Clinical Trials Phases

Up until the 1960s, drugs could be sold without any detailed knowledge of their quality, safety or efficacy. Heroin was marketed as a “non addictive cough suppressant” at the beginning of the 20th century.  In 1937, the toxic medicine Sulfanilamide Elixir caused the deaths of more than 100 patients in the USA, and following this tragedy it became mandatory to perform some safety testing on animals and to obtain approval from the state before selling a new drug.

It wasn’t until after the thalidomide (Contergan) disaster of 1961, where more than 10,000 babies suffered severe birth defects, that higher scientific requirements for the approval of drugs became an international requirement to protect patients from inefficient or dangerous drugs. Today, laws not only require manufacturers to demonstrate safety in animal experiments, but also in tests with human volunteers (clinical trials).  Proof is required that a new drug has the desired therapeutic effect and that the benefits exceed the risks.

Despite the progress of medicine during the last century, there are still no effective treatments for many severe diseases.  In several therapeutic areas there is also a strong need for new or better medications e.g. oncology and dementia.  Clinical research conducted by both commercial and non-commercial organisations continues to strive to find new treatments for diseases, and in 2012 there were more than 134,000 clinical trials conducted globally.

Development of a new medicine can take up to 15 years and cost 1.5 billion dollars.  Only one in three new medicines reaching the market achieves sufficient sales to cover its development costs.  The chance of success in obtaining a marketing approval is dependent on the quality of the application, and consequently the quality of the clinical trials being submitted.

Clinical development traditionally follows four phases described below:

• Phase I – these are clinical trials conducted either in healthy volunteers or patient volunteers to obtain information on the drug’s pharmacokinetic and pharmacodynamic profiles, as well as determining a tolerable dose level.  They are also conducted to get initial information on safety.  Some of these trials involve the use of the product for the first time in man.  The trials are usually conducted in specialised phase I units with immediate access to emergency care and involve small numbers of volunteers for short periods of time. 
• Phase II –these are clinical trials conducted in patients with the disease for which the drug is being developed.   The objective of these studies is to obtain proof-of-concept, dose finding and initial safety information.  These trials are usually divided into two sub-phases: phase IIa trials are usually to assess dosing requirements, and phase IIb are usually designed to obtain efficacy information within the optimum dose range.  These trials may include several hundred patients, be of short duration, and involve close medical supervision
• Phase III – these are large clinical trials involving several hundred to thousands of patients with the target illness/disease.  The objective of phase III trials is to assess efficacy and safety in the normal clinical setting.  Additionally, these trials may be designed to prove superiority over standard treatments, or they may investigate the impact of concomitant medications or age on the efficacy and safety of the new drug, or look at the metabolism in patients with renal or hepatic dysfunction.  These trials are often of a long duration, especially for chronic illnesses
• Phase IV – these are trials which are conducted after the medicine has received marketing authorisation and can be prescribed for a specific disease.  These studies are used for the collection of long-term safety information, for the analysis of cost-benefit, treatment optimisation and the collection of epidemiological information.  Sometimes they are used to show a benefit over a competitor’s product

There are many different designs of clinical trials, but the most important trials are those that are double-blinded.  This means that neither the doctor nor the patient knows whether they are receiving the new medicine, a comparator (usually best available treatment) or a placebo (inert substance).  It is also usually the case that the sponsor organisation and all personnel involved in the trial, are unaware of what patients have been randomised to.  This ensures that the trials are conducted objectively and that there is no possibility of bias.

The conduct of clinical trials is heavily regulated to ensure patients are protected and that data integrity is assured.  In Europe, Directives 2001/20/EC and 2005/28/EC govern the conduct of clinical trials.  In the USA, 21 CFR parts 50, 54, 56 and 312 are the primary regulatory requirements. Over recent years each country where trials are conducted have developed and implemented their own regulations. 

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