This is a brief introduction to the complex environment in which are developed within the EU and how their safety is monitored. Most of the information can be applied generally across the world but the focus here is on the way it works in the UK and the European Union
Once candidate molecules have been selected for Pharmacovigilance course development they go through a program of pre-clinical and clinical research which will hopefully end in an application for marketing authorisation. The vast majority of molecules fail to complete the course: as few as 1 in 10,000 of the molecules entering the program will be suitable to pass the entire programme and reach the market.
Initially the molecules are tested in a research program of animal, ex vivo and in vitro experiments as required by the rules laid out in detailed regulatory guidelines. These guidelines demand that some short-term animal studies have to be carried out before the substance can be tested in single doses in humans. These animal studies comprise: toxicology studies – working out what are the effects of large doses; pharmacology studies – looking at the effects of the substance on how the body systems function; and pharmacokinetic studies – investigating how the substance is absorbed, distributed, metabolised and eliminated in animals.
The law then requires longer term animal toxicology studies to be carried out before multiple doses can be given to humans, lengthening the periods of exposure and using a larger range of animals as the exposure in humans increases during the clinical research.
In addition to and at the same time as the animal pre-clinical studies, other studies are carried out for example mutagenicity studies (looking at effects on chromosomes and on genetic processes), studies of the effects on the foetus etc. as well as extensive tests on tissue cultures, using computer modelling and other tests which don’t require a live organism.
The rolling program of pre-clinical studies will be synchronised with the clinical study program so that at every step in the clinical trial program, there will have been reassuring information from animal studies. In fact even when it comes to the time applying for a marketing authorisation, there may be ongoing long-term animal studies – usually cancer studies – whose results might only become available after the product is on the market.
Phase 1: This will usually consist of up to around 100 subjects, investigating the tolerability of increasing single doses of the drug and looking at its pharmacology and pharmacokinetics.
Phase 2: This will usually include the first studies of efficacy in patients with the disease and studies – usually in a few hundred patients – to find a dose that is both effective and well-tolerated. Phase 1 studies sometimes continue concurrently alongside phase 2 studies.
Phase 3: This will usually be an extension to the testing into 1,500 patients though it can include up to several thousand. Here the focus is to demonstrate the efficacy of the product as well as showing acceptable safety in the population that will be using the drug. Where a drug will be given for long periods of time, long-term studies will be carried out. When this program finishes, the registration dossier is assembled and submitted to regulatory authorities. The registration dossier is called the application for marketing authorisation (MAA in Europe, NDA in the US) and is usually submitted electronically. The paper copy of the pharmaceutical, pre-clinical and clinical files often comprises many hundreds of volumes of data, each volume comprising several hundred pages. During the registration review period the clinical trials will usually continue.