Clinical trials arise as a scientific response to the ethical need to guarantee the efficacy and safety of the treatments received by patients. Clinical Trials provide a controlled, objective and reproducible method for measuring the effects of a treatment on health, thus enabling the objective establishment of an opinion of its use for the treatment or prevention of a disease.

A clinical trial requires extreme care, because its experimental nature makes it ethically important, because it involves humans and because of the enormous repercussion of its results, which can condition the type of treatment to be received by thousands of patients.

A clinical trial is thus characterised as follows:
· It is an experimental study conducted in humans assigned to a treatment group. Unlike in observational studies, the investigator intervenes in the normal course of events and conditions the treatment received by the patients.
· It is always prospective, planned and then conducted, following the evolution of the research subjects over time.
· An intervention is used, normally different from the usual treatment (substance not authorised as a medicinal product or in unauthorised conditions of use) and may therefore not be beneficial for the subject (reason for the legal and ethical connotations related to patient protection).
Therefore, a study which uses a medicinal product in its usual conditions of use, and in which prescription is not conditioned by the protocol, is not a clinical trial even when the objectives may be similar to those of clinical trials. These post-authorisation, observational studies have their own regulatory framework, available here RD 711/2002 and in annex VI of AEMPS (Spanish Agency for Medicines and Medical Devices) circular 15/2002 .
The experimental nature of clinical trials forces the investigator to consider three aspects: the method or scientific aspect, the ethical aspect and the regulatory aspect, since the integrity and rights of patients must be protected and data reliability guaranteed.

Bioethics in clinical research

The participation of humans in a clinical trial generates a potential situation of vulnerability in which his rights must be clearly protected. When a doctor takes part in a clinical trial as an investigator, he is acting simultaneously as a doctor and as a scientist, a situation which can create an ethical dilemma. As a doctor, he must strictly ensure the individual wellbeing of his patient, whereas as a scientist, he must make every effort to improve the possibilities of benefiting society, considering the common good. It is therefore necessary for all medical research involving the study of people to comply with a series of ethical requirements which are clearly established here: Declaration of Helsinki . Whether it is a clinical trial in health volunteers or patients, it is important to consider the ethical aspects of the study, so all clinical trial protocols must now be assessed by an independent body commissioned to review their ethical aspects and methods: the Research Ethics Committee (REC).

The first condition that a clinical trial must meet to be considered ethically acceptable is for there to be reasonable doubt concerning its risk-benefit ratio. The second condition is that the trial must be well designed. If the results generated by the application of a study protocol cannot be correctly interpreted because of methodological shortcomings, it is not ethical to subject people to the risks and discomfort involved in participation in a clinical trial.

In the sixties, the Congress of the United States created what is called “National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research”. In 1978, the commission published a document, the Belmont Report, defining the four principal bioethical principles, the practical application of which is still valid. They are:

•  Principle of justice: all people deserve to be treated with consideration and respect, with no differences between them, with special protection for the less favoured. This requires fair contributions to research benefits and charges.
• Principle of non-maleficence: bioethics principle preventing harm to patients, even upon request. The conduct of a clinical trial with no scientific validity, either because the working hypothesis is not plausible or because the design is not methodologically correct, is maleficence.
• Principle of beneficence: bioethics principle according to which people should be protected from harm and their wellbeing ensured, maximising benefit and minimising risk.
• Principle of respect for people (principle of autonomy): bioethics principle according to which people should be treated as autonomous beings, and people with reduced autonomy should be protected. In application of this principle, consent must be obtained from possibly study participants before they are included. Autonomy is reduced in cases of ignorance, immaturity or psychic disability.
  The Declaration of Helsinki, published by the World Medical Association in 1964, was the first document proposing criteria and methods for protecting the individuals participating in biomedical research. Its fundamental principles consist of the need for clinical trial protocols to be approved by an Ethics Committee and the need to obtain the prior, informed, free consent of the patient.

Clinical trials, then, should be conducted with respect for the fundamental rights of people and the ethical postulates affecting biomedical research in humans, following the Declaration of Helsinki , the original published in Helsinki (1964) and subsequently amended in Tokyo (1975), Venice (1983), Hong-Kong (1989), Somerset West (1996) and Edinburgh (2000). This declaration says that “In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. “

The pharmaceutical sector in the European Union is governed by a series of specific directives which establish the monitoring, verification, retention and data archive requirements for clinical trials. Most governments have in turn developed local standards and laws aimed at regulating medicinal products and specifically research and the protection of research subjects, based both on the Declaration of Helsinki and Good Clinical Practice standards ( see Legislation section)

• Declaration of Helsinki . Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects. Review of the 52nd General Assembly, Edinburgh, Scotland, October 2000. Note of Clarification on Paragraph 29, added by the WMA General Assembly, Washington 2002.
• Belmont report http://www.med.umich.edu/irbmed/ethics/belmont/belmontr.htm
• ICH harmonised tripartite guideline for Good Clinical Practice (GCP). June, 1996.
• Law on Medicinal Products of 1990 (Law 25/1990, article 59)
• Royal Decree of February 6, 2004 (RD 223/2004)
• Bakke OM, Carné Cladellas X, García Alonso F. Ensayos clínicos con medicamentos. Fundamentos básicos, metodología y práctica. Barcelona: Doyma 1994; 74-103
• Laporte JR, Tognoni G, EDS. Principios de la epidemiología del medicamento, 2nd ed. Barcelona, Masson-Salvat, 1993.
• Carné X, Costa J. Problemas y controversias en torno al ensayo clínico. Monografías Dr Antonio Esteve, 22. Barcelona: Doyma 1998; 31-36.
• Baños J, Farré M (eds). Principios de Farmacología Clínica. Bases Científicas de la Utilización de Medicamentos. Barcelona: Masson, 2002.