Royal Decree 1090/2015, of 4 December, regulating clinical trials with medicinal products, Ethics Committees for Investigation with medicinal products and the Spanish Clinical Studies Registry

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This is an unofficial English translation of the Royal Decree 1090/2015, revised by the

Spanish Agency of Medicines and Medical Devices

Royal Decree 1090/2015, of 4 December, regulating clinical trials

with medicinal products, Ethics Committees for Investigation with

medicinal products and the Spanish Clinical Studies Registry

Clinical research with medicinal products is the basic element that allows medicinal products to

be authorised by medicinal product agencies, to be marketed by their marketing authorisation

holders with the guarantees required by law, and finally to be used in clinical practice for the benefit

of patients. It also allows new or more efficient forms of use to be investigated once the medicinal

products have been marketed. In summary, clinical research enables high-quality knowledge to be

generated and therapeutic tools to be developed that improve those already available and

contributes to prevention, alleviation and cure of diseases and improvement of quality of life of the

population.

Clinical research must therefore be conducted in an environment that guarantees the protection

of individuals who participate in it in accordance with elements such as the Declaration of Helsinki,

approved by the World Medical Association, and the Council of Europe Convention for the protection

of human rights and human dignity with regard to the application of biology and medicine, signed in

Oviedo. Likewise, it must guarantee the basic principles set out in Act 41/2002, of 14 November,

regulating patient autonomy and rights and obligations in terms of clinical documentation and

information, and Act 26/2011, of 1 August, on the adaptation to the International Convention on the

Rights of People with Disabilities. Finally, it must also guarantee that the results derived from it are of

quality and useful for the purposes previously expressed and should therefore be conducted in a

context of maximum transparency.

At the same time, it is necessary to promote clinical research of orphan medicinal products and

medicinal products aimed at the treatment of population groups such as children, women, and

elderly people who traditionally have been poorly represented in clinical research.

The European Harmonisation regarding clinical trials takes due account of both the general

regulations on medicinal products and, specifically, Directive 2001/20/EC of the European

Parliament and of the Council, of 4 April 2001, on the approximation of the laws, regulations and

administrative provisions of the Member States as regards the implementation of good clinical

practice in the conduct of clinical trials on medicinal products for human use. In Spain, Royal Decree

223/2004, of 6 February, regulating clinical trials with medicinal products incorporated this directive

into the Spanish legal system in its entirety, establishing the principles and basic requirements that

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have regulated until the present time the conduct of clinical trials with medicinal products and Ethics

Committees as guarantors of their ethical and scientific quality. Subsequently, Act 29/2006, of 26

July, on guarantees and the rational use of medicinal products and medical devices, as well as

currently the consolidated text approved by Royal Legislative Decree 1/2015, of 24 July, covering

clinical trials with medicinal products in its Title III under the heading "On the guarantees of research

in medicinal products for human use" and, additionally, Order SCO/256/2007, of 5 February,

establishing detailed principles and guidelines of good clinical practice and the requirements for

authorisation of the manufacture or importation of investigational medicinal products for human use

incorporated in its entirety into national law Commission Directive 2005/28/EC, of 8 April, laying

down the principles and guidelines of good clinical practice as regards investigational medicinal

products for human use, as well as the requirements for authorisation of the manufacture or

importation of said products.

However, the regulation of clinical trials with medicinal products has been the object of some

criticism in recent years and public analyses that have focused on the complexity of the procedure of

trial authorisation, which imposed a disproportionate bureaucratic burden on authorisation that has

hindered clinical research in the European Union. Although the European Commission published

various documents to further improve and harmonise the application of legislation, Regulation (EU)

No 536/2014 of the European Parliament and of the Council, of 16 April 2014, on clinical trials on

medicinal products for human use, and repealing Directive 2001/20/EC, has finally been published,

in which profound changes are proposed seeking to simplify procedures without compromising

guarantees for participants in clinical trials.

The new Regulation sets out, on the one hand, common procedures for clinical trial

authorisation throughout Europe, urging Member States to cooperate in assessment by means of a

single common position, but on the other hand, leaves outside of this cooperation those aspects of

an intrinsically national nature requiring assessment by each Member State. Moreover, to promote

clinical research in the European Union, it sets very tight periods for assessing an application

dossier, maintains the concept of tacit authorisation and sets no minimum timelines for authorisation.

The new European Regulation also introduces some changes in definitions that are of great

relevance, particularly but not only, for research sponsored by academic investigators. Thus, it

introduces the concept of "low-intervention clinical trial", in which it calls for less rigorous rules in

aspects such as monitoring, the content of the master file, or traceability, without prejudice to the

safety of the individuals participating in these trials.

In summary, and given that the European Commission has opted for the legal form of a

Regulation, the aspects regulated in this are directly applicable for Member States and shall result in

a lower variability in the application of the rules. However, the same regulation leaves to national

development basic aspects such as the system by which each State reaches a single position in

assessment, assessment of ethical issues and informed consent, or mechanisms of compensation,

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among others. On the other hand, given that the date of application of the Regulation has been

delayed to not before May 2016, maintaining the possibility that the Sponsor requests the

authorisation of a clinical trial under Directive 2001/20/EC of the European Parliament and of the

Council, of 4 April 2001, for at least three years after the date of publication of the Regulation, some

aspects of the transposition of said Directive should be maintained on a temporary basis.

The changes made in Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, therefore require the introduction of significant amendments to national

legislation to allow for compliance when the Regulation is applicable. However, after 10 years of

implementation of Royal Decree 223/2004, of 6 February, some potential improvements had also

been identified as needing to be made in the procedure for authorisation of clinical trials in Spain. In

line with those included in the new Regulation, these cover aspects such as increased efficiency in

processes of communication and assessment or identification of the responsibilities of all agents

involved. This has made it advisable not to wait to the date of application of the Regulation to adopt

those necessary amendments to national legislation so as to adapt rapidly to the new Regulation and

maintain a competitive position of Spain in the European and international context of clinical

research.

In this regard, there are two aspects of national development of legislation that deserve

separate comment. On the one hand, it is necessary to include the Ethics Committees for Clinical

Investigation in the development of Act 14/2007, of 3 July, on biomedical research. This Act

determines in its third transitory provision that Ethics Committees for Clinical Investigation shall

cease to exist when Ethics Committees for Investigation are constituted. In the development of Act

14/2007, of 3 July, it was also planned to create a National Authority for Ethics Committees for

Investigation to be in charge of the general aspects of coordination and the registration of these

Committees. However, given the specific characteristics of clinical research with medicinal products

and the requirements imposed in the new Regulation, coordination of the single decision for clinical

trials with medicinal products, as well as other aspects of supervision concerning those Ethics

Committees for Investigation accredited for assessment of studies with medicinal products, shall

correspond, according to this Royal Decree, to the Spanish Agency of Medicines and Medical

Devices. Furthermore, the additional requirements to be met by the Ethics Committees for

Investigation in order to be accredited as Ethics Committees for Investigation with medicinal products

are established, taking into account the specificities applicable to clinical investigation with medicinal

products and medical devices, and taking as a reference the accreditation criteria that are

determined in the development of this Act.

Finally, this Royal Decree develops an aspect of the consolidated text of the Act on guarantees

and rational use of medicines and medical devices approved by Royal Legislative Decree 1/2015, of

24 July which, in its article 62, lays the foundation for the publicly accessible and free of charge

national registry of clinical trials with medicinal products for human use as a necessary measure for

transparency. For this, the Royal Decree establishes that the Spanish Agency of Medicines and

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Medical Devices must provide the general public with certain information about authorised clinical

trials on its website. In this Royal Decree, the Spanish Clinical Studies Registry is developed from a

broader perspective to also permit registration of non-interventional studies with medicinal products

that are classified by the Spanish Agency of Medicines and Medical Devices. In addition, the creation

of this registry takes into consideration the public utility proposed in the consolidated text of the Act

on guarantees and rational use of medicinal products and medical devices, for clinical trials with

medicinal products, extending it, on a voluntary basis, to all prospective clinical studies outside the

scope of medicinal products. Thus, the registry shall be mandatory and complete with regard to

clinical trials with medicinal products, but is open to use as a voluntary registry for any other clinical

study when its sponsors wish to use it for the purposes set forth in the World Health Organization

International Clinical Trials Registry Platform.

For the World Health Organization, the registration, publication, and public access to the

relevant contents of clinical trials is a scientific, ethical, and moral responsibility. The World Health

Organization itself has established the minimal data set of a clinical trial that should be made public.

This standard is the same as that adopted by the European Parliament and the Council to make

publicly accessible the data contained in the EudraCT database which contains information on the

clinical trials with medicinal products in which any site located in the European Economic Area and

that has been authorised by the competent national authority participates. The content of the

Spanish Clinical Studies Registry meets the standards set in the WHO International Clinical Trials

Registry Platform. It has also been taken into account that the applicant for authorisation of a clinical

trial with medicinal products or for classification of non-interventional studies already provides

information on the clinical trial with medicinal products to the Spanish Agency of Medicines and

Medical Devices in accordance with the Spanish and European regulation on this matter. Thus,

information and communication technologies shall be used to streamline processing.

This Royal Decree aims, therefore, to adapt Spanish legislation so as to make feasible the

current and future application of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, and to develop those aspects that the Regulation leaves to national

legislation. This is intended to promote and facilitate clinical research with medicinal products in

Spain, the generation of knowledge, transparency, the safety of participants and the usefulness of

the results or, in summary, to consolidate the confidence of society in research and to foster its

progress.

Pursuant to article 149.1.16 of the Constitution, this Royal Decree is enacted according to the

sole authority held by the State regarding legislation on pharmaceutical products, while guaranteeing

with regard to the processing of personal data, respect for Organic Act 15/1999, of 13 December, on

Personal Data Protection, and its development regulations.

In accordance with Act 16/2003, of 28 May, on cohesion and quality of the National Health

System, this Royal Decree has been subject to prior opinion by the Advisory Committee and the

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Plenary Session of the Inter-Territorial Board of the National Health System. Furthermore, the

Spanish Data Protection Agency has issued its mandatory opinion, pursuant to the provisions in

Organic Act 15/1999, of 13 December, and the Statute of this Agency, enacted by Royal Decree

428/1993, of 26 March.

In the preparation process of this Royal Decree, the Autonomous Communities, the cities of

Ceuta and Melilla, and the interested stakeholders have been consulted.

By virtue of the above, at the proposal of the Ministry of Health, Social Services and Equality,

with prior approval of the Ministry of Finance and Public Administration, in accordance with the State

Council and after deliberation by the Council of Ministers at its meeting of 4 December 2015,

I HEREBY DECREE:

CHAPTER I

General provisions

Article 1. Purpose.

1. This Royal Decree shall apply to clinical trials with medicinal products for human use

conducted in Spain and has as its purpose:

a) To develop specific regulations for application in Spain of Regulation (EU) No 536/2014 of

the European Parliament and of the Council, of 16 April 2014, on clinical trials on medicinal products

for human use, and by which Directive 2001/20/EC, regarding clinical trials with medicinal products

for human use conducted in Spain is repealed.

b) To regulate Ethics Committees for Research with medicinal products, as well as the Spanish

Clinical Studies Registry, formed by both clinical trials and non-interventional post-authorisation

studies conducted with medicinal products for human use.

To this end, the administration of an investigational medicinal product to individual patients

within the scope of standard medical practice and with the sole fundamental aim of achieving a

therapeutic benefit for those patients shall not be considered a clinical trial with medicinal products.

In this case, use of unauthorised medicinal products or under conditions of use different from those

authorised shall be governed by the provisions laid down in Royal Decree 1015/2009, of 19 June,

regulating the availability of medicinal products in special situations.

2. Clinical practice and the freedom of prescription of the physician or other healthcare

professionals shall under no circumstances protect the conduct of unauthorised clinical trials or the

use of secret remedies or others which have not been declared to the health authorities.

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Article 2. Definitions:

1. For the purposes of this Royal Decree, the following definitions shall apply:

a) "Medicinal product for human use": Any substance or combination of substances presented

as having properties for treating or preventing disease in human beings or which may be used in or

administered to human beings either with a view to restoring, correcting or modifying physiological

functions by exerting a pharmacological, immunological or metabolic action, or to making a medical

diagnosis.

b) "Radiopharmaceutical": Any medicinal product which, when ready for use for therapeutic or

diagnostic purposes, contains one or more radionuclides (radioactive isotopes).

c) "Adverse reaction": Any noxious and unexpected response to a medicinal product.

d) "Serious adverse reaction": Any adverse reaction which results in death, is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or

significant disability or incapacity, or is a congenital anomaly or birth defect. For reporting purposes,

suspected adverse reactions that are judged to be medically important shall also be considered

serious, even if they do not meet the preceding criteria, such as those that endanger the patient or

require an intervention to prevent any of the aforementioned outcomes and all suspected

transmissions of an infectious agent via a medicinal product.

e) "Immediate packaging": The container or any other form of packaging immediately in contact

with the medicinal product.

f) "Outer packaging": The packaging into which the immediate packaging is placed.

g) "Medical device": Any instrument, apparatus, appliance, software, material or other article,

whether used alone or in combination, including the software intended by their manufacturer to be

used specifically for diagnostic and/or therapeutic purposes and and necessary for its proper

application,, intended by the manufacturer to be used for human beings for the purpose of:

1. Diagnosis, prevention, monitoring, treatment or alleviation of a disease.

2. Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap.

