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NATIONAL

This database contains information about Portuguese Regulation on Clinical Trial’s. It also includes contact addresses of national authorities, national legislation and other relevant documents.


INFARMED- National Authority of Medicines and Health Products, IP/ Autoridade Nacional do Medicamento e Produtos de Saúde I.P.;
(Government agency accountable to the Health Ministy)
Health Products Directorate
 
Parque de Saúde de Lisboa
Avenida do Brasil, 53
1749-004 Lisboa
Portugal
 
Tel +351 21 798 7283
Fax: +351 21 798 7248
Email: cimi@infarmed.pt (general information on clincial trials); ensaios.clinicos@infarmed.pt (information on procedures)
                                                                
Website: http://www.infarmed.pt/
(The English web pages contain selected items from its Portuguese language site and will be continuously expanded)

No local CAs.
The sponsor must apply for a clinical trial authorisation to the national CA (INFARMED) according to Art 25-27 Law 21/2014 (pt).
 
Required submission format of the application dossier:
  • Application letter (“Carta de requerimento”) in paper format
  • Confirmation of payment (in electronic format on CD-ROM)
  • Standard application form: Annex 1: Clinical trial Application Form/ Formulário de pedido de AEC (in electronic format on CD ROM)
  • Further documentation as specified in Art 26 (1) Law 21/2014 (pt)
 
Detailed guidance for the applicant regarding the trial submission and the definite structure of the documentation on the CD-ROM is provided on the website in section:
Medicamentos Uso Humano> Ensaios Clinicos> Submissão ao INFARMED
 
Portuguese, English accepted (for official application documents and scientific documents only; NOT for documents intended for study subjects)
Fees for the authorization of
  • Clinical trial Phase I-III: 1.023,00 €
  • Clinical trial Phase IV: 460,35
  • Studies on Bioavailability and Bioequivalence: 255,75 €
  • Substantial amendment to protocol: 102,30 €
(Status 2014/ Fees are being revised annually)
 
Academic Studies: No submission fees.
 
Related information plus detailed guidance on the payment procedure is available on the INFARMED website in section Taxas > Ensaios Clínicos: „Guia para pagamento de taxa sobre ensaios clinico“ (in Portuguese only).
Approval timeline: 30 days

One clock stop is possible if CA requests complementary information or documentation from applicant. INFARMED usually sends an email confirmation and a letter.

+20 days: for clinical trials involving gene therapy, somatic cell therapy, GMOs.

+50 days: if additional consultation and involvement of a qualified expert committee is required No time limit: for clinical trials involving xenogeneic cell therapy medicinal products.
Explicit authorization might be necessary for clinical trials involving gene therapy, somatic cell therapy, GMOs xenogeneic cell therapy Respective timelines for CA approval is provided in Art 26 & 77 of Law 21/2014 (pt).

Submission to the EC, CA and Data Protection Authority can be done in any order or in parallel.
It is mandatory to have a sponsor. Co-sponsorship is not allowed.
The sponsor has to submit any substantial amendments to the study protocol to the CA, pursuant to Art 18 Law 21/2014 (pt). Standard notification form to be used by the applicant for submission of substantial amendments is provided on the INFARMED website in section: Medicamentos Uso Humano> Ensaios Clinicos> Formulários: “Substantial Amendment Notification Form (pdf)”/ “Formulário de pedido de alteração (pdf)”
The sponsor is obliged to notify the competent EC and the national CA of the end of the trial within 90 days (counted form last visit of study participant). Premature trial termination must be declared within 15 days with clearly stating the reasons for it. (Art 19 Law 21/2014 (pt)) The standard notification form (“Declaration of the End of Trial Form (pdf)”/ “Formulário de declaração de fim de EC”) to be used for declaration of the end of a clinical trial to the CA and the EC is provided on the INFARMED website in section Medicamentos Uso Humano> Ensaios Clinicos> Formulários:
Monitoring - Center Option (not mandatory)
Audit by Sponsor - Center Option (not mandatory)
Standard Operating Procedures (SOPs)
Center Option (not mandatory)
Reimbursement for study participants: Mandatory but compensation is limited to/provided for Expenses (e.g. transportation, meals, and others such as salary lost)
Additional Information Compensation for expenses is mandatory according to Art 13 Law 21/2014 (pt). The EC verifies and evaluates the compensation arrangements for study subjects, pursuant to Art 16 (6) Law 21/2014 (pt).
Insurance for study participants, investigators and sponsors is mandatory according to Art 15 & 16 Law 21/2014 (pt) and the General Liability Insurance Law, DL 72/2008 (pt). Art 137-148 DL 72/2008 provides the legal requirements of the insurance contract.

