Why medicines may fail in development
At each stage in the clinical development of new medicines, some compounds are discontinued. Phase 1 trials focus on how well a compound is tolerated and, as might be expected, almost half of the compounds dropped at this stage are discontinued because they were not tolerated well enough to be clinically useful. Phase 2 trials are mainly concerned with finding the best dose and looking for signs that it is effective as a treatment. Unacceptable side effects are a less common reason for stopping development at this stage; instead, the leading reason for discontinuation is that the medicine was not effective enough. Poor absorption, metabolism or unsuitable dosage form are also a significant reason for stopping development. Nevertheless, compounds that enter Phase 2 trials have a good chance (ca. 1 in 4 or 5) of eventually being approved.

In Phase 3 trials, the main focus is on establishing efficacy and safety as compared with existing treatments. Insufficient efficacy or an unfavourable safety profile remain the leading reasons for stopping development. Tolerability is still an issue at this stage because, as development progresses, a wider spectrum of patients is exposed to the compound, and this may show up effects not seen in smaller trials, or when the compound is given for a shorter period. The great majority of compounds that complete Phase 3 trials successfully are subsequently authorised for clinical use.

Trial results
When a trial has been completed, the investigators who organised it will want to publish the results in some way. The study organisers may also provide information to participants about the final results, although this is not automatic.

Under proposals drawn up by the world's major pharmaceutical industry trade associations and agreed by major companies, results of all industry-sponsored clinical trials on medicines that have received marketing authorisation, and which evaluate its safety and benefit, will be publicly disclosed via free, widely accessible databases, regardless of outcome. Also, details of all clinical trials being performed to determine a medicine's therapeutic benefit will be publicly registered at initiation so that patients and clinicians will have information about how to enrol. Both requirements were adopted by the worldwide pharmaceutical industry during 2005.

The results are published in a standard, non-promotional summary that includes a description of trial design and methodology, results of primary and secondary outcome measures described in the protocol, and safety results. However, if the results are also published in a peer-reviewed medical journal, the database will alternatively include a link to the relevant article and, in some cases, the summary as well. By publishing not just the results of trials that have taken place and also those that are just starting, a major step has been taken towards achieving greater transparency. The results should normally be published within one year after the medicine is authorised or, for post-authorisation trials, within one year of them being completed. Information is on the clinical trials website of the international industry association (www.ifpma.org/clinicaltrials.html).

When an application for marketing approval is made, a company must provide all trials results, whether positive or negative, to the licensing authorities. A summary of this information is made available to the public on the granting of marketing authorisation. This summary, called a European Public Assessment Report (EPAR) is produced by the European Medicines Evaluation Agency (EMEA), and is accessible through the EMEA's website (www.emea.eu.int/htms/human/epar/epar.htm). For medicines authorised by the MHRA in the UK, the Public Assessment Report (UKPAR) is available on the MHRA website (www.mhra.gov.uk).

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This booklet attempts to give a snapshot of where medicines research stands on a global basis in major disease areas, and of what may lie in store over the next few years. Inevitably, this tends to focus on the new active substances that are in companies' research pipelines, but it should not be forgotten that no progress could be made in this important endeavour without the active collaboration both of researchers and clinicians in institutes and hospitals outside the industry and, especially, the commitment of all those who take part as subjects in the many trials mentioned here. It is thanks to them, as much as to industry, that progress continues to be made in overcoming the burden of disease.

The A to Z of Medicines Research shows that the pharmaceutical industry is strong in terms of creativity and diversity. There remain many diseases for which doctors lack cures and treatments, but there has been great progress over the past twenty years in improving treatments for major killers such as heart disease, diabetes and leukaemias. Even where cures are not yet in sight, however, access to better medicines has transformed the prospects and quality of life of many patients with breast cancer, HIV infection, osteoporosis, psoriasis, viral hepatitis and other conditions, and the expertise of British researchers and clinicians has made a significant contribution towards such progress. Responding to these challenges with a keen eye on the future, British medicines development has the potential to build further on its reputation as a world leader over the next 50 years.