3. Investigation, replacement or modification of the anatomy or of a physiological process.

4. Control of conception, and which does not achieve its principal intended action in or on the

human body by pharmacological, immunological or metabolic means, but which may be assisted in

its function by such means.

h) "Clinical study": Any research in relation to humans intended:

1. To discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or

more medicinal products.

2. To identify any adverse reaction to one or more medicinal products.

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3. To study the absorption, distribution, metabolism and excretion of one or more medicinal

products, with the objective of ascertaining the safety and/or efficacy of said medicinal products.

i) "Clinical trial": A clinical study which fulfils any of the following conditions:

1. The assignment of the subject to a particular therapeutic strategy is decided in advance and

does not fall within normal clinical practice of the Member State concerned.

2. The decision to prescribe the investigational medicinal products is taken together with the

decision to include the subject in the clinical study.

3. Diagnostic or monitoring procedures in addition to normal clinical practice are applied to the

subjects.

j) "Low-intervention clinical trial": A clinical trial which fulfils all of the following conditions:

1. The investigational medicinal products, excluding placebos, are authorised.

2. According to the protocol of the clinical trial:

1. The investigational medicinal products are used in accordance with the terms of the

marketing authorisation; or

2. The use of the investigational medicinal products is evidence-based and supported by

published scientific evidence on the safety and efficacy of those investigational medicinal products in

any of the Member States concerned.

3. The additional diagnostic or monitoring procedures do not pose more than minimal additional

risk or burden to the safety of the subjects compared to normal clinical practice in any Member State

concerned.

k) "Non-interventional study": A clinical study other than a clinical trial.

l) "Investigational medicinal product": A medicinal product which is being tested or used as a

reference, including as a placebo, in a clinical trial.

m) "Normal clinical practice": The treatment regime typically followed to treat, prevent, or

diagnose a disease or a disorder.

n) "Advanced therapy investigational medicinal product": An investigational medicinal product

which is an advanced therapy medicinal product as defined in point (a) of article 2(1) of Regulation

(EC) No 1394/2007 of the European Parliament and of the Council, of 13 November 2007, on

advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No

726/2004.

ñ) "Auxiliary medicinal product": A medicinal product used for the needs of a clinical trial as

described in the protocol, but not as an investigational medicinal product.

o) "Authorised investigational medicinal product": A medicinal product authorised in accordance

with Regulation (EC) No 726/2004 or in any Member State concerned in accordance with Directive

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2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an

investigational medicinal product.

p) "Authorised auxiliary medicinal product": A medicinal product authorised in accordance with

Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive

2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an

auxiliary medicinal product.

q) "Member State concerned": The Member State where an application for authorisation of a

clinical trial or a substantial modification has been submitted under Chapters II or III of Regulation

(EC) No 536/2014 of the European Parliament and of the Council of 16 April 2014.

r) "Substantial modification": Any change to any aspect of the clinical trial which is made after

notification of the decision referred to in articles 8, 14, 19, 20 or 23 of Regulation (EC) No 536/2014

of the European Parliament and of the Council of 16 April 2014 and which is likely to have a

substantial impact on the safety or rights of the subjects or on the reliability and robustness of the

data generated in the clinical trial.

s) "Sponsor": An individual, company, institution or organisation which takes responsibility for

the initiation, management and setting up the financing of the clinical trial.

t) "Investigator": An individual responsible for the conduct of a clinical trial at a clinical trial site.

u) "Principal Investigator": An investigator who is the responsible leader of a team of

investigators who conduct a clinical trial at a clinical trial site.

v) "Trial subject": An individual who participates in a clinical trial, either as recipient of an

investigational medicinal product or as a control;

w) "Informed consent": A subject's free and voluntary expression of his or her willingness to

participate in a particular clinical trial, after having been informed of all aspects of the clinical trial that

are relevant to the subject’s decision to participate or, in the case of minors and of incapacitated

subjects, an authorisation or agreement from their legally designated representative to include them

in the clinical trial.

x) "Protocol": A document that describes the objectives, design, methodology, statistical

considerations and organisation of a clinical trial. The term "protocol" encompasses successive

versions of the protocol and protocol modifications.

y) "Investigator's brochure": A compilation of the clinical and non-clinical data on the

investigational medicinal product or products which are relevant to the study of said product or

products in humans.

z) "Manufacturing": The total and partial manufacture, as well as the various processes of

dividing up, packaging and labelling (including blinding).

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aa) "Start of a clinical trial": The first act of recruitment of a potential subject for a specific clinical

trial, unless defined differently in the protocol.

ab) "End of a clinical trial": The last visit of the last subject or at a later point in time as defined in

the protocol.

ac) "Early termination of a clinical trial": The premature end of a clinical trial due to any reason

before the conditions specified in the protocol are complied with.

ad) "Temporary halt of a clinical trial": An interruption not provided in the protocol of the conduct

of a clinical trial by the sponsor with the intention of the sponsor to resume it.

ae) "Suspension of a clinical trial": Interruption of the conduct of a clinical trial by a Member

State.

af) "Good clinical practice": A set of detailed ethical and scientific quality requirements for

designing, conducting, performing, monitoring, auditing, recording, analysing and reporting clinical

trials ensuring that the rights, safety and well-being of subjects are protected, and that the data

generated in the clinical trial are reliable and robust.

ag) "Inspection": The act by a competent authority of conducting an official review of

documents, facilities, records, quality assurance arrangements, and any other resources that are

deemed by the competent authority to be related to the clinical trial and that may be located at the

clinical trial site, at the sponsor's and/or contract research organisation's facilities, or at any other

establishments which the competent authority sees fit to inspect.

ah) "Adverse event": Any untoward medical occurrence in a trial subject to whom a medicinal

product is administered and which does not necessarily have a causal relationship with this

treatment.

ai) "Serious adverse event": Any untoward medical occurrence that at any dose requires

inpatient hospitalisation or prolongation of existing hospitalisation, results in persistente or significant

disability or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in

death.

aj) "Unexpected serious adverse reaction": A serious adverse reaction, whose nature, severity

or outcome is not consistent with the reference safety information.

ak) "Clinical study report": Report on the clinical trial presented in an easily searchable format,

prepared in accordance with Annex I, Part I, Module 5 of Directive 2001/83/EC and accompanying

an application for marketing authorisation.

2. The following definitions shall also be applied:

a) " Ethics Committee for Investigation (hereinafter CEI)": An independent body with a

multidisciplinary composition whose main purpose is to oversee the protection of the rights, safety

and well-being of subjects participating in a biomedical investigation project and offer public

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assurance in this respect by giving an opinion on the corresponding documentation of the

investigation project, taking into account the views of laypersons, in particular, patients or patient

organisations.

b) "Ethics Committee for investigation with medicinal products (hereinafter CEIm)": Ethics

Committee for Investigation which is also accredited in accordance with the terms of this Royal

Decree to issue an opinion on a clinical study with medicinal products and on a clinical investigation

with medical devices.

c) "Co-sponsors": Those sponsors who conduct together a clinical trial and are subject to the

obligations of a sponsor under this Royal Decree, unless the sponsors establish otherwise in a

written contract setting out their respective responsibilities.

d) "Clinical investigation with medical devices": Any systematic investigation in one or more

human subjects undertaken to assess the safety or performance of a device.

e) "Non-commercial clinical research": Investigation conducted by investigators without the

participation of the pharmaceutical or medical devices industry, which fulfil all the following

characteristics:

1. The sponsor is a university, hospital, public scientific organisation, non-profit institution,

patient organisation or individual investigator.

2. The ownership of the investigation data belongs to the sponsor from the inception of the

study.

3. There are no agreements between the sponsor and third parties that allow them to use the

data for regulatory or marketing purposes.

4. The design, conduct, recruitment, recording of data and reporting of the results of the

investigation remains under the control of the sponsor.

5. Given their characteristics, these studies cannot be part of the development programme for a

marketing authorisation of a medicinal product.

f) "Coordinating investigator": Investigator responsible for coordinating the investigators of the

sites participating in a multicentre trial.

g) "Contracted clinical investigator": An investigator contracted by the site or related

investigation entities to conduct one or more clinical trials, provided they have the required

qualification to perform their assigned functions and are able to develop these in the clinical setting

of the site.

h) "Minor": A trial subject who is, according to Act 41/2002 of 14 November regulating patient

autonomy and rights and obligations in terms of clinical documentation and information, under the

age of legal competence to give his/her informed consent.

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i) "Monitor": A qualified professional with the necessary training and clinical and/or scientific

competence, chosen by the sponsor, who is responsible for the direct follow-up of the conduct of the

trial. The monitor is the link between the sponsor and the principal investigator when they are not the

same person. In no case should the monitor be part of the investigator team.

j) "Contract research organisation (hereinafter CRO)": A natural or legal person contracted by

the sponsor to perform the sponsor’s functions or duties in connection with the clinical trial.

k) "Incapacitated subject": A trial subject who is, for reasons other than the age of legal

competence to give informed consent, incapable of giving his/her informed consent according to

national law.

l) "Spanish Clinical Studies Registry": A database owned by Spanish Agency of Medicines and

Medical Devices, accessible on its website, publicly accessible and free of charge for any user,

whose purpose is to serve as a source of information on clinical trials for the general public.

For the purposes of this Registry, any investigation that prospectively assigns participating

subjects to one or more health-related interventions that are not medicinal products to study their

effects on health indicators shall be considered as "another type of clinical study".

m) "Legal representative of the sponsor": A person accredited by the sponsor to represent

him/her when the sponsor is not established in a Member State of the European Union.

n) "Legally designated representative": A natural or legal person, authority or body which, in

accordance with the national law of the Member State concerned, is empowered to give informed

consent on behalf of a subject who is an incapacitated subject or a minor.

ñ) "Substudy": A study that is part of the clinical trial but that may be related or not to the

primary study objective, in which some of the subjects included in the clinical trial participate

voluntarily and for which an additional informed consent is requested, for example, pharmacokinetic

or pharmacogenetic substudies.

CHAPTER II

Protection of trial subjects and informed consent

Article 3. General requirements.

1. A clinical trial subject to this Regulation may only be conducted when the CEIm and the

Spanish Agency of Medicines and Medical Devices have considered that all of the following

conditions are met:

a) The clinical trial is ethically and methodologically sound and is designed to obtain reliable and

robust data.

b) The anticipated benefits for the subjects or public health justify the foreseeable risks and

inconveniences and compliance with this condition is constantly monitored. However, the rights,

safety, human dignity, and well-being of the subjects prevail over any other interest.

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c) Freely given informed consent is obtained and documented from each trial subject before the

subject is included in the trial in accordance with the terms laid down in articles 4 to 8.

d) The rights of the subjects as regards their physical and mental integrity, privacy and the

protection of the data concerning them are safeguarded in accordance with Organic Act 15/1999, of

13 December, on Personal Data Protection, and its development regulation, as well as European

regulations in force on this matter.

e) The clinical trial has been designed to involve as little pain, discomfort, fear and any other

foreseeable risk as possible for the trial subjects and both the level of risk and the degree of

discomfort are specifically defined in the protocol and constantly monitored.

f) The medical care provided to the subjects is the responsibility of an appropriately qualified

medical doctor, a qualified dental practitioner or any other healthcare professional, always in

accordance with their competencies to provide this necessary care.

g) The trial subject or, where the subject is not able to give informed consent, his/her legally

designated representative has been provided with the contact details of an entity where further

information can be received in case of need. In the case of persons with a disability, this

supplemental information shall be provided according to the rules established by the design for all

principle, so that it is accessible and comprehensible to them.

h) No undue influence, including that of a financial nature, is exerted on trial subjects to

participate in the clinical trial.

In this regard, subjects participating in trials with a potential direct benefit for the subject or their

legal representatives may only receive reimbursement from the sponsor of extraordinary expenses

and losses of productivity resulting from their participation in the trial. In special situations, the CEIm

may report favourably on compensation of trial subjects for the discomfort resulting from their

participation in said trial, provided that it is ensured that such compensation does not influence the

decision of the subject to participate in the study.

Whatever compensation may have been agreed for voluntary participation in the trial, it shall

always be received by the subject, although it shall be reduced in proportion to his/her participation

in the investigation, in the event that the subject decides to revoke consent and withdraw from the

trial.

i) The insurance or equivalent financial guarantee referred to in article 9.2 has been arranged,

or the coverage specified in article 9.4 for "low-intervention clinical trials" is available.

2. Clinical trials should be conducted in accordance with the Declaration of Helsinki on ethical

principles for medical research in human beings, approved by the General Assembly of the World

Medical Association, and taking into account the Oviedo Convention for the protection of human

rights and human dignity with regard to the application of Biology and Medicine, as well as any other

regulations that may apply.

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3. In the case of collection of biological samples being envisaged in the clinical trial, appropriate

provisions shall be made so that on completion of the trial their use in research is in accordance with

the provisions of Royal Decree 1716/2011, of 18 November, which establishes the basic

requirements for authorisation and operation of biobanks for biomedical research purposes and the

processing of human biological samples, and regulates the operation and organisation of the

National Registry of Biobanks for biomedical research, particularly with regard to the relevant

sections of informed consent and possible documents for transfer of biological materials.

Article 4. Informed consent.

1. The obtaining and contents of the informed consent shall conform to the provisions of article

29 of Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014,

as well as to articles 8 and 9 of Act 41/2002 of 14 November.

2. When the person who is to give consent is an disabled person, the information shall be

provided in appropriate formats in accordance with the rules established by the design for all

principle, so that it is accessible and comprehensible for them, and the pertinent support measures

shall be agreed so as to facilitate their ability to provide their own consent.