The insurance covers all cases of liability for property damage and injuries suffered by the patient during the study and the year following its completion (if the damage to health it is imputable to the trial).

Further legislation: The Norma Regulamentar n.º14/2008-R (de 27 de Novembro) is a liability law for mandatory insurance (applicable to many cases including clinical trials).
The investigator must inform the sponsor immediately (not later than 24 hours) on the occurrence of any SAEs.
A detailed written report must follow within 5 days. The sponsor shall ensure that any SUSARS being fatal or life-threatening are reported to the competent EC, the national CA and the CA of any EEA State in which the trial is being conducted, not later than 7 days after sponsor’s first knowledge All other SUSARS are reported to the competent EC, the national CA and the CA of any EEA State in which the trial is being conducted as soon as possible and in any event not later than 15 days after the sponsor is first aware of the reaction.

The reporting timelines are provided in Art 22 Law 21/2014 (pt).

An Annual Safety report shall be submitted to the competent EC and the national CA by the sponsor pursuant to Art 22 (10) Law 21/2014 (pt)
Submission for Ethical review mandatory for:
Clinical IMP trials
Clinical ATMP trials

Submission to CA and EC to be performed in the following order:
In parallel
Sequentially (in any order)

Additional Information:
NB! For performing clinical trials in Portugal, sponsors have to get authorization from the Competent Authority and ethical approval from the Ethics Committee (CEIC) plus approval from the National Data Protection Authority (CNPD – “Comissão Nacional de Proteção de Dados”) according Art 16 & 25 Law 21/2014 (pt).
Responsible for study submission: Sponsor or delegated CRO

Guidance on study submission available: Yes

Guidance on study submission: "Note on Procedures for issuing CEIC s single opinion to carrying out Clinical Trials with medicinal products for human use" (also available in English on the CEIC website in section: Utilities/Information 

The request for approval includes the application form, proof of payment of fees to INFARMED and the required documentation.

National Ethics Committee for Clinical Research/ Comissão de Ética para a Investigação Clínica (CEIC)
Phone:+351 21 798 53 40
Fax:+351 21 798 72 09
Address: Parque da Saúde de Lisboa; Av. do Brasil, 53 - Pav. 17-A
1749-004 Lisboa

E-Mail: ceic@ceic.pt

Additional Information: In addition, there are almost 100 institutional ECs in each hospital and university (public and private, health and academic) in Portugal.
General timespan for single or multi center studies (max nr days):30

ATMP/GMO trials (max nr days): 50
external expert advice required: Timespan (max nr days): 100
Xenogeneic cell therapy:  No time limit

Clock-stop possible if complementary information requested: Yes

Applicable national legal framework/ Reference: 16 & 17 of Law 21/2014

Additional Information: The given timelines also apply to any designated ECs. In most cases, requests for permission to conduct clinical trials are answered by INFARMED, CEIC, and CNPD within 60 days, if the applications are submitted concurrently.
Standard Informed Consent form (ICF) available: Not specified
Informed Consent is regulated by law: Yes

Informed Consent - Definition/ Requirements: English translation for Portuguese definition for informed consent (“Consentimento informado”):

Applicable national legal framework/ Reference
Chapter 1, Art 2(j) Law 21/2014 - Definition
Art 7 & 8 Law 21/2014 (pt)- Vulnerable persons


Additional Information: Specific provisions apply to vulnerable persons such as minors and adults incapable of giving informed consent.

