Pre-clinical Research

The research program consists of animal, ex vivo and in vitro experiments, carried out in accordance with the requirements laid down in detailed regulatory guidelines. A number of short-term animal studies must be carried out before the substance can first be tried in single doses in humans. The animal studies comprise: toxicology studies –the effects of large doses; pharmacology studies – the effects of the substance on how the body systems function; and pharmacokinetic studies – looking at how the substance is absorbed, distributed, metabolised and eliminated in the animal.

Longer duration animal toxicology studies must then be performed before multiple doses may be administered in humans, with increasing periods of exposure and a larger range of animals being studied as exposure in humans increases during clinical research.

Alongside the above animal pre-clinical studies, other studies are carried out e.g. mutagenicity studies (effects on chromosomes and on genetic processes), studies of effects on the foetus etc.

This rolling program of pre-clinical studies synchronises with the clinical study programme. At each step in the clinical trial program, there must first have been reassuring information from animal studies. However, even at the time of application for a marketing authoriztion, there may be ongoing long-term animal studies – usually carcinogenicity studies – the results of which may only become available after the product is on the market.

Clinical Research

The clinical trial program in humans can be considered as comprising four phases. In phase 1, generally involving up to about 100 subjects, there is study of the tolerability of increasing single doses of the drug and investigation of its pharmacology and pharmacokinetics. Phase 2, usually includes the first study of efficacy in patients with the disease and studies – commonly in a few hundred patients – to find a dose that is effective and well-tolerated. However, phase 1 studies may continue alongside phase 2 studies. Phase 3 potentially extends the studies into several thousand patients – although the average is around 1,500. The focus is on demonstrating efficacy and acceptable safety in the intended population. If the drug is to be used over long periods of time, there will be long-term studies. At the end of the program comes the assembly and submission of a registration dossier to regulatory authorities. This is the application for marketing authorisation (MAA in Europe, NDA in the US). The dossier is usually submitted electronically but 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. The clinical trials usually continue during the registration review period, and Phase 4 studies are set up after marketing.

Each step in the clinical research program is heavily regulated. Before first exposure in man, there is assessment by the regulatory authorities of all the animal and in vitro studies. Every trial thereafter has to be approved by the appropriate regulatory authorities –and separately by ethics committees in each country – based on summaries of the available evidence to date. All new relevant safety information arising from animal studies must be submitted to the authorities and the ethics committees during the clinical research program (and to the regulatory authorities if arising thereafter).

An investigator brochure summarising all knowledge to date about the safety and efficacy of the study drug is created by the company and updated at intervals. This is supplied to all investigators and to the ethics committees and regulators.

Serious, unexpected adverse reactions that occur during clinical trials and are suspected of being related to the study drug (SUSARs) must be submitted to the appropriate regulatory authorities within specified short time frames (expedited reports). They must also be notified to all investigators and to ethics committees. Each year during the course of the clinical trial program, annual reports (Annual Safety Reports in the EU, IND Annual reports in the US) including a summary and analysis of all the serious adverse events that have arisen during that period and all new safety findings from animal studies, as well as evaluations of benefit and risk, must be submitted to the regulatory authorities and ethics committees. All of these submissions are required by law and compliance by the companies is checked by a combination of internal company audit and regulatory authority inspection.

The review of safety in clinical trials pre-registration is performed throughout the clinical research program by R&D and pharmacovigilance departments within the sponsor companies. The conduct of the clinical trials is often contracted out to Contract Research Organizations (CROs) – but the responsibility for safety lies with the sponsor company. In addition, safety may be reviewed continuously by independent Drug Safety Monitoring Boards set up for specific studies.