3. In the case of minors or incapacitated persons, where consent has been given by their legally

designated representative, when their capacity to give their consent has been attained or recovered,

their consent must be obtained to continue participating in the clinical trial.

4. The person participating in the trial, particularly in the case of patients with special vulnerability,

shall be informed of the routes of access to the normal clinical practice for their pathology.

5. The person participating in a clinical trial, alone or with the assistance of his/her legally

designated representative, or a family member or other person close to the participant, may revoke

his/her consent at any time, without giving a reason and without it resulting in any detriment or

responsibility for the person participating. Withdrawal of consent shall not affect activities performed

based on the subject's consent before it was withdrawn, while also ensuring that neither the data or

samples obtained based on said consent may be used in analyses or studies after the date of

withdrawal unless the subject's consent is subsequently obtained to use them or, if the purpose is

legitimate, the information can be obtained from publicly accessible sources.

6. When collection of biological samples is envisaged in the clinical trial, the potential participant

must be informed about the provisions with regard to the future use of the samples. In accordance

with Royal Decree 1716/2011 of 18 November, the samples may be destroyed after the study is

completed, be incorporated into a collection or an authorised biobank. In the last two cases, the

participant shall be informed of the biobank or the person responsible for collection, as well as the

location where the samples shall be kept.

7. When a clinical trial is to be conducted exclusively in Spain, without prejudice to the

provisions in the previous paragraphs and notwithstanding the provisions in article 3 and in articles 5

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to 8 of this Royal Decree, the investigator may be allowed to obtain informed consent by the

simplified means set out in paragraph 2 of article 30 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council of 16 April 2014, provided all conditions set out in paragraph

3 of the aforementioned article 30 are fulfilled.

Article 5. Clinical trials on minors.

1. A clinical trial on minors may be conducted only when, in addition to the conditions set out in

articles 3 and 4 of this Royal Decree, all the conditions listed in article 32 of Regulation (EU) No

536/2014 of the European Parliament and of the Council, of 16 April 2014, are met.

2. The CEIm who is in charge of assessing Part II of the assessment report of a clinical trial on

minors must have paediatric experts among its members or have obtained advice on the clinical,

ethical and psychosocial issues in the field of paediatrics.

3. Prior informed consent of the parents who hold custody or of the legal representative of the

minor must be obtained, and the minor, if under 12 years of age, must be heard if the minor has

sufficient judgment. The informed consent form of the parents shall be valid provided it is signed by

one of them with the express or tacit consent of the other, which should be adequately documented,

as stipulated in article 156 of the Civil Code. When the subject's condition allows, or in any case

when the minor is twelve years of age or older, the subject must also give his/her consent to

participate in the trial.

Article 6. Clinical trials on incapacitated subjects.

1. A clinical trial may only be conducted on adults who are not in a state to give informed

consent and have not given, or refused to give consent prior to being incapacitated, when, in addition

to the conditions set out in articles 3 and 4 of this Royal Decree, all the conditions listed in article 31

of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014, are

met.

2. The protocol must be approved by an CEIm that has experts in the disease in question or has

obtained advice from experts on the clinical, ethical and psychosocial problems in the field of the

relevant disease and the patient population concerned.

3. Prior informed consent must have been obtained from the legal representative of the person

participating in a clinical trial or consent from a family member or other person close to the

participant, as appropriate. In any case, the investigator shall make reasonably sure that there are no

previous instructions of the person expressed in this regard before suffering a change in his/her

capacity, which must be respected. This possibility and the procedure to be followed must be

provided for in the trial documentation approved by the CEIm.

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Article 7. Clinical trials in emergency situations.

1. Notwithstanding the provisions laid down in article 3.1.c) and articles 4 to 6 of this Royal

Decree, when the clinical trial has a specific interest for the population where the investigation is

conducted, and the reasons for the need to administer the investigational medicinal product are

justified, a person may be included in a clinical trial without obtaining prior informed consent when all

the conditions listed in article 35, paragraphs 1 and 2, of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014, are met.

2. In this case, whenever circumstances permit, family members or other persons close to the

subject shall be previously consulted.

3. This possibility and the procedure to be followed must be provided for in the trial

documentation approved by the CEIm, and the person or his/her legally designated representative

shall be informed as soon as possible and must give their consent to continue in the trial, where

appropriate, or ratify it in any case.

4. If the trial subject or, if applicable, his/her legal designated representative cannot give their

consent, they shall be informed of their right to object to the use of the data obtained from the clinical trial.

Article 8. Clinical trials on pregnant or breastfeeding women.

A clinical trial may only be conducted on pregnant or breastfeeding women if, in addition to the

conditions set out in articles 3 to 6 of this Royal Decree, all the conditions listed in article 33 of Regulation

(EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014, are met.

CHA

PTER III

amage compensation and liability scheme

Article 9. Damage compensation.

1. In clinical studies other than "low-intervention clinical trials", the sponsor shall ensure that the

trial subject is compensated for any damage suffered as a result of the trial. This compensation shall

be independent of the financial capacity of the sponsor, investigator, and site.

2. The trial sponsor is responsible for contracting insurance or a financial guarantee covering

the damage indicated in paragraph 1, as well as any liability that might be incurred by the sponsor,

principal investigator and members of the investigator team, including contracted clinical

investigators, and the hospital or site where the clinical trial is conducted, which must be

documented prior to the trial, unless it is a "low-intervention clinical trial".

3. In the case of clinical trials included in the definition of "non-commercial clinical research", an

application may be submitted without having contracted the insurance or financial guarantee referred

to in paragraph 2. However, in the event of a favourable opinion from the CEIm, the decision on

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authorisation of the trial shall be subject to the submission of this documentation to the CEIm within

thirty calendar days and the study may not be started until the required insurance or financial

guarantee is considered available.

4. Damage to the study subject that could result from a low-intervention clinical trial shall not

need to be covered by the insurance or financial guarantee referred to in paragraph 2 if it is covered

by the insurance of individual or collective professional civil liability insurance or equivalent financial

guarantee of the site where the clinical trial is conducted.

5. When the sponsor and principal investigator are the same person and the clinical trial is

conducted in a health centre belonging to the public health administration, the administration may

take the measures it deems appropriate to facilitate the guarantee of the specific risks resulting from

the trial in the terms set out in the above paragraphs, with the aim of promoting research.

6. The actions of "contracted clinical investigators" related to the medical care to the subject

which is provided during the conduct of the trial for reasons not related to or arising from the trial

must be covered by insurance similar or equivalent to that protecting the rest of the site personnel for

those aspects not covered by the clinical trial insurance.

Article 10. Liability scheme.

1. It shall be presumed, unless proven otherwise, that any harm to the health of a trial subject

during the course of the trial and within one year from the end of treatment has occurred as a result

of the trial. However, once the year has concluded, the trial subject is obliged to prove the

connection between the trial and the harm caused.

2. For the purposes of the liability scheme set out in this article, all expenses derived from

impairment in the health or physical status of the subject undergoing the clinical trial shall be

considered liable for compensation, as well as any economic losses directly derived from such

impairment, provided this is not inherent to the disease under study or due to the natural course of

the disease as a result of the ineffectiveness of treatment.

3. The minimum amount that shall be guaranteed as civil liability shall be 250,000 Euros per

subject undergoing the clinical trial, which may be received as a flat rate payment or as an income

equivalent to the same capital. A maximum insured capital or maximum amount of the financial

guarantee per clinical trial and per year of 2,500,000 Euros may be established.

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CHAPTER IV

thics Committees for investigation with medicinal products

Article 11. Supervision and coordination of the Ethics Committees for investigation with

medicinal products.

1. The CEIm shall be supervised in ethical, training and material aspects in the same way as

other Ethics Committees for Investigation (CEI), in accordance with the regulations of the latter.

2. The Spanish Agency of Medicines and Medical Devices shall facilitate the assessment

procedure and issuing of an opinion by the CEIm in clinical trials with medicinal products in order to

integrate the assessment of one and the other into a single opinion per clinical trial, valid throughout

the Spanish State. For the integrated assessment to be positive, the assessment by the Spanish

Agency of Medicines and Medical Devices and the opinion of the CEIm must both be positive.

3. For coordination of the opinion in clinical trials with medicinal products, the Spanish Agency

of Medicines and Medical Devices shall carry out the following activities:

a) Facilitate the exchange of information between the Spanish Agency of Medicines and

Medical Devices and the CEIm.

b) Coordinate with the Autonomous Communities, the supervisory bodies of the CEI and the

CEIm, the development and maintenance of a single integrated information system for clinical trials

with medicinal products.

c) Manage the database of clinical trials with medicinal products of the national network of CEIm.

d) Provide advice to the CEIm on issues related to the procedure of clinical trials with medicinal

products.

e) Any other action related to the activities of the CEIm that fall under its responsibility in

accordance with applicable regulations.

Article 12. Functions of Ethics Committees for investigation with medicinal products.

1. The CEIm, in addition to the functions that could be commissioned as a CEI, shall perform

the following functions with regard to the assessment of clinical trials with medicinal products or

medical devices:

a) Assess the methodological, ethical and legal aspects and issue the respective opinion.

b) Assess substantial modifications to authorised clinical trials and issue the respective opinion.

c) Conduct a follow-up of the study from its initiation to receipt of the final report.

2. To perform these functions in clinical trials with medicinal products, the provisions set out in

Chapter V should be taken into account.

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Article 13. Accreditation of Ethics Committees for investigation with medicinal products.

1. In addition to the requirements established for the accreditation of the CEI in Act 14/2007, of

3 July, on Biomedical Research and its development regulations, CEIm must meet the specific

requirements for accreditation set out in this Royal Decree.

2. CEIm shall be accredited by the competent health authority in each Autonomous Community

or, in the case of sites belonging to the General State Administration, by the competent State body.

The Spanish Agency of Medicines and Medical Devices, in coordination with the Autonomous

Communities, through the Technical Inspection Committee, shall set common specific criteria for the

accreditation, inspection, and renewal of accreditation of these committees.

3. This accreditation must be renewed periodically by the competent health authority, without

prejudice to the procedure provided for maintenance of accreditation as a CEI, according to the

procedures and timelines established by the Technical Inspection Committee. Both the initial

accreditation and its renewals must be notified to the Spanish Agency of Medicines and Medical

Devices, which shall publish them on its website, as well as to whom is determined in the applicable

regulations of the CEI.

Article 14. Technical secretariat.

1. Each accredited CEIm must have a stable professional technical secretary integrated in the

organisational chart of the institution to which this person is assigned or from its supporting institutions.

2. The technical secretariat shall have the following functions:

a) To manage the activity of the CEIm.

b) To act as the interlocutor on behalf of the CEIm as regards communication with all agents

concerned, including the Spanish Agency of Medicines and Medical Devices.

c) To ensure that the necessary on-site and non-on-site meetings are held so that the CEIm

complies with its duties in the established time periods.

d) To prepare, in collaboration with the members of the CEIm, any reports that are requested by

the Spanish Agency of Medicines and Medical Devices or any other competent authority to maintain

its accreditation as an CEIm.

3. The technical secretariat must have the following resources and facilities:

a) A person in charge holding a higher degree and with knowledge of medicine, investigation

methodology, bioethics, pharmacology, and medicinal product regulation and biomedical

investigation in general.

b) Specific facilities for the performance of their work under conditions that ensure

confidentiality. They should have an appropriate space for holding meetings and for the handling and

filing of confidential documents.

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c) Computer equipment with sufficient capacity to handle all the information received and

generated by the committee and connection to the information system of the country-specific

database of clinical trials with medicinal products and "EU portal" and "EU database", when they are

available.

d) A specific annual financial budget, approved by the management of the institution, to be used

for training activities organised for members of the CEIm and, where appropriate, a budget allocated

to allowances for attendance of its members or possible experts or guests.

Article 15. Composition of Ethics Committees for investigation with medicinal products.

1. The CEIm shall include a minimum of ten members, at least one of which shall be a

layperson outside the field of biomedical investigation or clinical care, who shall represent the

interests of patients.

The members of this committee shall include physicians, one of whom shall be a clinical

pharmacologist, a hospital or primary care pharmacist and a certified or graduate nurse.

If there is a Committee for Investigation or an Ethics Committee for clinical practice in the site, a

member of each should be included in the CEIm.

At least two members must be professionals outside the field of healthcare, one of whom should

have a law degree.

In addition, at least one of its members must have accredited training in bioethics.

2. The composition of the CEIm should ensure the independence of its decisions and the

competence and experience of its members in the methodological, ethical and legal aspects of

research, pharmacology, and clinical care practice in both hospital and community medicine.

3. The CEIm shall have a Chair, a Vice-Chair, and a technical secretary who shall

simultaneously have the consideration of committee members.

The Chair shall be the representative of the committee and its holder shall be chosen by the

members in such a way that independence is ensured.

The Vice-Chair shall be selected similarly and shall perform the functions of the Chair in cases

of vacancy, absence or illness of its holder.

The head of the technical secretariat shall correspond to the person mentioned in article 14.3.a).

All committee members shall have one vote of equal value except for the holder of the technical

secretariat who shall have voice but no vote.

4. The CEIm shall ensure a system for renewal of members that allows new members to be

incorporated on a regular basis while also maintaining the experience of the committee.

5. Membership of an CEIm shall be incompatible with any other class of interests derived from

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the manufacture or sale of medicines and medical devices. Members of the CEIm must ensure the

confidentiality of the information to which they have access and must make a public conﬂict of

interest statement.

6. The competent authorities with regard to the CEIm shall establish criteria by which the

activities of its members may have a positive impact on their professional career.