@Safety protection of Trial subjects
The new law further emphasizes the importance that is to be given to the clinical trial participant. Article 3 introduces a new statement, highlighting that “in clinical studies, all precautions must be taken to respect the privacy of the individual and minimize any damage to their rights of personality and their physical and mental integrity.”
 
On the evaluation of risk/benefit by the national competent authority, now includes a short statement, declaring that the experimental therapy risk/benefit can be reviewed at any time during the trial, if new evidence appears or through interim analyses of the study itself. This highlights the growing trend in clinical trial design of adopting interim analysis in their statistical analysis plan.
 
Some minimum requirements for the protection of participants are also more fleshed out and detailed in comparison to the previous law. The assigned ethic committee (either the CEIC or a CES) is also provided with the authority to, in non-interventional studies and exceptional situations, remove the need for explaining to the participant what the trial is about and attaining informed consent.
Specific provisions are established for clinical trial participants, including the minimum requirements for the protection of participants, specific provisions regarding the participation of minors and disabled individuals in clinical trials, as well as provisions related to obtaining informed consent.
 
The procedure for attaining consent on minors has also been more detailed. Alongside the other requirements, a clinical trial can only be performed on minors when it has been obtained the informed consent of a minor aged above 16 years and his legal representative. If the minor has less than 16 years, the representative is the sole responsible for grating informed consent, although it must reflect the presumed will of the minor. The assigned ethic committee again is given the right, under exceptional circumstances, to waive the requirements of informed consent and informing the minor patients in clinical studies without intervention. The assigned ethic committee is given the same right for participants of age unable to provide informed consent.
 
Law 21/2014 on clinical research (pt) published 16 April 2014 in Diário da República/ Lei n.º 21/2014, of 16th of April. This law repeals Law 46/2004 of 19 August 2004 (Clinical Trials on Medicinal Products for Human Use) that incorporated the principles of the Clinical Trials Directive 2001/20/EC. This law covers all clinical research with humans including not only clinical trials with IMP but also investigations with MD and all kind of observational studies. It also regulates the organization of the Comissão de Ética para a Investigação Clínica / National Ethics Committee for Clinical Research (CEIC ). Law 73/2015 of 27th July is an amendment to Law 21/2014 and sets the conditions in which monitors, auditors and inspectors have access to the registries of clinical studies’ participants.
(3) Data Protection Act – Act 67/98 of 26 October (en)/ Lei n.o 67/98- Lei da Protecc?a?o de Dados Pessoais (pt)
 
Orphan diseases:
There is no specific Portuguese law for orphan diseases. We follow the European regulation for orphan Diseases and their human medicines (e.g. EC 141/2000).
There are however specific Portuguese ministry of health lists of orphan drugs not for investigational purposes, but for reimbursement.
A list of applicable Portuguese legislation is available on:
 - INFARMED website via: Medicamentos Uso Humano> Ensaios Clinicos> Normativos de referência
Nacional Law: Legislação nacional aplicável
Notification to Data Protection Authority is mandatory: Yes

Approval/ authorisation required: Yes

Language of notification:Official National Language(s)
English accepted

Notification format: e-notification via electronic system on the CNPD website

Notification fee required: Yes

Fee: 150 € for prior authorization (75 € for simple registration)

Guidance on notification requirements available: Yes

Guidance on notification requirements: Further guidance on the e-notificatoin procedure is provided on the CNPD website in section 'Notification'.

