The impact of clinical trialsAccording to the European Medicines Agency (EMA), around 4,000 trials are authorised each year across the EEA and this phenomenal effort, in partnership with other global research partners is transforming the way we care for patients and treat many diseases. Over the last 60 years, life expectancy across the EU has increased by nearly a decade. Since the 1980s, death rates from HIV have fallen by around 80% and since the 1990s, death rates from cancer have fallen by 20% in some countries. Hepatitis C can now, in most cases, be cured, and advances in targeted, precision medicines are transforming the way we will treat patients in the future.
Medicine development takes an average of 12 years until approval for use in patients. Clinical research is an essential part of the development process but it is also the lengthiest and most expensive. Clinical Trials represent on average 58,6% of a product total development costs. EFPIA continues to work with stakeholders to further harmonization of Member States’ administrative requirements and procedures for approval of clinical trials. The goal is to ensure Europe remains competitive in attracting investment in clinical trials, increasing the speed, reducing the costs and allowing the European citizens access to the innovative medicines.
The legislative framework for clinical trialsThe conduct of clinical trials (CT) in humans in the EU is regulated through Commission Directive 2001/20/EC and reinforced by Directive 2005/28/EC, laying down rules on Good Clinical Practice (GCP). Compliance with them ensures the rights, safety, and wellbeing of clinical trial participants, consistent with the principles of the Declaration of Helsinki; and that the clinical trial data are credible. Compliance with Good Manufacturing Practice (GMP) under Commission Directive 2003/94/EC is also required and ensures that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. The directives and supplementary guidance must be read in conjunction with relevant national Member State level legislation and guidelines.
From animals to human phase 1 trialsIf pre-clinical test results support further development, the candidate compound is tested in humans in a phase 1 clinical trial. All clinical trials, including phase 1 trials must first be registered in European EudraCT database after which the clinical trial application (CTA) is scrutinised by a Competent Health Authority and an Ethics Committee, in each country where the trial is intended to be conducted.
All clinical trials, including phase 1 trials only include participants who give their free, written consent prior to participation, after being informed about the possible harm the trial medicine may cause. This consent may be withdrawn at any time by the participant.
Phase 1 trials are conducted in a small number (20 to 80) of healthy volunteers and last approximately one year. The aim is to find the lowest dose at which the treatment is effective and the highest dose at which it can be taken without causing harm. The trial also measures the participant’s clinical response to the medicine, e.g. how it absorbs into the blood or the tissue.
From healthy volunteers to larger patient populationsWhere the phase 1 trial is successful, the compound is then evaluated in about 100 to 500 patients with the disease, in a phase 2 trial, for its potential efficacy while gathering further safety data. Taking around two years, it helps determine the most effective dosages, the best method of delivery (e.g. tablet form or injection) and begins evaluating the benefits and risks of the medicine.
Phase 3 – which can take over four years and involves several hundreds to many thousands of patients – is used to test the results of earlier phase 2 trials in larger populations and generate robust data about safety, efficacy and the overall benefit-risk relationship of the medicine. The compound at this stage is almost always compared to placebo (non-active substance) if ethical considerations permit, and/or to an active comparator. Active comparators are usually the best standard treatment (where this exists) for the investigated disease .The active comparator is used to determine if the new medicine has additional benefit beyond current treatment.
If the phase 2 and 3 trials meet their objectives, and/or the benefit/risk ratio of the medicine is favourable for a specific indication/ disease condition, the CT sponsor, commonly a pharmaceutical company, submits an application containing in depth information on the safety, efficacy and manufacturing (quality) of the medicine to a Competent Health Authority. A successful application results in a marketing authorisation for the medicine in that specific indication/ disease condition.
Often, phase 4 post-authorisation trials, that include thousands of patients globally and can take over 10 years to finalise, will be conducted to get more detailed information on medicine’s efficacy and safety in even larger patient populations. It is also more common to use data from disease and product registries to anticipate trends at this stage.