Article 16. General rules on the functioning of Ethics Committees for investigation with medicinal

products.

1. Neither the CEIm as a whole nor any of its members may receive directly nor indirectly any

remuneration from the study sponsor.

2. The collection of fees for performance of any of the functions of the CEIm referred to in article

12 shall be governed by article 33.

An agreement between the site and the sponsor for payment of administrative expenses shall

be possible, but it must always be regulated as an additional economical condition to those specified

in the contract referred to in article 32.1, or be published by the competent national or autonomic

health authority in their respective official journals and, in any event, may never be established as an

item contingent on compliance with any of the functions of the CEIm referred to in article 12.

3. The CEIm must prepare and follow standard operating procedures for its functioning, which

should refer to at least the following:

a) The composition and requirements that must be fulfilled by its members.

b) The frequency of on-site and non-on-site meetings which must at least ensure compliance

with the assessment timelines of this Royal Decree. The CEIm shall make public the schedule of its

meetings with information about its availability for assessment of new clinical studies at each

meeting.

c) The procedure for convening its members.

d) The aspects relating to administrative functioning.

e) The cases in which an expedited review of the documentation of a clinical study may be

performed and the procedure to be followed in these cases, including "low-intervention clinical trials".

f) The initial assessment of protocols and the procedure for follow-up of studies.

g) The mechanisms for ordinary and extraordinary decision-making which should include a

written procedure for decision-making.

h) The preparation and approval of the minutes of the meetings.

i) The archiving and storage of committee documentation and that related to assessed clinical

trials in accordance with paragraph 7.

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j) A procedure to declare an incompatibility occurring in a member of the CEIm and the

guarantees to ensure confidentiality in its internal functioning.

4. When the CEIm does not possess the knowledge and experience necessary to evaluate a

specific clinical study, it shall seek the advice of at least one expert not belonging to the committee,

who shall be obliged to maintain confidentiality. This advice shall be considered specifically when:

a) The committee assesses clinical research protocols with surgical procedures, diagnostic

techniques, medical devices or advanced therapies. In this case, it shall be advised by at least one

expert in the procedure or technology to be assessed.

b) The committee assesses clinical trials on subjects with special vulnerability. In this case, it

shall be advised by at least one person with experience in the treatment of the study population and,

if applicable, in the treatment of the disease.

5. The principal investigator or members of the investigator team of a clinical study cannot be

take part in the assessment or give an opinion on their own protocol, even when they are members

of the committee. When such circumstances occur, it shall be noted in the minutes referring to the

assessment of the trial by the committee that this principle was respected.

6. Non-on-site meetings may be held by telephone multiconference, videoconference or any other

analogous system, so that members of the CEIm can attend this meeting by the indicated system,

provided communication between them is ensured in real time and, therefore, the unity of the act.

Each meeting of the CEIm shall be recorded in the corresponding minutes, which as a minimum

shall specify the members in attendance, both on-site and non-on-site, and the consultants

attending, if applicable, and it shall be indicated that for each assessed study the aspects included in

the applicable regulation have been considered and the decision adopted for each study shall be

recorded.

7. The committees shall keep all essential documents related to each clinical study assessed for

at least three years after completion of the study or for a longer period if this is established by the

Spanish Agency of Medicines and Medical Devices in collaboration with the Autonomous

Communities. The contents of the clinical trial file shall be indicated in the instructions for the conduct of

clinical trials in Spain that are published by the Spanish Agency of Medicines and Medical Devices.

CHA

PTER V

ubmission, validation, and procedure for assessment and authorisation of clinical trials with

medicinal products

Section 1. Common provisions

Article 17. Requirements for the conduct of clinical trials.

1. Clinical trials with medicinal products shall be subject to prior authorisation from the Spanish

Agency of Medicines and Medical Devices, after a scientific and ethical assessment of Parts I and II.

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2. In order to start a clinical trial with medicinal products in a site, the following shall be required:

a) The favourable opinion issued by an CEIm in Spain as indicated in article 24, which shall be

single and binding.

b) The decision for authorisation by the Spanish Agency of Medicines and Medical Devices.

c) The agreement of the participating site management which shall be expressed by the signing

of the contract between the sponsor and the site referred to in article 32. Only in clinical trials in

which the sponsor/investigator belongs to the site and signing of the contract is not required shall the

express agreement of the participating site management be required.

This contract may be concluded at any time and shall be effective when the clinical trial is

authorised by the Spanish Agency of Medicines and Medical Devices and the favourable opinion of

the CEIm for conducting the trial at said site is available.

3. No clinical trials with gene therapy medicinal products which result in modifications to the

subject's germ line genetic identity may be conducted.

Article 18. Collaboration and information exchange between the Spanish Agency of Medicines

and Medical Devices and the CEIm.

1. The Spanish Agency of Medicines and Medical Devices shall establish the mechanisms and

procedures for cooperation and exchange of information on clinical studies with medicinal products

and clinical investigations with medical devices with the CEIm, which shall be made public.

2. This shall be set out in a "collaboration memo" containing and specifying the responsibilities

of the CEIm and of the Spanish Agency of Medicines and Medical Devices, as well as those aspects

which, in accordance with article 22 and successive articles, shall be subject to assessment and

responsibility by each of them, so as to ensure the greatest efficiency and guarantees in the

assessment and permit, in the multinational clinical trials conducted in the European Union, a single

decision for Spain.

3. The "collaboration memo" shall establish which parts of the application dossier shall be

submitted in Spanish and which may be accepted in a language commonly understood in the

medical field as indicated in Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014.

Article 19. Exchange of information between the Spanish Agency of Medicines and Medical

Devices and the Autonomous Communities.

1. The Spanish Agency of Medicines and Medical Devices shall establish with the competent

bodies of the Autonomous Communities the framework of cooperation and a procedure for exchange

of information on clinical studies with medicinal products and clinical investigations with medical

devices.

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2. The instructions for the conduct of clinical trials in Spain published by the Spanish Agency of

Medicines and Medical Devices shall contain the contact points of the Autonomous Communities to

which the information must be sent while this process is still not available.

Article 20. Aspects of a clinical trial requiring assessment.

1. The CEIm and the Spanish Agency of Medicines and Medical Devices shall assess the

clinical trial documentation.

2. The assessment shall be differentiated into two parts, called Part I and Part II of the

assessment report:

a) Part I shall include the aspects listed in article 6 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of April 16 2014.

b) Part II shall include the aspects listed in article 7 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014. The assessment referred to in point h) of

paragraph 1 of article 7 must include the arrangements as regards the collection, storage and

possible future use of the biological samples of trial subjects obtained at the same site or

collaborating sites, including pre-screening samples of the subjects, ensuring that no procedure is

performed that would prevent future application of article 3.2 of Royal Decree 1716/2011, of 18

November.

3. The Spanish Agency of Medicines and Medical Devices and CEIm shall agree in the

"collaboration memo" on the distribution of responsibilities for the assessment of applications.

4. In accordance with article 29.5 of Royal Decree Act 9/2014, of 4 July, establishing the

standards of quality and safety for the donation, procurement, testing, processing, safeguarding,

storage and distribution of human tissues and cells and approving the standards of coordination and

operation for use in humans, in cell therapy clinical trials, in addition to the provisions in paragraph 2,

the Spanish Agency of Medicines and Medical Devices shall request a report from the National

Transplant Organisation. This report must be issued in the form and timelines required for fulfilling

the requirements set out in Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014.

Section 2. Procedure for authorisation of a clinical trial

Article 21. Submission of applications and receipt of notifications.

1. The sponsors shall submit their applications and communications and shall receive

notifications through the portal mentioned in article 80 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014 ("EU portal"), addressed to the Spanish

Agency of Medicines and Medical Devices and the CEIm that has accepted the assessment.

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2. The documentation that must accompany the application for authorisation and an opinion on

the clinical trial is set out in Annex I of Regulation (EU) No 536/2014 of the European Parliament and

of the Council, of 16 April 2014, in current European guidelines and, if applicable, in the instructions

for the conduct of clinical trials in Spain which, developing the aforementioned Annex I, are published

by the Spanish Agency of Medicines and Medical Devices.

Article 22. Validation of the application.

1. The Spanish Agency of Medicines and Medical Devices shall assess whether or not to accept

the status of "clinical trial" for the study and shall verify that the application is complete with regard to

the documents of Part I, so as to perform the assessment referred to in article 6 of Regulation (EU)

No 536/2014 of the European Parliament and of the Council, of 16 April 2014.

2. The CEIm shall verify that the application is complete regarding the documents of Part II so

as to perform the assessment referred to in article 7 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014.

3. The validation shall be performed in accordance with the timelines and the procedure set out

in article 5 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16

April 2014.

Article 23. Part I of the assessment report.

1. The Spanish Agency of Medicines and Medical Devices shall be responsible for notifying the

sponsor of Part I of the assessment report, including those aspects that have been assessed by the

CEIm, in such a way that the sponsor is notified in the timelines and according to the procedure

indicated in article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the Council,

of 16 April 2014.

2. The participation of the CEIm in the assessment of Part I shall be established in the

collaboration memo referred to in article 18, as well as the timelines for transmitting its report to the

Spanish Agency of Medicines and Medical Devices, so that the indications in the preceding

paragraph can be adhered to.

3. In the case of an assessment coordinated by a reporting Member State, the terms specified

in paragraph 2 of article 8 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, shall be borne in mind.

Article 24. Part II of the assessment report.

The CEIm shall be responsible for preparing Part II of the assessment report so that it is in

compliance with the timelines and the procedure specified in article 7 of Regulation (EU) No

536/2014 of the European Parliament and of the Council, of 16 April 2014.

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Article 25. Decision on authorisation.

1. The Director of the Spanish Agency of Medicines and Medical Devices, within five days as

prescribed in article 8 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, shall issue the decision authorising the clinical trial, authorising the clinical

trial subject to conditions, or refusing the authorisation.

2. This decision ends the administrative proceedings, so the interested party may file an appeal

for reversal or reconsideration in accordance with the provisions set forth in articles 116 and 117 of

Act 30/1992, of 26 November, on the Legal Regime of Public Administration and Common

Administrative Procedure or a contentious-administrative appeal in accordance with Act 29/1998, of

13 July, on Contentious-Administrative Jurisdiction.

3. The authorisation of the clinical trial shall be understood to be granted without prejudice to the

application, where appropriate, of Act 9/2003, of 25 April, on the legal regime of confined utilisation,

voluntary release and commercialisation of genetically modified organisms.

Article 26. Modification of the conditions of authorisation of clinical trials.

1. Any "substantial modification" in the authorised conditions for a clinical trial may not be made

without the prior favourable opinion of the CEIm and authorisation from the Spanish Agency of

Medicines and Medical Devices.

However, should there be any circumstances that might affect the safety of the participating

subjects, the sponsor and the investigator shall take the appropriate urgent safety measures to

protect the subjects against any immediate risk. The sponsor shall inform both the Spanish Agency

of Medicines and Medical Devices and the CEIm of these circumstances and the measures taken as

soon as possible.

2. As a rule, the CEIm and the Spanish Agency of Medicines Products and Medical Devices

shall assess those aspects on which they had already reached a decision in the initial assessment

report referred to in articles 23 and 24, without prejudice to when the "collaboration memo" referred

to in article 18 establishes a different distribution of the tasks.

3. The application must be submitted to the Spanish Agency of Medicines and Medical Devices and

to the CEIm that assessed the initial application as indicated in Chapter III and article 25 of Regulation

(EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014, in current European

guidelines and, where appropriate, in the corresponding part of the instructions for the conduct of clinical

trials in Spain published by the Spanish Agency of Medicines and Medical Devices.

4. The validation and assessment of Part II of the substantial modification by the CEIm, where

applicable, shall be in accordance with the deadlines and assessment procedure set out in articles

20, 21 and 22 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16

April 2014.

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5. The validation and assessment of Part I of the substantial modification by the Spanish

Agency of Medicines and Medical Devices shall be in accordance with the terms specified in articles

17, 18, 21 and 22 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of

16 April 2014.

6. The authorisation decision shall be issued taking into account the provisions contained in

articles 19, 20, and 23 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, and as indicated in article 25 of this Royal Decree. However, in the event

of substantial modifications that only involve changes in aspects included in Part II of the

assessment report, the authorisation shall be considered granted or refused on the date when the

CEIm informs the sponsor of its decision with the conclusions of Part II of the assessment report.

Article 27. Suspension or revocation of the authorisation of a clinical trial.

1. The authorisation of the clinical trial shall be suspended or revoked, ex officio or on the

justified request by the sponsor, by decision of the Spanish Agency of Medicines and Medical

Devices in the cases listed in article 77 of Regulation (EU) No 536/2014 of the European Parliament

and of the Council, of 16 April 2014.

2. The decision to suspend or revoke authorisation of the trial shall be adopted by the Spanish

Agency of Medicines and Medical Devices after initiating the appropriate procedure, including

granting a hearing to the interested party who must reply within seven calendar days from notification

of the start of the procedure.

Once this decision is adopted, the Spanish Agency of medicines and Medical Devices shall

notify the decision reached, expressly indicating the reasons, to the CEIm, the European

Commission, the European Medicines Agency, the health authorities of the Autonomous

Communities and the health authorities of other Member States.

3. The health authorities of the Autonomous Communities may order a precautionary

suspension of the clinical trial in the cases laid down in paragraph 1 and shall notify it immediately,

accompanied by a duly detailed and justified report, to the Spanish Agency of Medicines and Medical

Devices, which, in accordance with that established in paragraph 2, shall decide on suspension or

revocation of the clinical trial authorisation or, where appropriate, lift the precautionary measure.

