| How Medicines are developed in the European Union | | | | testing into 1,500 patients though it can include up to |
| and how their safety is monitored. | | | | several thousand. Here the focus is to demonstrate |
| This is a brief introduction to the complex | | | | the efficacy of the product as well as showing |
| environment in which are developed within the EU | | | | acceptable safety in the population that will be using |
| and how their safety is monitored. Most of the | | | | the drug. Where a drug will be given for long periods |
| information can be applied generally across the world | | | | of time, long-term studies will be carried out. When |
| but the focus here is on the way it works in the UK | | | | this program finishes, the registration dossier is |
| and the European Union | | | | assembled and submitted to regulatory authorities. |
| How drugs are developed. | | | | The registration dossier is called the application for |
| Once candidate molecules have been selected for | | | | marketing authorisation (MAA in Europe, NDA in the |
| development they go through a program of | | | | US) and is usually submitted electronically. The paper |
| pre-clinical and clinical research which will hopefully end | | | | copy of the pharmaceutical, pre-clinical and clinical files |
| in an application for marketing authorisation. The vast | | | | often comprises many hundreds of volumes of data, |
| majority of molecules fail to complete the course: as | | | | each volume comprising several hundred pages. |
| few as 1 in 10,000 of the molecules entering the | | | | During the registration review period the clinical trials |
| program will be suitable to pass the entire | | | | will usually continue. |
| programme and reach the market. | | | | Phase 4: This is the post-marketing phase and any |
| Pre-clinical research | | | | tests, trials or reviews once the marketing |
| Initially the molecules are tested in a research | | | | authorisation has been granted, are usually referred |
| program of animal, ex vivo and in vitro experiments | | | | to as Phase 4 studies. These can be both |
| as required by the rules laid out in detailed regulatory | | | | interventional studies and observational studies |
| guidelines. These guidelines demand that some | | | | looking at the pharmacoepidemiological statistics. |
| short-term animal studies have to be carried out | | | | Every step and every part of every step in the |
| before the substance can be tested in single doses in | | | | clinical research program is heavily regulated. So prior |
| humans. These animal studies comprise: toxicology | | | | to the drug first being tried in humans the regulatory |
| studies - working out what are the effects of large | | | | authorities will carry out an assessment all the animal |
| doses; pharmacology studies - looking at the effects | | | | and in vitro studies. Every trial after this first |
| of the substance on how the body systems function; | | | | assessment will have to be approved by the |
| and pharmacokinetic studies - investigating how the | | | | appropriate regulatory authorities and separately by |
| substance is absorbed, distributed, metabolised and | | | | ethics committees in each country. The assessments |
| eliminated in animals. | | | | of the regulatory authorities will be based on |
| The law then requires longer term animal toxicology | | | | summaries of the available evidence to date. All of |
| studies to be carried out before multiple doses can | | | | the new relevant safety information from animal |
| be given to humans, lengthening the periods of | | | | studies has to be submitted to the authorities and to |
| exposure and using a larger range of animals as the | | | | the ethics committees during the clinical research |
| exposure in humans increases during the clinical | | | | program and if the results come through once |
| research. | | | | marketing authorisation has been granted, the results |
| In addition to and at the same time as the animal | | | | must go to the regulatory authorities. |
| pre-clinical studies, other studies are carried out for | | | | The pharmaceutical company then creates an |
| example mutagenicity studies (looking at effects on | | | | investigator brochure which is a summary of all the |
| chromosomes and on genetic processes), studies of | | | | knowledge about the drug, its safety, its efficacy |
| the effects on the foetus etc. as well as extensive | | | | and anything else known about the drug. The |
| tests on tissue cultures, using computer modelling and | | | | company must then keep this document updated at |
| other tests which don't require a live organism. | | | | intervals and supply a copy to any investigators, |
| The rolling program of pre-clinical studies will be | | | | ethics committees and regulators. |
| synchronised with the clinical study program so that | | | | When unexpected serious adverse reactions occur |
| at every step in the clinical trial program, there will | | | | during clinical trials that might have been related to |
| have been reassuring information from animal studies. | | | | the study drug (SUSARs), full details of them must |
| In fact even when it comes to the time applying for | | | | be sent to the regulatory authorities within short time |
| a marketing authorisation, there may be ongoing | | | | frames as set out in the various rules - these are |
| long-term animal studies - usually cancer studies - | | | | called expedited reports. Comprehensive reports of |
| whose results might only become available after the | | | | these SUSARs also have to be sent to any |
| product is on the market. | | | | investigators and to ethics committees working with |
| Clinical research | | | | the trial substance. Every year while the clinical trial |
| Clinical trials in humans go through four phases: | | | | program is running, annual reports (Annual Safety |
| Phase 1: This will usually consist of up to around 100 | | | | Reports in the EU, IND Annual reports in the US) |
| subjects, investigating the tolerability of increasing | | | | which include a summary and analysis of all the |
| single doses of the drug and looking at its | | | | serious adverse events that occurred during that |
| pharmacology and pharmacokinetics. | | | | period and any new safety findings from animal |
| Phase 2: This will usually include the first studies of | | | | studies, as well as evaluations of benefit and risk, |
| efficacy in patients with the disease and studies - | | | | must be submitted to the regulatory authorities and |
| usually in a few hundred patients - to find a dose | | | | ethics committees. The submission of these |
| that is both effective and well-tolerated. Phase 1 | | | | documents is required by law and companies are |
| studies sometimes continue concurrently alongside | | | | monitored to see if they are complying by a |
| phase 2 studies. | | | | combination of internal company audit and regulatory |
| Phase 3: This will usually be an extension to the | | | | authority inspection. |