of the clinical trial process. Should a drug prove both safe and effective in clinical trials, a drug developer will then seek approval to sell the drug from regulatory agencies, such as the US Food and Drug Administration (FDA) or European Medicines Agency (EMA).
Once a drug is identified as having therapeutic potential through research or discovery, preclinical trials are undertaken. These trials focus on examining the drug’s toxicity, which organs are targeted and aim to discover the drug’s ultimate safety profile.
There are then three phases of human clinical trials prior to a drug's approval under a Marketing Authorisation Application (Phases I-III) and one phase which normally commences when a drug is approved and available (Phase IV). During Phase I the focus is on safety as the optimal dosing and delivery method are explored and refined. A key area of exploration during Phase II trials is discovering and quantifying a drug’s ‘efficacy’ (effectiveness) in treating a condition; normally in a small patient population. Phase III trials confirm this data, further understanding and seek to confirm evidence of efficacy in larger patient populations. Phase IV studies monitor a drug’s ongoing safety and efficacy over extended periods of time, generally at the request of a regulatory agency.
The success, or otherwise, of a drug hinges on the results gathered from these clinical trials and subsequent analysis and research.
Phase I Trials
Phase I trials are carried out on healthy volunteers and are primarily focused on further exploring a drug’s potential toxicity and tolerability in humans. Alongside this are extensive PK and PD studies. These trials normally consist of a small number of healthy volunteers (20-100) and usually include studies on ways of administering the substance, dose ranging, or dose escalation, where the different amounts of the drug are administered to help ascertain the optimum balance of effectiveness versus adverse events (side effects).
If the drug is proved safe and well tolerated in phase I, the drug will progress to phase II trials where the focus is on the substance's ‘activity’. This phase traditionally consists of 100-1000 patients and has a maximum trial length of two years. Patient numbers will vary, however, according to the rarity of the indication being studied in the trial.
Phase II Trials
Phase II trials involve assessing the activity of a drug on patients suffering from a specific disease or disorder (indication) where the clinical trial may lead to scientific evidence that a drug is effective in preventing, treating or curing a condition, without posing an unacceptable risk to the patient population. During this phase adverse events are monitored and optimal dosages are assessed.
Phase II is often the point at which many drugs fail to meet clinical trial endpoints, as they prove to be ineffective for the chosen indication or the treatment is discovered to be impractical or inefficient. If a drug shows that it is effective in treating an indication, it will progress to phase III.
Phase III Trials
Phase III trials aim to provide a definitive study of a drug and, if there is an existing treatment for the indication, to prove that the new treatment is its equal or better. The primary focus is on a drug’s efficacy and the gathering of statistical proof of this, while continuing to monitor safety. These trials can involve between 1000 and 5000 patients and run for up to several years.
Phase IV Trials
Phase IV trials are carried out after authorisation has been granted by a regulator and a drug is on the market; often Phase IV trials are a requirement of a drug’s approval. Their role is to monitor a drug’s safety and efficacy over a longer time period and with a broader group of patients than can be included in clinical trials prior to approval of the drug.