4. This decision ends the administrative proceedings, so the interested party may file an appeal

for reversal or reconsideration in accordance with the provisions set forth in articles 116 and 117 of

Act 30/1992, of 26 November, or a contentious-administrative appeal in compliance with Act

29/1998, of 13 July.

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Article 28. Corrective measures to be adopted by the Spanish Agency of Medicines and Medical

Devices.

1. The Spanish Agency of Medicines and Medical Devices, ex officio or on justified request by

the CEIm may require the sponsor to modify any aspect of the clinical trial.

2. The decision to require modification of any aspect of the trial shall be adopted after initiating

the appropriate procedure, including granting of a hearing to the interested party, who must reply

within seven calendar days from notification of the start of the procedure.

3. This decision ends the administrative proceedings, so the interested party may file an appeal

for reversal or reconsideration in accordance with the provision set forth in articles 116 and 117 of

Act 30/1992, of 26 November, or a contentious-administrative appeal in accordance with Act

29/1998, of 13 July.

Article 29. Reporting of serious breaches.

1. Serious breaches of the authorised protocol or of this Royal Decree occurring in Spain must

be reported by the sponsor without undue delay and no later than seven calendar days from

becoming aware of the breach to the Spanish Agency of Medicines and Medical Devices and the

CEIm by the means indicated in article 21.

2. To this end, a serious breach shall be defined as a breach that may significantly affect the

safety and rights of the trial subjects or the reliability and robustness of the data generated in the

clinical trial.

3. The Spanish Agency of Medicines and Medical Devices shall inform the health authorities of

the Autonomous Communities on those serious breaches directly affecting sites belonging to their

community.

Article 30. End of a clinical trial, temporary halt and early termination of a clinical trial and

submission of the results.

1. The sponsor shall notify the date of the end of the clinical trial in Spain, the date of the end of

the clinical trial in all countries where the trial has been conducted, as well as any temporary halt of

the trial and the results thereof in accordance with the timelines and the procedure indicated in

articles 37 and 38 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of

16 April 2014.

2. In the event of early termination of the clinical trial, the notification shall indicate the reasons

for such action and shall specify the follow-up measures, without prejudice to the subsequent

sending of the summary of the results required in Annexes IV and V of Regulation (EU) No 536/2014

of the European Parliament and of the Council, of 16 April 2014. This information shall be

transmitted to the health authorities of the Autonomous Communities as specified in article 19. The

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date of the end of the clinical trial and the reasons for early termination must be published by the

Spanish Agency of Medicines and Medical Devices.

CHAPTER VI

ontinuation of treatment after the trial

Article 31. Continuation of treatment with a medicinal product without marketing authorisation in

Spain after the end of the trial.

Any continuation in the administration of an investigational medicinal product without marketing

authorisation in Spain to subjects who have completed their participation in a clinical trial, for as long

as the medicinal product is not actually marketed in Spain for those conditions of use, shall be

governed by the rules established in Royal Decree 1015/2009, of 19 June, regulating the availability

of medicinal products in special situations. Supply of these medicinal products should adhere to the

provisions contained in paragraph f) of article 39.3, if the sponsor obtains any information from the

administration and use of said medicinal product under these conditions.

CHAPTER VII

Financial aspects

Article 32. Financial aspects of a clinical trial.

1. All financial aspects related to a clinical trial must be reflected in a contract between the

sponsor and each of the sites where the trial is to be conducted.

A financial budget for the project including all the aspects specified in the contract of all

participating sites must be sent to the CEIm.

2. The competent health administrations for each health department shall establish common

requirements and conditions for financing and shall agree on a single contract form which shall be

valid for the whole National Health System. This single contract form shall be prepared in

accordance with the general principles of coordination agreed by the Inter-Territorial Board of the

National Health System and must have its approval before it is used.

3. The contract shall state:

a) The initial budget for the clinical trial, specifying the indirect costs that shall be applied by the

site as well as the extraordinary direct costs, considering as such any extra expenses to those which

would have been incurred if the subject had not participated in the clinical trial, such as:

1. Additional laboratory tests and examinations.

2. Changes in the duration of the care afforded to patients.

3. Reimbursement of expenses to patients.

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4. Purchase of devices and compensation for trial subjects and investigators.

b) The payment terms and periods.

c) Any other subsidiary liability assumed by the parties in accordance with the conditions

established in each site.

4. No additional amounts to those foreseen in the financial budget submitted to the CEIm may

be required by the sites, except for those which may be approved in accordance with article 31 and

that referred to in article 16.

Article 33. Fees.

1. Pursuant to article 87 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, payment of a single fee shall be required for the assessment of a clinical

trial, regardless of whether various organisations are involved in the assessment. This fee shall be

set in the current legislation in a transparent manner and on the basis of cost recovery principles.

The sponsor must pay this fee to the Spanish Agency of Medicines and Medical Devices which shall

be responsible for transferring to the CEIm the part corresponding to their assessment.

2. In no case may the payment of fees not covered in the corresponding legal framework be

required by the sites with regard to the conduct of the trial or in connection with the performance of

any of the functions of an CEIm related to the assessments referred to in article 12.

3. Clinical studies corresponding to the definition of "non-commercial clinical research" shall

benefit from the exemptions of fees or reduced fees, in accordance with the consolidated text of the

Act on guarantees and rational use of medicinal products and medical devices, approved by Royal

Legislative Decree 1/2015, of 24 July.

CHAPTER VIII

Medicinal products used in a clinical trial

Article 34. Manufacture and importation of investigational medicinal products or auxiliary

medicinal products.

1. The manufacture and importation of investigational medicinal products for their use in the

context of a clinical trial can only be performed by manufacturers and importers of medicinal

products that have the appropriate authorisation in accordance with the provisions of Royal Decree

824/2010, of 25 June, regulating pharmaceutical laboratories, manufacturers of active substances for

pharmaceutical use and foreign trade in medicinal products and investigational medicinal products.

2. The aforementioned authorisation shall not be required for relabelling or repackaging, if it is

performed at an authorised pharmacy department of a participating site, provided the investigational

medicinal products are intended to be used only in hospitals, health centres, or clinics participating in

the same clinical trial.

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3. When in the context of a specific clinical trial whose sponsor is an investigator or a group of

investigators, an authorised pharmacy of a participating site wishes to perform a manufacturing

operation different from those previously considered, it must request prior authorisation from the

Spanish Agency of Medicines and Medical Devices and the medicinal product may only be used in

the specific clinical trial. The Spanish Agency of Medicines and Medical Devices shall agree with the

Autonomous Communities on the verification procedures of good manufacturing practice of

medicinal products applicable in these cases.

4. In addition, the authorisation as a manufacturer and importer of medicinal products indicated

in paragraph 1 shall not be required for sites linked to the National Health System where

investigational advanced therapy medicinal products are prepared for use in clinical trials approved

by the Spanish Agency of Medicines and Medical Devices, without prejudice to the requirement for

specific quality standards.

5. The manufacture of investigational medicinal products must comply with the applicable

guidelines of good manufacturing practice in the European Union.

6. The manufacturer must have permanently and continuously at their disposal a qualified

person or technical director, in accordance with the provisions of Royal Decree 824/2010, of 25

June. The responsibilities of the qualified person or technical director are established in the

aforementioned Royal Decree.

In the case of an investigational medicinal product from a third country and that has a marketing

authorisation in that country, when documentation cannot be obtained to certify that each

manufacturing batch was manufactured according to correct manufacturing practices at least

equivalent to those indicated above, the qualified person or technical director must ensure that each

manufacturing batch has been subject to all the pertinent analyses, tests or checks required to verify

its quality.

7. The authorisation for the importation of investigational medicinal products for use in the

context of a clinical trial shall be considered as granted if within sixty calendar days from receipt of

the application, the Spanish Agency of Medicines and Medical Devices has not notified any

reasoned objections to the sponsor, provided that the trial is authorised.

8. The application for importation of investigational medicinal products may be requested in a

single act with the application for conduct of the clinical trial for which they are intended.

The authorisation for manufacture or importation of blood derivatives, narcotics or psychotropic

agents shall be governed by the specific regulations in this area.

Article 35. Labelling.

1. Labelling of the investigational or auxiliary medicinal products shall be as indicated in articles

66 to 68 of Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April

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2014, taking into account the requirements set out in the detailed guidelines for good manufacturing

practice applicable to investigational medicinal products in the European Union and, where

applicable, the instructions of the Spanish Agency of Medicines and Medical Devices.

2. Except for justified exceptions, labelling should appear in at least the official language of the

State.

Article 36. Purchase of medicinal products for clinical trials.

1. Wholesalers and pharmaceutical manufacturers may supply to the sponsor of an authorised

clinical trial the medicinal products included in this trial, against prior presentation by the same of the

authorisation issued by the Spanish Agency of Medicines and Medical Devices for the trial.

2. When the medicinal products to be used in a clinical trial come from a third country, the

provisions in article 34 as regards importation of investigational medicinal products shall be borne in

mind.

Article 37. Remaining medication of a clinical trial.

1. In the case of investigational medicinal products and auxiliary medicinal products marketed in

Spain, once the clinical trial has ended, the remaining packs that are unchanged, that is, which have

not been modified either in their inmediate or outer packaging, may be used in normal clinical

practice, in the conditions stipulated in its marketing authorisation and always under express and

previous authorisation by the sponsor.

2. In the case of investigational medicinal products not marketed in Spain, after finalisation of

the clinical trial the sponsor may request the use of unaltered remaining packs for continuation of

treatment outside the study in accordance with the terms specified in article 31.

CHAPTER IX

ood clinical practice guidelines

Article 38. Good clinical practice guidelines.

1. The sponsor of a clinical trial and the investigator shall ensure that the clinical trial complies

with the protocol and with the principles of good clinical practice.

2. Without prejudice to other provisions, the sponsor and the investigator, when preparing the

protocol and applying this Royal Decree to the protocol, shall take duly into account the quality

standards and guidelines of the International Conference on Harmonisation (ICH) on good clinical

practice.

3. Clinical trials with advanced therapy medicinal products shall additionally comply with the

guidelines for good clinical practice which are specific for advanced therapy medicinal products.

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4. The Spanish Agency of Medicines and Medical Devices shall make the good clinical practice

guidelines referred to in this article publicly accessible.

Article 39 Sponsor.

1. The sponsor or his/her legal representative must be established in one of the Member States

of the European Union.

2. The sponsor is responsible for signing the application for an opinion by the CEIm and the

application for authorisation by the Spanish Agency of Medicines and Medical Devices.

3. The responsibilities of the sponsor are:

a) To establish and maintain a quality assurance and quality control system with written

standard operating procedures so as to ensure that trials are conducted and data are generated,

documented and reported in compliance with the protocol, good clinical practice guidelines and the

provisions of this Royal Decree. The sponsor should have in place standard operating procedures to

ensure quality standards in all the phases of documentation of an adverse event, data collection,

validation, assessment, archiving, reporting and follow-up.

b) To sign jointly with the relevant investigator the protocol and any amendment to the protocol.

c) To select the most suitable investigator based on his/her qualifications and available

resources, and to ensure said investigator conducts the trial as specified in the protocol.

d) To provide all the basic and clinical information available on the investigational product and

maintain it updated throughout the duration of the trial.

e) To request the opinion of the CEIm and the authorisation by the Spanish Agency of

Medicines and Medical Devices, as well as notifying them of the start of the trial, serious breaches of

the protocol and other required information, and to obtain the relevant authorisations, without

prejudice to the notifications that must be submitted to Autonomous Communities in accordance with

article 19.

f) To provide the investigational medicinal products at no cost and to ensure that they have been

prepared according to good manufacturing practice and the samples are suitably packaged and

labelled. The sponsor is also responsible for the storage of samples and their manufacturing and

quality control protocols, keeping records of the samples delivered and ensuring that the site where the

trial is conducted establishes a procedure for the correct handling, storage and use of these samples.

In clinical trials sponsored by an investigator of a site or a non-profit scientific entity, or in those

where there is mutual agreement with the site management where the clinical trial is to be

conducted, other means of supply may be agreed with the site, particularly when treatment of the

patients in the trial, or part of it, was that they would receive in the event of having decided not to

participate in the trial.

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g) To ensure that participation of a subject in the clinical trial shall involve no other additional

cost than that which the subject would have had to incur in the context of normal clinical practice.

h) To appoint the monitor who shall supervise the conduct of the trial.

i) To report suspected unexpected serious adverse reactions in accordance with articles 49 to 53.

j) To immediately provide the investigator, the Spanish Agency of Medicines and Medical

Devices and the CEIm with any significant information related to the clinical trial to which the sponsor

has access during the trial.

k) To comply with the obligations of damage compensation according to the terms provided in

article 9. To provide the legal and financial cover to the investigator in these cases, except when the

injury arises from negligence or malpractice on the part of the investigator.

l) To agree with the investigator on the obligations for data processing, preparation of reports

and publication of results. In any case, the sponsor is responsible for preparing the final report and

annual reports of the clinical trial and for submitting them to the appropriate authorities.

m) The sponsor shall provide a contact point where the trial subjects may obtain further

information about the clinical trial, which may be optionally delegated to the investigator.

n) To comply with the obligations that are imposed by the Spanish Clinical Studies Registry for

publication of the clinical trials of which it is the sponsor.

