How Medicines are developed in the European Union and how their safety is monitored.

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

How drugs are developed.

Once candidate molecules have been selected for 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.

Pre-clinical research

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.

Clinical research

Clinical trials in humans go through four phases:

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.

Phase 4: This is the post-marketing phase and any tests, trials or reviews once the marketing authorisation has been granted, are usually referred to as Phase 4 studies. These can be both interventional studies and observational studies looking at the pharmacoepidemiological statistics.

Every step and every part of every step in the clinical research program is heavily regulated. So prior to the drug first being tried in humans the regulatory authorities will carry out an assessment all the animal and in vitro studies. Every trial after this first assessment will have to be approved by the appropriate regulatory authorities and separately by ethics committees in each country. The assessments of the regulatory authorities will be based on summaries of the available evidence to date. All of the new relevant safety information from animal studies has to be submitted to the authorities and to the ethics committees during the clinical research program and if the results come through once marketing authorisation has been granted, the results must go to the regulatory authorities.

The pharmaceutical company then creates an investigator brochure which is a summary of all the knowledge about the drug, its safety, its efficacy and anything else known about the drug. The company must then keep this document updated at intervals and supply a copy to any investigators, ethics committees and regulators.

When unexpected serious adverse reactions occur during clinical trials that might have been related to the study drug (SUSARs), full details of them must be sent to the regulatory authorities within short time frames as set out in the various rules - these are called expedited reports. Comprehensive reports of these SUSARs also have to be sent to any investigators and to ethics committees working with the trial substance. Every year while the clinical trial program is running, annual reports (Annual Safety Reports in the EU, IND Annual reports in the US) which include a summary and analysis of all the serious adverse events that occurred during that period and any new safety findings from animal studies, as well as evaluations of benefit and risk, must be submitted to the regulatory authorities and ethics committees. The submission of these documents is required by law and companies are monitored to see if they are complying by a combination of internal company audit and regulatory authority inspection.

The Research and Development departments and Pharmacovigilance departments of sponsor companies will carry out the review of safety in clinical trials before registration. The trials are often run by Contract Research Organizations (CROs) - but responsibility for safety lies with the sponsor company. Safety may also be reviewed on an ongoing basis by independent Drug Safety Monitoring Boards which may be set up for specific studies.

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