1 - What is the scope of the Law no. 21/2014 of 16 April?
The Law No. 21/2014 of 16 April establishes the legal framework for conducting clinical studies in Portugal. This law governs clinical research, considered as any systematic study to discover or verify the distribution or effect of health factors, of health conditions or outcomes, of health or disease processes, of performance and/or the safety of interventions or the provision of health care.
This law covers, among other clinical studies, clinical trials with medicinal products for human use, transposing Directive 2001/20/EC of the European Parliament and of the Council of 4 April, as well as clinical research with medical devices, partially transposing the Directive no. 2007/47/EC of the European Parliament and of the Council of 5 September.
With regard to clinical trials with human medicinal products the Law no. 21/2014 of 16 April repeals the Law no. 46/2004 of 19 August.
2 - What is the date of entry into force of the Law no. 21/2014 of 16 April?
The Law no. 21/2014 of 16 April, entered into force on the 16th of June 2014.
3 - What does the meaning of "clinical study" in the context of the Law no. 21/2014 of 16 April?
For the purposes of the Clinical Investigation Law:
The term "clinical studies" includes:
- "Non-interventional clinical studies" and
- "Interventional clinical studies"
The term "interventional clinical studies" includes (in addition to others not specified) as follows:
- "Clinical trials" and
- "Interventional clinical studies with medical devices" and "clinical studies with cosmetics products".
4 - What is the difference between "clinical trial" and "interventional clinical study" as per Law no. 21/2014 of 16 April?
For the purpose of the Law the term "clinical trial" includes studies in which one or more investigational medicinal products are used.
The investigational medicinal products may or may not be authorized or marketed in Portugal. What defines them is that they are tested or used as a reference in a clinical trial (as defined in article 2 of the Law) that is transcribed:
«Investigational medicinal product», the pharmaceutical form of an active substance or placebo, being tested or used as a reference in a clinical study including medicinal products already with a marketing authorization, but are used or prepared, as to the pharmaceutical form or package, in a different manner from the authorised one, or are used for a non authorised indication or intended to get more information on the authorized form;
5 - The Law no. 21/2014 of 16 April does not clarify if the sponsor or his legal representative must be established in the European Union (EU).
a) Any sponsor who is established outside of the EU needs a legal representative established in the EU, according to the guidelines on the Volume 10 of EudraLex.
b) The term "authorized representative" is applicable to clinical studies with medical devices. For clinical trials with medicinal products for human use, the corresponding term is "legal representative".
6 - Which are the principles of Good Clinical Practice (GCP) that are applicable to clinical trials?
Any research that involve the participation of human subjects must be carried out in accordance with Good Clinical Practice (GCP) which is an international ethical and scientific quality standard for designing, conducting, recording and reporting those trials. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected and that the clinical trial data are credible.
According to the Article 4 of the Law no. 21/2014 of 16 April, GCP shall be observed in all clinical studies.
7 - Does the Decree-Law no. 102/2007, of 2 Abril (establishes the principles and detailed guidelines for GCP as regards investigational medicinal products for human use, as well as requirements for authorization of the manufacturing and importation of such products) is in force?
Yes, the Decree-Law no. 102/2007, of 2 Abril, which is the transposition into the Portuguese Law of the Directive 2005/28/EC of 8 April, is in force, and complements the Directive 2001/20/EC.
8 - What is needed to conduct a clinical trial in Portugal in accordance with the Law no. 21/2014 of 16 April?
Conducting clinical trials in Portugal requires prior authorization of the INFARMED, IP Management Board and favorable opinion of the National Ethics Committee for Clinical Research (CEIC).
9 - Which are the legal timeframes established by Law No. 21/2014 of 16 April for a clinical trial application authorization by INFARMED, IP and an opinion by CEIC?
Please consult the website area: "Clinical Trial Application"
10 - How to submit clinical trials applications and notifications to INFARMED and CEIC, after the entry into force of the Law No. 21/2014 of 16 April?
The clinical trial applications shall be submitted to both INFARMED, IP and CEIC through RNEC platform, according to the applicable legal requirements and after payment of the applicable fee through the gateway provided by the RNEC platform.
The submission of a substantial amendment notification through RNEC is only possible if it regards to a clinical trial that was submitted through this portal.
All notifications and other communications regarding clinical trials that were not submitted to INFARMED, IP and CEIC via RNEC, should be done independently, and if applicable, to these two entities, according to instructions to the applicants available at INFARMED and CEIC websites.
11 - How is the procedure for record and notification of adverse reactions and events laid down in Article 22 of the Law no. 21/2014 of 16 April?
With regard to clinical trials, Law no. 21/2014 of 16 April, revised by Law no. 73/2015 of 27 July, transposes Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. As such applicable technical requisits are provided in the guidance " Communication from the Commission - Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use («CT-3»)".
With regard to sponsor`s report to INFARMED, a Guidance to applicants, updated at 27/07/2015, aims to clarify sponsors about reporting of SUSAR's and annual safety reports and are available at the clinical trials pharmacovigilance area of INFARMED website.