ñ) To agree with the investigator, the site management and the CEIm on alternative modes of

distribution in those cases where the site has no Pharmacy Department. In this case, shipments of

the investigational products to the research site by the sponsor shall be possible, the investigator of

this site assuming the responsibilities as regards correct administration, custody and delivery of

these medicinal products, in accordance with that specified in the study protocol.

4. The sponsor of a clinical trial may delegate all or part of his/her tasks to an individual, a

contract research organisation (CRO), an institution or body, which must have a quality assurance

and quality control system.

5. Sponsor obligations established in good clinical practice guidelines that have been delegated

shall apply to the contracted individual, CRO, company, institution or body. However, in these cases,

the sponsor shall still be responsible for ensuring that the conduct of the clinical trial and the final

data generated in this study comply with the provisions in this Royal Decree. Any delegation of

sponsor functions in connection with a clinical trial should be specifically documented in a contract

between both parties.

6. The sponsor and the investigator may be the same person.

7. If a clinical trial has more than one sponsor, all co-sponsors shall assume the sponsor

responsibilities established in this article, unless they decide otherwise in a contract detailing their

respective responsibilities. If the contract does not specify to which co-sponsor a given responsibility

is attributed, this shall fall on all of them.

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8. Without prejudice to paragraph 7, all co-sponsors shall be jointly responsible for designating:

a) A sponsor responsible for compliance with the sponsor obligations regarding the

authorisation procedures established in Chapter V.

b) A sponsor responsible for being the contact point for receiving and answering all questions of

the trial subjects, investigators, the CEIm, or the Spanish Agency of Medicines and Medical Devices

relating to the clinical trial.

c) A sponsor responsible for applying any corrective measures that are imposed on him/her.

Article 40. Monitor.

1. The responsibilities of the monitor are:

a) To work according to sponsor standard operating procedures, visit the investigator before,

during and after the trial, according to the type of study, to control compliance with the protocol and

ensure that all data are correctly and completely recorded and reported, as well as ensuring that

informed consent is obtained from all subjects prior to their enrolment in the clinical trial.

b) To ensure that the investigators and the sites where the trial is conducted are adequate for

this purpose throughout the duration of the clinical trial.

c) To ensure that both the principal investigator and the members of the team of investigators

have been adequately informed and to guarantee that communications between the investigator and

the sponsor are prompt at all times, particularly with regard to supervision of trial safety.

d) To verify that the investigator complies with the protocol and all its approved modifications.

e) To check that the storage, distribution, returns and documentation of the investigational

medicinal products is safe and appropriate.

f) To submit to the sponsor reports on monitoring visits and all relevant contacts with the

investigator.

2. Under no circumstance may the monitor be part of the research team.

Article 41. Investigator.

1. The investigator directs and is responsible for the practical conduct of the clinical trial in a

certain site.

2. Only a doctor or a person practising a profession recognised in Spain for conducting

investigations given his/her scientific background and experience in the required patient care can act

as the investigator.

3. The responsibilities of the investigator are:

a) To sign the protocol of the clinical trial together with the sponsor.

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b) To be thoroughly familiar with the properties of the investigational medicinal products.

c) To ensure that informed consent is obtained in compliance with this Royal Decree.

d) To collect, record and report trial-related data appropriately and to ensure their accuracy.

e) To follow the instructions for the reporting of adverse events established in the protocol.

f) To notify the sponsor immediately of any serious breaches of the protocol.

g) To ensure that all persons involved in the clinical trial shall respect the confidentiality of any

information concerning trial subjects, as well as the protection of their personal data.

h) To submit regular progress reports to the CEIm on the status of the clinical trial.

i) To be jointly responsible with the sponsor for the preparation of the final report of the clinical

trial, and signing of the same report to confirm his/her agreement.

4. Each person participating in the conduct of a clinical trial shall be qualified by his/her

education, training, and experience to perform his/her tasks. Likewise, the investigator shall ensure

that his/her research team is informed about the protocol, the investigational medicinal products and

their functions in the study.

5. The principal investigator may delegate tasks to the members of the research team. Such

delegation does not exempt the investigator from being responsible for conducting the clinical trial in

accordance with current legislation. The investigator responsibility delegation sheet of each clinical

trial must not only state the participating personnel but also the co-investigators, to whom the

performance of any function has been delegated, as well as their functions and responsibilities. If

changes are made, they should be noted.

6. Contracted personnel must be authorised by the management of the site, specifying if they

have access or not to the clinical history and personal data of the subjects included in the trial. This

authorisation may be accomplished in two ways, by:

a) The signing of a contract, if the personnel are contracted by the site.

b) A separate access document if the personnel are contracted by third parties.

Article 42. Publications.

1. The sponsor is obliged to publish the results, whether positive or negative, of authorised

clinical trials, preferably, in scientific journals before being disclosed to the non-healthcare public,

regardless of the obligations of publication of the summary of the results in the Spanish Clinical

Studies Registry (REec) and of the applicable provisions of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014.

2. Whenever research work or studies on medicinal products directed to the scientific

community are published, they shall state the funds obtained by the author for or by the conduct of

the study and the funding source.

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3. The anonymity of the subjects participating in the clinical trial shall be maintained at all times.

4. Treatments of as yet undetermined efficacy shall not be made known in a premature or

sensationalist fashion, nor shall their efficacy be exaggerated. No advertising shall be made of

interim results that may compromise the reliability of the final results of the trial.

5. Advertising of investigational medicinal products for human use is strictly prohibited, as

specified in the consolidated text of the Act on guarantees and rational use of medicinal products

and medical devices approved by Royal Legislative Decree 1/2015, of 24 July, in Royal Decree

1416/1994, of 25 June, regulating the advertising of medicinal products for human use, in Royal

Decree 1907/1996, of 2 August, on advertising and commercial promotion of products, activities, and

services for alleged health purposes, and in General Act 34/1988, of 11 November, on advertising.

6. In all cases, publication of general research results once the clinical trial is completed shall be

in accordance with the European Commission guidelines and, where appropriate, the instructions of

the Spanish Agency of Medicines and Medical Devices.

7. When a substudy of a clinical trial ends on a later date than the rest of the clinical trial, it shall

be required to publish the summary of its results in the year following its completion, without this

implying a delay in submitting the results of the rest of the clinical trial.

Article 43. Content and archiving of the clinical trial master file.

1. The clinical trial master file shall comply with the provisions laid down in articles 57 and 58 of

Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014. The

content must take into account the supplementary guidelines in this regard published by the

European Commission.

2. The sponsor and investigator shall keep the contents of the master file in paper or digital

format of each clinical trial during at least twenty-five years after the end of the clinical trial, or for a

longer period if this is laid down in other applicable requirements, such as in the event of the study

being submitted as a basis for the authorisation of a medicinal product which must comply with

Annex I of Royal Decree 1345/2007, of 11 October, or an agreement between the sponsor, the

investigator and the site.

3. The contents of the master file shall be archived in a way that ensures that it is readily

available and accessible, upon request, to the competent authorities.

4. The clinical history of trial subjects shall be kept in safekeeping as provided for under the

provisions laid down in Act 41/2002, of 14 November, and in accordance with the maximum period

allowed by the hospital, institution or private clinic.

5. Any transfer of ownership of the content of the clinical trial master file shall be documented

and the new owner shall assume the responsibilities set out in this article.

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6. The sponsor shall appoint individuals within its organisation to be responsible for archives

and access to these archives shall be restricted to those designated individuals.

7. The media used to archive the essential documents shall generally be in electronic format

and they must ensure that the content remains complete and legible throughout the planned period

of retention and is accessible, upon request, to the competent authorities. Any alteration to the

records must be traceable, allowing the original and corrected data entry to be known, along with the

date and signature of the author.

This documentation must be archived, preferably grouped by protocols, in a location that

ensures the confidentiality of the information throughout the required archiving period.

In the case of pending legal proceedings, the essential documents shall be kept while there is

no final court decision.

CHAPTER X

Verification of compliance with the good clinical practice guidelines

Article 44. General provisions regarding inspection.

1. The Spanish Agency of Medicines and Medical Devices and the competent health authorities

of the Autonomous Communities, within the scope of their respective competences, shall verify

compliance with this Royal Decree, good clinical practice guidelines and good manufacturing

practice guidelines in clinical trials conducted in Spain through the corresponding inspections.

2. The authorities of the General State Administration and the competent Autonomous

Communities shall provide mutual assistance in these inspections.

3. In the activity of inspection of good clinical practice, they must comply with the requirements

on personal data protection set out in Organic Act 15/1999, of 13 December.

4. The inspections shall be carried out in accordance with the guidelines prepared at European

level to support mutual recognition of the conclusions of inspections within the European Union.

5. The relationship with the competent authorities of the Member States of the European Union

regarding inspection of good clinical practice shall be carried out through the Spanish Agency of

Medicines and Medical Devices.

6. When a health authority of a Member State of the European Union requests information

related to an inspection by a reasoned letter, the Spanish Agency of Medicines and Medical Devices

shall send the relevant report. For this, where appropriate, the report shall be requested from the

competent authorities of the Autonomous Community in which the site is situated.

7. Likewise, when information needs to be requested from another Member State on an

inspection carried out in that State, the Spanish Agency of Medicines and Medical Devices shall

address the competent body of that State by a reasoned letter, and shall request the relevant

information.

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8. The competent authorities of third countries that are to carry out inspections of good clinical

practice in Spain must inform the Spanish Agency of Medicines and Medical Devices with sufficient

time. The sponsor shall be responsible for informing the competent authority of the third country of

this obligation of notification. The Spanish Agency of Medicines and Medical Devices shall inform the

Autonomous Community where the site to be inspected is located.

9. The Spanish Agency of Medicines Products and Medical Devices shall inform the European

Medicines Agency on the inspections carried out in Spain and their results. For this purpose, the

Autonomous Communities shall send to the Spanish Agency of Medicines and Medical Devices the

information on the inspections carried out in the format agreed in the Technical Inspection

Committee.

Article 45. Inspection procedure.

1. Inspections shall be carried out by duly qualified inspectors, appointed for this purpose, in the

sites related to the conduct of the clinical trials and, among others, in the trial site or sites where the

clinical trial is being conducted, the manufacturing site of the investigational medicinal product, any

laboratory used for analyses in the clinical trial, the CEIm, and the facilities of the sponsor and/or

research organisations or companies involved by contract in the conduct of the trial.

2. At the end of each inspection, inspectors shall draw up a regulatory inspection report that

shall be signed by the inspector or inspectors performing the inspection as well as by the inspected

parties. The report shall contain the facts and most relevant findings resulting from the inspection

actions.

3. Subsequently, the inspectors shall write a report on compliance with good clinical practice

and the requirements established in this Royal Decree, which shall conform to the agreed format by

the European Union. Before adopting the report, the inspected entity shall be given the opportunity to

submit observations on the inspection made.

4. This report must be made available to the inspected parties, the competent authorities in

Spain, and the sponsor, safeguarding the confidential aspects. Upon reasoned request, the report

can be made available to the corresponding CEIm, if it had not been direct object of the inspection,

as well as to the health authorities of the European Union, European Medicines Agency and health

authorities with which there are agreements.

5. In the event of the inspection having found serious breaches, as defined in article 52.2 of

Regulation (EU) No 536/2014 of the European Parliament and of the Council, of 16 April 2014, or

having led to the adoption of the precautionary measures stated in article 109 of the consolidated

text of the Act on guarantees and rational use of medicinal products and medical devices approved

by Royal Legislative Decree 1/2015, of 24 July the health authority approving the precautionary

measure should immediately inform this to the sponsor, the CEIm and other health authorities

according to their respective competences.

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CHAPTER XI

ommunications

Article 46. Information systems.

1. The Spanish Agency of Medicines and Medical Devices shall be the national contact point

established by article 83 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014.

2. All communications between the agents involved in the application, assessment, and

authorisation of clinical trials with medicinal products shall be submitted, when available, through the

EU portal and the EU database to which reference is made in articles 80 and 81 of Regulation (EU)

No 536/2014 of the European Parliament and of the Council, of 16 April 2014.

3. Until the information systems referred to in paragraph 2 are available or as a complement to

them:

a) The Spanish Agency of Medicines and Medical Devices shall enter in the European clinical

trials database (EudraCT) the data related to the clinical trials with medicinal products for human use

conducted in Spain.

b) The Spanish Agency of Medicines and Medical Devices shall maintain the information system

for clinical trials with medicinal products for human use conducted in Spain. This information system

shall serve as the single contact point for the sponsor in all matters relating to their clinical trials,

redirecting the information, as appropriate, to the Spanish Agency of Medicines and Medical Devices

and the CEIm, as well as to the competent authorities of the Autonomous Communities and the

REec.

4. The information system referred to in the previous paragraph shall also serve for all types of

communication and transmission of decisions between the Spanish Agency of Medicines and

Medical Devices and the CEIm with the sponsor, as well as communication and transmission of

opinions or other documents between the CEIm and the Spanish Agency of Medicines and Medical

Devices.

Article 47. Spanish Clinical Studies Registry (REec).

1. The Spanish Agency of Medicines and Medical Devices shall maintain a registry of clinical

studies with medicinal products for human use on its website.

2. The REec shall include the following information:

a) Compulsorily, clinical trials with medicinal products for human use that are authorised by the

Spanish Agency of Medicines and Medical Devices, in accordance with this Royal Decree.

b) Compulsorily, non-interventional post-authorisation studies that are to be conducted and

have been classified by the Spanish Agency of Medicines and Medical Devices.

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c) Voluntarily, as with other similar databases, other types of clinical studies sponsored by

national or international, public or private entities, provided they have at least one participating site

located in Spain including cases, or although not including cases, that have a Spanish contribution

considered as significant.

