The Royal Decree that regulates observational studies with medicines for human use approved


Royal Decree 957/2020, of November 3, establishes the conditions that must be met to proceed with the evaluation, performance and monitoring of observational studies with medicinal products for human use carried out in Spain.

The standard considers these observational studies with medicines for human use as an essential instrument to obtain data on their conditions of use, safety and effectiveness in the real context of health care, which allows complementing the information available on them and outline the conditions in which the benefits of drugs outweigh their risks, in addition to providing information to position the place of drugs in therapeutics.

The Royal Decree considers an “observational study with medicines” to be any investigation with the collection of individual data related to people’s health, provided that it does not meet any of the conditions required to be considered a clinical trial established in article 2.1.i) of Royal Decree 1090 / 2015, of December 4, and that it is carried out with the purpose of determining the beneficial effects of drugs, identifying or quantifying their adverse reactions or obtaining information on the patterns of drug use in the population.

Observational drug studies should be aimed at complementing the information already known about the drug without interfering with routine clinical practice.

Conditions for conducting observational studies with drugs
The text incorporates those conditions that must be met to perform these observational studies with drugs.

To do this, it first indicates their characteristics, providing that their promoters must take into account the guidelines of the European Commission and the instructions for conducting observational studies with medicines published by the Spanish Agency for Medicines and Health Products in its website, which will be prepared in collaboration with the Ethics Committees for Drug Research (CEIm) and the competent health administrations of the autonomous communities. Likewise, it prohibits the planning, conducting or financing of observational studies in order to promote the prescription of the drugs under study.

In the case of an observational study with prospective follow-up medications, the protocol must explicitly state the procedures that will be used to guarantee that the study does not modify the prescription or dispensing habits of the medications, which must follow the usual channels. Annex I of the Royal Decree includes the recommended structure and content of said protocol.

With regard to the prerequisites for the start of observational studies with drugs, in order to simplify the procedures in force to date and given the merely observational nature of this type of studies with drugs that are already part of clinical practice, eliminates the requirement of classification of the study protocols, as well as the prior authorization of the Spanish Agency for Medicines and Health Products in the cases in which it was mandatory, and the Post-authorization Studies Coordination Committee is abolished, considering that its Tasks overlapped with the functions of CEIm.

The prerequisites for the beginning of observational studies with medicines are limited to the favorable opinion of the CEIm accredited in Spain and the agreement of the health center where the participating subjects are treated. For observational studies with prospective follow-up drugs, once the favorable opinion of the CEIm has been obtained, the competent health authorities may establish additional duly justified requirements so that such studies can be started in the centers of their competence.

Studies that involve obtaining information directly from the participating subject or the healthcare professional who attends to them in a health center, service or establishment, will require the prior agreement of the person responsible for the same to the protocol and to the rest of the documentation that has obtained the favorable opinion of the CEIm, expressed by signing a contract with the promoter.

However, it may be exempted from requesting the informed consent of the participating subject when the CEIm considers that the observational research has an important social value, that its conduct would not be feasible or viable without said dispensation, and that it entails minimal risks for the participants.

In this sense, the norm regulates the protection of the personal data of the participating subjects.

Likewise, the text includes the guarantees of transparency and information to be fulfilled by the promoter, and the Spanish Agency for Medicines and Health Products must enable the inclusion of information from the observational studies with medicines carried out in Spain in the REec.

The Royal Decree deals with the economic aspects related to the study, which is exempt from the obligation to arrange insurance or other specific financial guarantee.

The remuneration of the health professionals who participate in the observational studies will be limited to compensation for the time invested and the expenses incurred, without prejudice to the regulations applicable to the remuneration received by public employees, as well as the internal regulations of the employing entities of researchers on this issue.

In all studies, the figures of the sponsor and the main investigator must be identified as ultimately responsible for the research, with one of the study investigators being the promoter. The norm details the obligations that both figures must assume.

Presentation, validation and evaluation
The text specifies the methodological, ethical and legal aspects of the observational study with drugs to be evaluated by the CEIm.

Likewise, it regulates the procedure for requesting said evaluation by the CEIm, indicating in Annex II the documentation that must be attached to said request, as well as the issuance of the corresponding opinion.

Follow-up of observational studies
In this area, the standard addresses issues such as substantial modifications to the protocol of an observational study with drugs, communication by health professionals of suspected adverse drug reactions to the Spanish Pharmacovigilance System and communication to the Spanish Agency for Medicines and Health Products of monitoring information and study results by the promoter of the study of the information resulting from this when it may involve the modification of the benefit-risk ratio of a drug, in order to evaluate its impact on the conditions of marketing authorization , in coordination with the competent authorities of the Member States of the European Union.

In addition, it points out that it will be the competent health authorities that verify compliance with the regulatory regulations of observational studies with drugs carried out in Spain, through the corresponding inspections and in accordance with the procedures that are established, and that they will constitute infractions those provided for in article 111 of the consolidated text of the Law on guarantees and rational use of medicines and health products, and will be sanctioned in accordance with the provisions of article 114 of the same legal body. Likewise, the general provisions, prescription regime and other measures, provided for in chapter II of title IX of the consolidated text of the Law of guarantees and rational use of medicines and health products, will be applicable.

Legislative amendments
– Statute of the Spanish Agency for Medicines and Health Products, approved by Royal Decree 1275/2011, of September 16, which creates the Spanish Agency for Medicines and Health Products and its Statute is approved: the paragraph is deleted f) of section 2 of article 17, the remaining paragraphs are reordered alphabetically, and two paragraphs are added, k) and l); a paragraph c) is added in paragraph 4 of article 18 and a paragraph d) in paragraph 5 of article 19; Paragraph b) of section 4 of article 20 and sections 1, 2 and 3 of article 28 bis are amended; Article 23 is deleted and a new Article 28 ter is created.

– Royal Decree 1090/2015, of December 4, which regulates clinical trials with drugs, the Ethics Committees of Research with drugs and the Spanish Registry of Clinical Studies: paragraphs h) and k) of section 1 of article 2, paragraph 2 of article 12, the second paragraph of paragraph 1 of article 15, paragraph b) of paragraph 2 of article 47, deleting its paragraph c), and paragraph 6 of article 48.
Are repealed:

– Articles 2.16, 2.18, and Chapter VI of Royal Decree 577/2013, of July 26, which regulates the pharmacovigilance of medicines for human use.

– Order SAS / 3470/2009, of December 16, which publishes the guidelines on observational post-authorization studies for medicinal products for human use.

Entry into force and transitional provisions
Royal Decree 957/2020, of November 3, will enter into force on January 2, 2021.

Observational studies with drugs that had been the subject of a classification resolution by the Spanish Agency for Medicines and Health Products prior to the entry into force of the standard, this will not apply, and must be governed by current regulations in the moment of obtaining said classification resolution.

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