CEIC follows the understanding of INFARMED, which is the competent authority in this matter. For reporting of adverse reactions to INFARMED and additional guidance please consult the clinical trials pharmacovigilance area at INFARMED website.
12 - Where can I find information about submission of Clinical Studies requests through RNEC electronic platform?
Please find the full version of the User¿s Manual at the RNEC portal, accessible at: RNEC/ Medicamentos Experimentais/ Informação ao Promotor
Which types of studies can I submit through RNEC electronic platform?
The submission of Clinical Studies through RNEC portal is applicable to:
A Interventional studies with Investigational Medical Products (Human)
B Interventional studies with Medical Devices
C Interventional studies with cosmetic products
D Non-interventional Post Authorization Efficacy Studies (PAES)
E Non-interventional Post Authorization Safety Studies (PASS)
Only Categories A and B studies should be submitted to CEIC. Studies from categories C,D and E should be submitted to the Clinical Site¿ s Ethics Committee (CES) according to the respective procedures.
Only when the Clinical Site does not own a local Ethics Committee (CES), Categories C,D and E studies can be submitted through RNEC portal to CEIC.
NOTE: All Studies that are submitted to CEIC outsider of the scope of its evaluation will be automatically stored without any evaluation or associated procedure according to Law 21/2016 from April 16.
13- For studies submitted prior and outside RNEC, how can I submit amendments and notifications?
The submission of amendments and notifications through RNEC is restricted to the studies that have been initially submitted through this platform. Notifications and amendment to all other studies (submitted prior to RNEC) should be submitted according to the usual procedures (cover letter +CD-ROM).
14 - According to the User Manual, each company will register as Applicant. Will it be allowed for different collaborators in the same company to perform simultaneous submissions using a single registry?
The User¿s registration is attributed to each entity (Applicant/Sponsor). In this sense, it is up to the Entity to determine internally who should have access to the login credentials. Nonetheless, it is possible to have multiple systems logging in with the same credentials and performing simultaneous submissions and management activities.
15 - Can a CRO, representing a specific Sponsor, be responsible for registering the sponsor¿s Entity in the platform?
Each Entity is responsible for registering in RNEC platform. The registration process will require restricted information such as NIF/NIPC. However, if a specific Entity chooses to delegate the registration responsibility in another, that activity can be ensured by the 2º Entity (eg:.CRO)
16- If a Sponsor is represented by multiple CROs, how will the registration be managed?
Regardless of who they are representing, each entity (CRO) will have an individual registration and specific login credentials.
17- If the sponsor¿s representative/applicant changes for one or more Studies, how should the new Applicant proceed?
A notification for "Change of Applicant" should be submitted through RNEC. For further information please refer to the User¿s Manual.
18 - RNEC platform does not allow the registration of multiple Investigators for the same clinical Site. How should we procced to register simultaneously a Principal Investigator and a Coordinating Investigator?
The platform is restricted to the registration of a single investigator per clinical site. In the cases where a Coordinating Investigator and a Principal Investigator are affiliated with the same clinical site, the applicant should register only the Principal Investigator. The information regarding the Coordinating Investigator is included in XML file.
19 - For the payment of fees- a bank transfer reference will be provided. What happens if the payment deadline expires? Can I request a new reference?
The MB reference will have a considerably extended period of validity. For this reason, it will not be required to generate a new reference
20 - In situations where the payment of the fee is through ATM reference, can I effect the payment immediately?
The ATM reference issued by RNEC will be available for payment two business days after. For processing purposes, applications will only be considered after payment of the fee.
21 - In case the files are larger than 20MB, how should we proceed to submit the documentation through RNEC platform?
In situations where it is not possible to submit documentation directly on the platform, it must be submitted via eudralink.
1. The cover letter shall identify the submission of documentation by eudralink, providing its URL, for access to the supporting documentation;
2. The eudralink subject should identify the study / request / notification to which the supporting documentation refers;
3. The time available for the documentation via eudralink should be at least 90 days.
Eudralinks should not be forwarded to other emails
22 - Considering the differences in the structure of the folders submitted to INFARMED and CEIC, how should we submit them?
For simultaneous/parallel submissions to INFARMED and CEIC, please include separate folders respectively named: INFARMED and CEIC. Each folder should be organized according to the requirements/guidelines available at the website the respective authority (www.infarmed.pt and www.ceic.pt )
23 - Besides the electronic documentation submitted through RNEC platform is it necessary to submit a hardcopy (CD-ROM)?
No. New submissions will be exclusively electronic through RNEC platform. The previously approved submission procedure remains applicable only for clinical studies submitted prior to the implementation of RNEC platform.
24 - Is it possible to temporarily save a request? In the sense that I can initiate a submission, save it, and continue it later on.
Yes, it is possible to temporarily save any activity in RNEC platform. For instructions please consult the User¿s Manual