3. Registration of a clinical trial or study in the REec shall be compatible with inclusion in other

national or international registries. The REec shall include prospective information in its scope of

application from the start of its operation.

4. The REec shall include for each study the information specified in the Annex, including the

data set required in the International Clinical Trials Registry Platform of the World Health

Organisation. The Spanish Agency of Medicines and Medical Devices shall publish the

correspondence between these fields and those of the application form for authorisation of the

clinical trial submitted to the Agency for the case of clinical trials with medicinal products, as well as

those of the application form for classification of non-interventional studies.

5. In all cases, the sponsor must publish in this registry the results of the registered research

studies when they have concluded. This shall be done in accordance with the standard and the

timelines indicated in the European Commission guidelines and, where appropriate, in the

instructions published by the Spanish Agency of Medicines and Medical Devices.

Article 48. Procedure for publication of a study in the REec.

1. The REec aims to provide reliable and comprehensible information for the general public so

the information contained in some fields could be limited in extent and should be written in a simple

and accessible language to the public with no special scientific knowledge.

In order for the REec to be included in the WHO International Clinical Trials Registry Platform,

all information shall be available in Spanish and English.

2. The sponsor shall be responsible for the quality, accuracy, and regular updating of all study

information included in the REec. The Spanish Agency of Medicines and Medical Devices shall

confirm before inclusion that the data are complete and appropriate for its purposes.

3. The registration of the study must be processed, in any case, after obtaining all the

authorisations deemed necessary according to current regulations and before the inclusion of the

first subject in the study, regardless of whether the study has been previously registered in another

public registry or included or not in the WHO International Clinical Trials Registry Platform.

4. As a general rule, publication of the clinical trials shall be performed in accordance with one

of the procedures established in paragraphs 5, 6 and 7.

5. The information on clinical trials with medicinal products, which is common to the European

Union Clinical Trials Registry, shall be published by the Spanish Agency of Medicines and Medical

Devices at the time of trial authorisation. The sponsor of a clinical trial with medicinal products shall

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have a maximum of 14 calendar days from the notification of this authorisation to complete the

required additional information in the REec, with a brief summary of the clinical trial and participating

sites.

6. For registration of non-interventional post-authorisation studies in the REec, the sponsor shall

include the study data in the registry before its initiation or within 14 calendar days after obtaining the

relevant authorisations according to the applicable regulations for those studies requiring prior

authorisation.

7. The sponsor of the type of studies included in article 47.2.c) may freely choose to register

their data in the REec once the study has a favourable opinion from a REC and, where appropriate,

the relevant administrative authorisation. The opinion of the REC shall be submitted to the Spanish

Agency of Medicines and Medical Devices on applying for registration in the registry.

However, the Spanish Agency of Medicines and Medical Devices reserves the final right to

verify the information received and permit its publication in the REec or, if the information cannot be

validated, not to include it.

In any case, the Spanish Agency of Medicines and Medical Devices shall publish a document

listing the rules to be complied with for registration of studies in the REec.

8. The Spanish Agency of Medicines and Medical Devices may decide to make public partial

information about a clinical trial or a non-interventional post-authorisation study in which the sponsor

has failed to comply with the periods for submitting the information, expressly stating the sponsor

details and the reasons why this information of the registry is partial. This shall be independent of the

imposing of any punitive actions that might be applicable in accordance with current legislation.

9. It is the responsibility of the sponsor to update regularly the information included in the REec.

This update shall be mandatory with regard to the study start date in Spain, the participating sites,

the recruitment completion date in Spain, substantial modifications involving a change in the data

included in the registry and the study completion date in Spain. Updating shall be done on an overall

basis and in any event at annual intervals until the end of the study and publishing of the results.

CHAPTER XII

onitoring of the safety of investigational medicinal products

Article 49. Obligations of investigators in the recording and reporting of adverse events.

1. The investigator shall record and document any adverse events or abnormal laboratory

results that are identified in the protocol as critical to the assessment of safety and report them to the

sponsor in accordance with the reporting requirements and within the periods specified in the

protocol, as established in article 41 of Regulation (EU) No 536/2014 of the European Parliament

and of the Council, of 16 April 2014.

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2. The investigator shall report all serious adverse events to the sponsor without undue delay

but not later than 24 hours from the time he/she has knowledge of these events, unless, for certain

serious adverse events, the protocol provides that no immediate reporting is required. The

investigator, where applicable, shall send a follow-up report to the sponsor to allow the sponsor to

assess whether the serious adverse event has impact on the benefit-risk balance of the clinical trial.

The initial and follow-up reports shall identify the trial subjects only by a subject identification code

assigned in the trial, specific for each of them.

3. If the death of a subject participating in a clinical trial has been reported, the investigator shall

provide the sponsor and the CEIm with any additional information requested.

4. If the investigator becomes aware of a serious adverse event with a suspected causal

relationship to the investigational medicinal product that occurs after the end of the clinical trial in a

subject treated by him/her, this serious adverse event shall be reported, without undue delay, to the

sponsor.

5. In any case, the indications specified in the European Commission guidelines should be

taken into account or, where appropriate, in the procedures established in the instructions for the

conduct of clinical trials in Spain published by the Spanish Agency of Medicines and Medical

Devices.

Article 50. Other obligations of the sponsor in the recording, assessment and reporting of

adverse events.

1. The sponsor shall keep detailed records of all adverse events which are reported to the

sponsor by the investigators. These adverse events shall be submitted to the Spanish Agency of

Medicines and Medical Devices upon its request.

2. The sponsor is responsible for the continuous assessment of the benefit-risk balance of the

clinical trial, which includes a continuous safety assessment of the investigational medicinal products

using all the information available. Likewise, the sponsor must report to the Spanish Agency of

Medicines and Medical Devices and the CEIm, without undue delay, in the period of fifteen calendar

days, by the means indicated in article 21, any information substantially affecting the benefit-risk

balance of the clinical trial, except for suspected unexpected serious adverse reactions which shall

be reported according to article 51. This reporting shall be made in accordance with the European

Commission guidelines or, where appropriate, the procedures established in the instructions for the

conduct of clinical trials in Spain published by the Spanish Agency of Medicines and Medical

Devices.

3. The sponsor shall promptly report to the investigators any important information that could

adversely affect the safety of the subjects or the conduct of the clinical trial. Reporting of this

information shall be concise and practical. Reporting shall conform to the criteria and the procedure

specified in the European Commission guidelines.

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Article 51. Reporting of suspected unexpected serious adverse reactions to the Spanish Agency

of Medicines and Medical Devices.

1. The sponsor shall report to the Spanish Agency of Medicines and Medical Devices all

suspected unexpected adverse reactions associated with investigational medicinal products of which

it becomes aware, which have occurred in the clinical trial, whether occurring in Spain or in other

countries. In addition, any suspected serious adverse reactions and, at the same time, unexpected

occurring outside the clinical trial shall be reported according to the criteria established in the

European Commission guidelines.

2. In all cases, this reporting shall be carried out through European Eudravigilance CTM

database.

3. The timelines for reporting suspected unexpected serious adverse reactions by the sponsor

to the Spanish Agency of Medicines and Medical Devices shall depend on the seriousness of the

reaction and shall be determined as follows:

a) In the case of fatal or life-threatening suspected unexpected serious adverse reactions, as

soon as possible and, in any event, not later than seven days after the sponsor became aware of the

reaction.

b) In the case of non-fatal or non-life-threatening suspected unexpected serious adverse

reactions, not later than fifteen days after the sponsor became aware of the reaction.

c) In the case of suspected unexpected serious adverse reactions which were initially

considered to be non-fatal or non-life-threatening but which turns out to be fatal or life-threatening, as

soon as possible and, in any event, not later than seven days after the sponsor became aware of the

reaction being fatal or life-threatening.

When required to ensure prompt reporting, the sponsor may submit an incomplete initial report

which must be completed as far as possible in the following eight days.

4. The reporting of serious and unexpected adverse reactions by the sponsor to the Spanish

Agency of Medicines and Medical Devices shall conform, in any event, to the criteria and the

procedure specified in articles 42, 45 and 46 of Regulation (EU) No 536/2014 of the European

Parliament and of the Council, of 16 April 2014.

Article 52. Exchange of information about clinical trials with the competent bodies of the

Autonomous Communities.

1. The Spanish Agency of Medicines and Medical Devices shall provide a system by which

suspected unexpected serious adverse reactions associated with the investigational medicinal

product and occurring in patients included in a clinical trial in Spain are available to the competent

bodies of the Autonomous Communities in real time through the clinical trial information system.

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2. Until a valid system of electronic exchange of information is available for all Autonomous

Communities, as indicated in article 19, reporting to the Autonomous Communities by the sponsor

shall be carried out according to the criteria established in the relevant instructions of the Spanish

Agency of Medicines and Medical Devices.

Article 53. Annual safety report and other safety reports.

1. The sponsors of clinical trials shall prepare an annual safety report in which the safety of the

investigational medicinal product is assessed taking into account all the information available. This

report shall be submitted to the Spanish Agency of Medicines and Medical Devices and the CEIm.

2. Irrespective of the annual safety report, the sponsor shall prepare an "ad hoc" assessment

report whenever there is a relevant safety problem. This report shall be submitted immediately to the

Spanish Agency of Medicines and Medical Devices and the CEIm as stated in the previous

paragraph.

3. Submission of the annual safety report and other safety reports by the sponsor shall conform

in all cases to the criteria and the procedure specified in articles 43, 45 and 53 of Regulation (EU) No

536/2014 of the European Parliament and of the Council, of 16 April 2014.

4. The sponsors of clinical trials in which the investigational medicinal products, excluding

placebos, are authorised and, according to the clinical trial protocol, are used in accordance with the

terms of marketing authorisation, may submit a simplified report in accordance with the instructions

for the conduct of clinical trials in Spain published by the Spanish Agency of Medicines Products and

Medical Devices.

CHA

PTER XIII

nfringements

Article 54. Administrative infringements related to clinical trials.

Administrative infringements shall be those laid down in Chapter II of Title IX of the consolidated

text of the Act on guarantees and rational use of medicinal products and medical devices , approved

by Royal Legislative Decree 1/2015, of 24 July, and they shall be sanctioned in accordance with

article 114 of this Act.

First additional provision. Ethics Committees for Clinical Investigation.

1. Within the period of two years from the effective date of this Royal Decree, Ethics

Committees for Clinical Investigation may be accredited as CEIm by the competent health authorities

of the Autonomous Communities, taking into account for this purpose the criteria established in

Chapter IV.

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2. Once this period of two years has elapsed, those Ethics Committees for Clinical Investigation

that are not CEIm may continue to perform the functions of Ethics Committees for Investigation not

related to the assessment of clinical trials with medicinal products or medical devices until the

specifications established in the third transitional provision of Act 14/2007, of 3 July, are met.

3. The references to Ethics Committees for Clinical Investigation indicated in the consolidated

text of the Act on guarantees and rational use of medicinal products and medical devices approved

by Royal Legislative Decree 1/2015, of 24 July shall be understood to be performed by the CEIm

under the terms established in this Royal Decree.

Second additional provision. Non-interventional studies.

Without prejudice to the provisions specified in Chapter IV in articles 18, 47 and 48, the non-

interventional studies defined in paragraph k) of article 2.1 shall be governed by their specific

regulations.

Third additional provision. Clinical investigations with medical devices.

1. Clinical investigations with medical devices shall be governed by the ethical and

methodological principles and those of protection of trial subjects laid down in this Royal Decree,

taking into account the provisions of the medical devices regulation.

2. The CEIm shall issue an opinion on clinical investigations with medical devices. This shall be

done, taking into account, in particular, the provisions specified in article 16.4.a). When this research

is conducted in various sites, the opinion shall be issued by an CEIm in Spain and shall be single

and binding.

3. The start of clinical research with medical devices bearing CE marking and which are used

for the same indications included in the conformity assessment procedure shall be notified to the

Spanish Agency of Medicines and Medical Devices whenever any intervention modifying standard

clinical practice is performed in these investigations.

Fourth additional provision. Collegiate bodies of the Spanish Agency of Medicines and Medical

Devices.

Within a year from the effective date of this Royal Decree, the Spanish Agency of Medicines

and Medical Devices shall submit a proposal to the Ministry of Finance and Public Administration for

rationalisation of the collegiate bodies attached to it, pursuant to Royal Decree 776/2011, of 3 June,

dissolving certain collegiate bodies and establishing criteria for the standardisation of the creation of

collegiate bodies in the General State Administration and its Public Bodies.

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Fifth additional provision. No increase in personnel costs.

The measures provided for in this Royal Decree shall not involve any increase in remuneration,

provisions or other personnel costs.

Sixth additional provision. Application of this Royal Decree to health services of the Armed

Forces.

Pending development of the stipulations contained in the second additional provision of the

consolidated text of the Act on guarantees and rational use of medicinal products and medical

devices approved by Royal Legislative Decree 1/2015, of 24 July application of this Royal Decree to

the health services of the Armed Forces shall be according to the following rules:

a) The Ministry of Health, Social Services and Equality shall hold the accreditation as the CEIm

of the health services of the Armed Forces.

b) The Ministry of Defence, through the General Public Health Inspection of Defence, shall

exercise the competences concerning inspection, receipt of communications and reports and other

matters that are attributed by this Royal Decree to the Autonomous Communities, in their area of

competences.

Seventh additional provision. Adoption of developing instructions.