Data Protection Authority/ Agency - Contact Details
National Data Protection Authority/ Comissão Nacional de Protecção de Dados (CNPD)

Phone:+351 213928400
Fax:+351 213976832
E-Mail: geral@cnpd.pt

Web address: https://www.cnpd.pt

Address: Rua de São Bento n.º 148-3º, 1200-821 Lisboa

Additional Information: All personal data processing must be notified to the CNPD (Art 27 of the Data Protection Act.). The processing of personal data obtained from study subjects requires prior authorization according to Art 28 Data Protection Act. 


Timelines for authorization: 30 days according to Art 16 (9) Law 21/2014 (pt).

INFARMED- National Authority of Medicines and Health Products, IP/ Autoridade Nacional do Medicamento e Produtos de Saúde I.P.;
(Government agency accountable to the Health Ministy) Health Products Directorate

Parque de Saúde de Lisboa
Avenida do Brasil, 53
1749-004 Lisboa, Portugal
 
Tel +351 21 798 7235
Fax +351 21 798 7182
Email: daps@infarmed.pt

Website: http://www.infarmed.pt/
(The English web pages contain selected items from its Portuguese language site and will be continuously expanded)

No local CAs.
The sponsor is responsible for submission of the clinical investigation to the national CA according to Art 25-27 Law 21/2014 (pt).

Clinical investigations with MDs of Class IIa, IIb and III as well as MDs without CE mark or used outside label have to be submitted to the Competent Authority for authorisation (cat II-III, V-VI). All others are only subject to notification and EC approval. (see Art 33 Art Law 21/2014 (pt) and Art 12 DL 145/2009 (pt))  

Format: Paper; Electronic format
 
The required documentation to be sent to the CA is provided in Annex VIII and Annex XV, DL 145/2009 (pt).
 
The templates for the Notification form (“Notice form for medical devices and active implantable devices in Clinical Investigation”) and the “Statement of clinical investigation with (active implantable) medical devices” are available (in pt and en) on the INFARMED website in the following section:
Dispositivos Médicos> Investigação Clínica / Avaliação Funcional> Investigação Clínica
 
Portuguese, English accepted (for official application documents and scientific documents only; NOT for documents intended for study subjects)
Fees for trial submission mandatory: Yes

Fees for the authorization of
• MD without CE marking or with CE marking for other indication:600,00€
• MD with CE marking: 400,00 €
• Substantial amendment to protocol: 200,00 €

NB! Status 2015 - Fees are being revised annually 

Academic Studies: No submission fees.


Waiver for academic (non-commercial) studies possible: Yes

Applicable national legal framework/ Reference:
Portaria nº63/2015 (Fee Ordinance)

Related information plus currently applicable Fee Ordinance (Portaria) is available on the INFARMED website in section Taxas (in Portuguese only).

Approval timeline: 30 days if no objections have been raised by the CA.

Additional Information

Timeline applies if no objections have been raised by the CA.
NB! CA authorization requires EC favorable opinion.

(see Art 33 Law 21/2014  (pt))
 
 
It is mandatory to have a sponsor in cat I-VIII. Co-sponsorship is not allowed.
The investigator must inform the sponsor immediately (not later than 24 hours) on the occurrence of any SAEs (or any defects of the MD, potentially leading to a SAE). A detailed written report must follow within 5 days. The sponsor shall ensure that any information on SADEs/ SAEs being fatal, life-threatening, or deteriorating health, are reported to the competent EC, the national CA and the CA of any EEA State in which the investigation is being conducted not later than 2 days after sponsor’s first knowledge (applicable to cat I-VIII). All other AEs or AEs related to defects of MDs, potentially leading to a SAE, are reported to the competent EC, the national CA and the CA of any EEA State in which the trial is being conducted as soon as possible and in any event not later than 7 days after the sponsor’s awareness of the reaction. The reporting timelines are according to Art 22 Law 21/2014 (pt), Annex XVI (23) DL 145/2009 (pt) and in line with the EC’s guidance document MEDDEV 2.7/3 on SAE reporting in clinical investigations under directives 90/385/EEC and 93/42/EC) The standard reporting form to be used for SAE declaration to the CA is the EC’s SAE reporting form Appendix of MEDDEV 2.7/3. An Annual Safety is mandatory for cat-s II,III,V,VI and shall be submitted (to the competent EC and the national CA by the sponsor pursuant to Art 22 (10) Law 21/2014 (pt). SAE Definition: Any untoward occurrence that may led to death or led to serious deterioration in the health of the subjects, according to Art 3, DL 145/2009 (pt).
Substantial amendments to the study plan shall be simultaneously notified to the competent EC and the national CA, pursuant to Art 4, Deliberação n.º 514/2010, de 3 de Março and Art 18 Law 21/2014 (pt)- Standard Notification form to be used by the applicant for submission of substantial amendments is the same as used for IMP studies and is provided on the INFARMED website in section Medicamentos Uso Humano> Ensaios Clinicos> Formulários: “Substantial Amendment Notification Form (pdf)”/ “Formulário de pedido de alteração (pdf)”
The sponsor is obliged to notify the competent EC and the national CA of the end of the trial within 90 days (counted form last visit of study participant).
The final report must be submitted to the EC within 12 month after trial termination.
Premature trial termination must be declared within 15 days with clearly stating the reasons for it. (Art 19 Law 21/2014 (pt))  
 
Archiving: To keep for a minimum period of 5 years or, regarding the implantable medical devices, 15 years, all relevant information regarding the medical device, including the Statement, for inspection purposes.
@Approval of European/ Interantional guidelines: I must add that Infarmed IP, approves guidelines for clinical trials and clinical studies with the use of medical devices or cosmetics and body care, taking into account the guidelines adopted at EU level, in particular: EN ISO 14155 - This International Standard addresses good clinical practices for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety and performance of medical devices for regulatory purposes. However, it does not apply to in vitro diagnostic medical devices. The latest revision of the standard has been released in Feb, 2011 and hence, the current version of the standard is ISO 14155:2011.
Insurance for study participants (patients and healthy volunteers), investigators and sponsors in studies Cat I-VI is mandatory according to Art 15 & 16 Law 21/2014 (pt) and Art 14, Annex VIII and Annex XVI (15f) DL 145/2009 (pt). There is no mandatory compensation sum coverage.
CEIC - National Ethics Committee for Clinical Research/ Comissão de Ética para a Investigação Clínica
www.ceic.pt

Parque da Saúde de Lisboa
Av. do Brasil, 53 - Pav. 17-A
1749-004 Lisboa
Tel: +351 21 798 53 40
Fax: +351 21 798 72 09
ceic@ceic.pt

Local ECs
There are almost 100 institutional ECs (public and private, health and academic)
@CA submission/ approval:
Concerning the approval of a clinical trial, according to law 21/2014,as the law before it, an approval request has to be sent to the Portuguese National Competent authority (INFARMED). Under the new law, the sponsor is to request permission to INFARMED through the RNEC (RNEC – National Clinical Trials Registry) . Within 30 business days, the governing board of the INFARMED has to issue an opinion. However, the RNEC is still not in operations as of this moment, and so the submission procedure is still conducted under Law 46/2004.
 
 
A positive vote from the EC is required for cat I-VIII. Sponsor is responsible for the submission to the local EC(s). Format: Paper form The required documentation for EC application is provided in Deliberação n.º 514/2010, de 3 de Março The National Research Ethics Committee (CEIC) is responsible for assessing Clinical Trial applications, though it may delegate to a research ethics committee established by a local health institution, hospital or clinical trial site. For multi-centre trials, the sponsor submits the application to the National Research Ethics Committee – CEIC NB: CA authorization requires EC favourable opinion!
Portuguese; English accepted NB: Informed Consent, short summary of the protocol and all documents related to the patient must always be in Portuguese!
No fee is directly charged by CEIC (INFARMED I.P, charge sponsors according to a scale of fees.
@Safety protection of Trial subjects
The new law further emphasizes the importance that is to be given to the clinical trial participant. Article 3 introduces a new statement, highlighting that “in clinical studies, all precautions must be taken to respect the privacy of the individual and minimize any damage to their rights of personality and their physical and mental integrity.”
 