The Spanish Agency of Medicines and Medical Devices is empowered to adopt the good clinical

practice guidelines and instructions for the conduct of clinical trials in Spain, which it shall maintain

updated on its website.

First transitional provision. Transitional regime related to the functions of assessment of clinical

studies with medicinal products or medical devices of the Ethics Committees for Clinical

Investigation.

During the two years following entry into force of this Royal Decree, Ethics Committees for

Clinical Investigation already accredited at the time of its entry into force shall assume the functions

of Ethics Committees for Investigation with medicinal products related to assessment of clinical

studies with medicinal products or medical devices and shall be supervised and coordinated in

respect of these functions in the same manner as the latter.

Second transitional provision. Procedure for applications for clinical trial authorisation and

modification, communications and notifications before full functionality of the EU portal and the EU

database.

1. Until the date of full application of Regulation (EU) No 536/2014 of the European Parliament

and of the Council, of 16 April 2014, as provided in its article 99, the submission of applications and

communications and receipt of notifications listed in articles 21.1, 26.3, 30.1, 51.2, 51.4 and 53.3 of

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this Royal Decree, shall conform to the provisions of the following paragraphs taking into account the

provisions in article 46, paragraphs 3 and 4:

a) Applications for authorisation and an opinion on the clinical trial, as well as all subsequent

communications, shall be submitted by the sponsor only via or by electronic means and

simultaneously to the Spanish Agency of Medicines and Medical Devices and the CEIm who accepts

assessment at the proposal of the sponsor, in accordance with the provisions of article 27.6 of Act

11/2007, of 22 June, on citizen electronic access to public services, unless it is justified that access

and availability of the required technological resources is not guaranteed. In any case, if this

simultaneous submission did not occur, the date of the last application submitted shall be considered

for the purpose of processing of the procedure.

b) For submission by electronic means, the Portal of Clinical Trials with medicinal products of

the Ministry of Health, Social Services and Equality has been enabled, which may be accessed at

the electronic headquarters of the Spanish Agency of Medicines and Medical Devices.

Alternatively, electronic submission may be performed without a recognised digital certificate by

submitting in the registry of the Spanish Agency of Medicines Medical Devices or the CEIm, as

appropriate, the proof of the electronic submission with a handwritten signature.

c) Notifications of the Spanish Agency of Medicines and Medical Devices to the sponsor shall

be made electronically. The sponsor must therefore appear at the electronic headquarters of the

Spanish Agency of Medicines and Medical Devices. Likewise, the CEIm shall send its notifications

by e-mail.

d) To make the submission electronically and receive electronic notifications, the sponsor must

have a computer, an Internet connection and a recognised digital certificate issued by any of the

certification service providers that are registered in the registry of the Secretary of State for

Telecommunications and Information Society in accordance with article 30 of the Electronic

Signature Act 59/2003, of 19 December. Furthermore, to receive electronic notifications, the sponsor

must have an e-mail account and have expressed his/her consent when submitting the application.

e) When a sponsor, due to lack of resources, is unable to report a suspected unexpected

serious adverse reaction to the Eudravigilance CTM database, he/she may report it to the Spanish

Agency of Medicines and Medical Devices according to the procedure established in the instructions

for the conduct of clinical trials in Spain published by said Agency.

2. In accordance with the provisions of article 98 of Regulation (EU) No 536/2014 of the European

Parliament and of the Council, of 16 April 2014, during the year following the date of full application of

this Regulation, the sponsor may choose to request authorisation of a clinical trial pursuant to article

21.1 of this Royal Decree or as indicated in the previous paragraph. In this latter case, subsequent

notifications referring to the clinical trial shall continue to be made in accordance with the terms in this

provision up to three years after the date of full application of this Regulation (EU).

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Third transitional provision. Procedure for authorisation of a clinical trial before full functionality

of the EU portal and the EU database.

Until full application of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014, as provided in its article 99, the procedure for authorisation of a clinical

trial, regulated in articles 21 to 30 of this Royal Decree, must conform to the following rules:

a) For validation of an application, the sponsor must submit an application containing all the

necessary documents related to Part I and Part II. In the case of clinical trials with a medicinal

product not authorised in any country of the European Economic Area which contains an active

substance or a combination of active substances not authorised in Spain, qualification as “a product

under clinical investigation” (producto en fase de investigación clínica or PEI) shall be requested for

this medicinal product.

The Spanish Agency of Medicines and Medical Devices and CEIm shall notify the sponsor if the

application for Part I and Part II, respectively, are complete in a maximum period of ten calendar

days. If any part is incomplete, this shall be notified to the sponsor setting a maximum period of ten

calendar days for this sponsor to submit his/her comments. This period may be extended to thirty

calendar days in the case of clinical trials meeting the definition of "Non-commercial Clinical

Research".

If the sponsor does not answer within the stipulated period, the application shall be deemed to

have lapsed and shall be so notified. If the sponsor submits supplementary documentation that

permits the application to be completed, the CEIm, or the Agency, as appropriate, shall report the

assessment schedule to the sponsor within five calendar days, which shall start from the day

following the date of receipt of this documentation which, for the purposes of this article, shall be

considered as the valid application date.

b) For Part I of the assessment report, regulated in article 23 of this Royal Decree, the Spanish

Agency of Medicines and Medical Devices shall be responsible for sending to the sponsor the

conclusions of Part I of the assessment report, including those aspects which have been assessed

by the CEIm, within the periods stipulated in article 6 of Regulation (EU) No 536/2014 of the

European Parliament and of the Council, of 16 April 2014. However, the assessment period shall

start from the valid application date.

c) With regard to Part II of the assessment report, regulated in article 24, it should be borne in

mind that the assessment period shall start from the valid application date.

d) Regarding the authorisation decision, regulated in article 25, the Director of the Spanish

Agency of Medicines and Medical Devices, in a period of five days from the last date of notification to

the sponsor of the conclusions of Part I and Part II, shall issue the decision authorising the clinical

trial, authorising the clinical trial subject to conditions, or refusing the authorisation.

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e) A clinical trial cannot commence without prior written authorisation from the Spanish Agency

of Medicines and Medical Devices in the following cases:

1. Clinical trials where the Agency has notified objections to the sponsor within the 45 day

period referred to in article 6 of Regulation (EU) No 536/2014 of the European Parliament and of the

Council, of 16 April 2014.

2. Clinical trials with medicinal products requiring qualification as a product under clinical

investigation.

3. Clinical trials with advanced therapy medicinal products, as well as clinical trials with

medicinal products containing genetically modified organisms.

In these cases, if after the period of five days specified in paragraph d), no notification of the

decision has been made to the interested party, it shall be understood that the application has been

refused.

For the authorisation of subsequent clinical trials with an investigational medicinal product

previously considered a product under clinical investigation, the documentation mentioned in article

22.1 should be updated, whenever necessary.

f) With regard to the modification of the clinical trial authorisation conditions, regulated in article

26, it shall be borne in mind that the assessment period shall start from the valid application date.

g) Finally, concerning the application of article 30, it shall be taken into account that, regardless

of the result of the clinical trial, within a year from completion of the trial the sponsor shall send the

Spanish Agency of Medicines and Medical Devices and the CEIm the summary of results of the trial

in accordance with the current European guidelines.

Sole repeal provision. Statutory repeal.

Any provisions of equal or lower rank that are contrary to the provisions in this Royal Decree are

hereby repealed and, in particular, Royal Decree 223/2004, of 6 February, regulating clinical trials

with medicinal products, as well as Order SCO/256/2007, of 5 February, establishing detailed

principles and guidelines of good clinical practice and requirements to authorise the manufacture or

importation of investigational medicinal products for human use.

First final provision. Modification of the Statute of the Spanish Agency of Medicines and Medical

Devices approved by Royal Decree 1275/2011, of 16 September, establishing the State Agency

"Spanish Agency for Medicinal Products and Medical Devices" and approving its Statute.

A new article is added to the Statute of the Spanish Agency for Medicinal Products and Medical

Devices approved by Royal Decree 1275/2011, of 16 September, establishing a State Agency

"Spanish Agency of Medicines and Medical Devices" and approving its Statute, as follows:

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"Article 28 bis. The Medical Devices Committee.

1. The Medical Devices Committee is the collegiate body that provides advice on technical,

scientific and clinical matters related to the safety, efficacy, and quality of medical devices in all

procedures undertaken by the Spanish Agency of Medicines and Medical Devices, both as the

competent authority and as notified body.

2. The functions of the Medical Devices Committee are:

a) To propose to the Spanish Agency of Medicines and Medical Devices the conduct of studies

and investigations it considers necessary regarding medical devices.

b) To advise the Spanish Agency of Medicines and Medical Devices on issues related to safety,

clinical efficacy, performance, quality, information, and proper use of medical devices.

c) To advise the Spanish Agency of Medicines and Medical Devices in the performance of the

function of evaluation of adverse incidents in its area of responsibility within the framework of the

Medical Devices Vigilance System, as well as in the evaluation of risks that may arise with marketed

medical devices.

d) To provide technical advice to the Spanish representatives in working groups and meetings

on medical devices held in the European Union and other international organisations.

e) To provide opinion on testing methods and technical standards.

f) To advise on the measures to be adopted that are aimed at safeguarding public health and

protection of patients and users with regard to medical devices, as well as on the recommendations

to be issued for protection of the health of the population, safe use of the products and follow-up and

treatment of patients.

g) To issue a report at the request of the Director of the Spanish Agency of Medicines and

Medical Devices, on the "CE" certification procedures of medical devices.

h) To provide opinion about any other issue related to medical devices.

3. The Medical Devices Committee shall consist of the following members:

a) Five members based on their position:

1. The Director of the Spanish Agency of Medicines and Medical Devices or designee.

2. The Head of the Department of Medical Devices of the Spanish Agency of Medicines and

Medical Devices.

3. The person responsible for the area of vigilance and market surveillance of the Department of

Medical Devices of the Spanish Agency of Medicines and Medical Devices.

4. The person responsible for the area of certification of the Spanish Agency of Medicines and

Medical Devices.

5. The person who chairs the Technical Inspection Committee.

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b) Four members on behalf of:

1º. The Spanish Ministry of Health, Social Services and Equality.

2º. The Carlos III Health Institute, proposed by its supreme governing body.

3º. The National Institute of Toxicology and Forensic Sciences, proposed by its supreme

governing body.

4º. The Higher Council for Scientific Research, proposed by its supreme governing body.

4. By virtue of the provisions of article 29.3, the Committee may request the collaboration of as

many experts as it deems appropriate.

5. The Chair of the Committee shall be the Director of the Spanish Agency of Medicines and

Medical Devices, or person designated as his/her replacement, and one of the members of the

Spanish Agency of Medicines and Medical Devices shall act as Secretary. In the event of vacancy,

absence or illness, the Chair of Committee shall correspond to the Head of the Department of

Medical Devices of the Spanish Agency of Medicines and Medical Devices.

6. The Medical Devices Committee shall hold such meetings as are required by its advisory

functions, in response to the needs of the Spanish Agency of Medicines and Medical Devices,

working in plenary sessions or in Committees, in accordance with the regulations established in its

Internal Rules of Operation.

Likewise, it may hold remote meetings and issue reports and adopt decisions by written

procedure, without the need to resort to the on-site meeting of its members."

Second final provision. Qualifying title.

This Royal Decree is enacted under the provisions of article 149.1.16 of the Spanish

Constitution, which grants the State the sole authority regarding the legislation on medicinal

products.

Third final provision. Development powers.

The Minister of Health, Social Services and Equality is empowered to issue the necessary

measures for the development of this Royal Decree, and for the updating of its Annex, according to

the advance of scientific and technical knowledge and in accordance with the guidelines of the

European Union. In particular, the Minister of Health, Social Services and Equality is empowered to

revise the limits established in article 10.3.

Fourth final provision. Entry into force.

This Royal Decree shall enter into force twenty days after its publication in the Official State

Journal, except for paragraph 1 of article 21, article 22, paragraphs 1 and 3 of article 23 and

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paragraph 1 of article 25 which shall be effective as from the date on which Regulation (EU) No

536/2014 of the European Parliament and of the Council, of 16 April 2014, is fully applicable as

provided in its article 99.

Done at Madrid, on 4 December 2015.

FELIPE R.

The Ministry of Health, Social Services and Equality

ALFONSO ALONSO ARANEGUI

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ANNEX

Data to be included in the REec

1. Study identification number in the primary registry.

2. Date of registration in the REec.

3. Secondary identification numbers.

4. Brief summary with rationale for the study.

5. Source of funding or material support.

6. Sponsor.

7. Contact for queries by the general public.

8. Contact for scientific queries.

9. Public study title.

10. Scientific study title and acronym, if the study has one.

11. Countries where it is planned to recruit subjects.

12. Trial sites.

13. Disease or health problem under study.

14. Interventions being studied.

15. Main inclusion and exclusion criteria.

16. Type and scope of study.

17. Date of recruitment of the first subject in Spain.

18. Sample size (number of subjects to be included).

19. Study status (uninitiated; recruitment started; recruitment concluded, temporarily

discontinued or discontinued; completed in Spain; completed in all participating countries).

20. Primary objective and study variables and times when they will be assessed.

21. Secondary objectives and study variables and times when they will be assessed.

22. Date of opinion by CEIm and authorisation by the Spanish Agency of Medicines and Medical

Devices or by the corresponding Autonomous Community (where applicable).

23. Study portal (if applicable).

24. Study results (the registry will contain a link to the scientific publications of the study.

Submission of the results will conform, where applicable, to the EU standard).

25. Date of last modification of the record in the REec.