On the evaluation of risk/benefit by the national competent authority, now includes a short statement, declaring that the experimental therapy risk/benefit can be reviewed at any time during the trial, if new evidence appears or through interim analyses of the study itself. This highlights the growing trend in clinical trial design of adopting interim analysis in their statistical analysis plan.
 
Some minimum requirements for the protection of participants are also more fleshed out and detailed in comparison to the previous law. The assigned ethic committee (either the CEIC or a CES) is also provided with the authority to, in non-interventional studies and exceptional situations, remove the need for explaining to the participant what the trial is about and attaining informed consent.
Specific provisions are established for clinical trial participants, including the minimum requirements for the protection of participants, specific provisions regarding the participation of minors and disabled individuals in clinical trials, as well as provisions related to obtaining informed consent.
 
The procedure for attaining consent on minors has also been more detailed. Alongside the other requirements, a clinical trial can only be performed on minors when it has been obtained the informed consent of a minor aged above 16 years and his legal representative. If the minor has less than 16 years, the representative is the sole responsible for grating informed consent, although it must reflect the presumed will of the minor. The assigned ethic committee again is given the right, under exceptional circumstances, to waive the requirements of informed consent and informing the minor patients in clinical studies without intervention. The assigned ethic committee is given the same right for participants of age unable to provide informed consent.
 
 
Medical Device Act:
Decree-Law No. 145/2009, 17 June as amended, concerning medical devices and active implantable medical devices/ Decreto-Lei n.º 145/2009, hereafter referred to as DL 145/2009 (pt), de 17 de Junho
It is the transposition of Directives 93/42/CEE, 90/385/CEE and 2007/47/CE into national law.

Law on clinical research
Law 21/2014 (pt), published 16 April 2014 in the Official Gazette (Diário da República): repeals Law 46/2004 of 19 August 2004 (Clinical Trials on Medicinal Products for Human Use) that incorporated the principles of the Clinical Trials Directive 2001/20/EC.
This law covers all clinical research with humans including not only clinical trials with IMP but also investigations with MD and all kind of observational studies.
It also regulates the organization of the Comissão de Ética para a Investigação Clínica / National Ethics Committee for Clinical Research (CEIC).
 
Law 73/2015 of 27th July is an amendment to Law 21/2014 and sets the conditions in which monitors, auditors and inspectors have access to the registries of clinical studies’ participants.
 
Data Protection
Data Protection Act – Act 67/98 of 26 October (en)/ Lei n.o 67/98- Lei da Protecc?a?o de Dados Pessoais (pt)
National Data Protection Authority. CNPD – Comissão Nacional de Protecção de Dados
 
Rua de São Bento n.º 148-3º
1200-821 Lisboa
Tel: +351 213928400
Fax: +351 213976832
e-mail: geral@cnpd.pt

For performing clinical trials in Portugal, sponsors have to request authorization from the national CA (INFARMED) and ethical approval from the EC (CEIC) plus approval from the National Data Protection Authority (CNPD).
 
All personal data processing must be notified to the CNPD (Art 27 of the Data Protection Act) The processing of personal data obtained from study subjects requires prior authorization according to Art 28 Data Protection Act (applicable to cat I-VIII)
 
Submission of Notification is performed via an electronic system (e-notification) via the CNPD website in section Notification
 
Notification fee: 150 € for prior authorization (75 € for simple registration
Submission language: Portuguese, English accepted.
Timelines for authorization: 30 days according to Art 16 (9) Law 21/2014 (pt).

Last update revision: 2014 November



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