Introduction

The research and development (R&D) of medicinal products is important both from an individual perspective, considering its objective to identify and treat pathologies (with the consequent improvement in patients' quality of life), and from a collective perspective, considering its role in controlling the spread of diseases or eradicating them altogether.

'R&D activities' can be defined as activities carried out in humans (who may be healthy or ill) to:

  • improve knowledge of pathologies;
  • develop new methodologies for diagnosing pathologies; and
  • identify forms of treatment.

R&D activities are subject to legal and regulatory frameworks and practitioners must comply with various requirements, including:

  • respecting the human dignity principle and trial subjects' fundamental rights;
  • adopting the measures necessary to protect and safeguard privacy, personality rights and the physical and mental integrity of the trial subjects, which inherently includes obtaining their consent;
  • complying with applicable ethical parameters and good practices;
  • performing a prior assessment to ensure that the potential benefits associated with the trial outweigh the foreseeable risks and inconveniences; and
  • obtaining the legally required approvals.

Clinical trials are a universally recognised method of performing R&D activities. They must be planned and controlled meticulously to ensure the scientific validity of the results.

Key legislation

In Portugal, clinical trials are governed by Law 21/2014 of 16 April 2014 (amended by Law 73/2015 of 27 July 2015 and Law 49/2018 of 14 August 2018), known as the 'Clinical Research Law' ('CRL'). The CRL includes:

  • the rules which govern the conduct of clinical trials of medicinal products for human use and which result from the incorporation of the EU Clinical Trials Directive (2001/20/EC) into Portuguese law; and
  • the legislation on clinical research into medical devices, which results from the partial incorporation of the EU Medical Device Directive (2007/47/EC) into Portuguese law.

The CRL defines a 'clinical trial' or 'trial' as:

any research conducted into human beings, intended to discover or confirm the clinical, pharmacological or other pharmacodynamic effects of one or more investigational medicinal products, or to identify the undesirable effects of one or more investigational medicinal products, or to analyse the absorption, distribution, metabolism and elimination of one or more investigational medicinal products, in order to ascertain their safety or efficacy.

Process for conducting clinical trials

In Portugal, conducting a clinical trial is subject to:

  • prior approval from the competent ethics committee (CEC); and
  • authorisation by the National Authority for Medicines and Healthcare Products (INFARMED), which is subject to the CEC's approval.

The sponsor (ie, the natural or legal person, institute or entity responsible for the design, conduct, management or financing of the clinical trial) must submit its applications to the CEC and INFARMED, respectively, through the National Clinical Trials Register's online platform.

Subject to certain situations provided for by law, the CEC must opine within 30 business days and state its position on various aspects of the application submitted by the sponsor, including:

  • the relevance of the clinical trial and the trial design;
  • the assessment of the anticipated benefits and risks;
  • the corresponding protocol;
  • the material and human conditions necessary to conduct the trial;
  • the method of recruiting trial subjects;
  • the timeframe and conditions for clinical follow up with subjects after the trial's completion; and
  • the procedure for obtaining informed consent, including the information to be provided to trial subjects.

Except in situations that require express authorisation as set out below, once the CEC has issued its approval, INFARMED's governing board must decide on the application within 30 business days. However, during that period, the board can request any additional documents, information or clarification which it considers necessary. The above period will be suspended until any such request is properly answered.

INFARMED can also present any well-founded objections to an application for authorisation which, in its opinion, could prevent the application's approval. Under these circumstances, the sponsor may change the application. It may do so only once and must do so within the period granted by INFARMED.

If INFARMED considers the change to be insufficient or if the sponsor chooses to make no change to the initial application, the application will be rejected and the clinical trial may not be conducted.

After a clinical trial begins, the sponsor may change the corresponding protocol, provided that it performs a prior assessment to ensure that the potential benefits continue to outweigh the foreseeable risks and inconveniences. However, no changes may be made if they would harm the subjects' safety or change the interpretation of the scientific evidence on which the trial is based.

To change the protocol, the sponsor obtain the CEC's permission. The clinical trial may proceed only:

  • after the CEC approves the change; and
  • if INFARMED has no well-founded objections.

If the CEC approves the change but INFARMED objects, the trial may proceed only if the protocol is adapted to address the objections or if the proposed amendment is withdrawn.

Unless the end of the clinical trial is brought forward, the sponsor must notify the CEC within 90 days of the end of the last subject's participation in the trial. The investigator or sponsor must also provide the CEC with the results of the trial in the form of a summary of the final report.

Clinical trials during COVID-19

The COVID-19 pandemic has made clinical trials even more important, particularly to bring effective drugs to combat the disease to the market as soon as possible. The pandemic has put the scientific community and the pharmaceutical industry under pressure to design medicinal products that quickly, safely and effectively control its spread. Therefore, the European Medicines Agency has called for:

  • coordination and communication between entities that are developing or plan to develop vaccines and medicines to combat the disease; and
  • fee waivers for clinical trials with these purposes.

INFARMED has published various measures which aim to mitigate the risks that the pandemic may pose to patients who participate in clinical trials, including:

  • discontinuation of treatment;
  • suspension of recruitment;
  • reviews of scheduled visits, with preference to be given, where possible, to remote visits;
  • centralised monitoring and review of source data;
  • direct home dispensing of experimental medication, with the principal investigator, the research team and the hospital pharmacy maintaining close and effective supervision of the process; and
  • transfers between clinical trial centres, provided that good clinical practice and the EU General Data Protection Regulation are followed.

In this context, INFARMED allows sponsors to change the terms of their clinical trial authorisation to ensure the safety and protection of their subjects without requiring prior notification or approval. However, this does not apply to cases where treatment is interrupted, which must be notified to INFARMED as an urgent safety measure.

The sponsor – in conjunction with the investigator and based on a risk analysis – must assess and adopt measures to mitigate the risk of contamination for each clinical trial, considering:

  • the characteristics of the trial;
  • the trial site; and
  • the trial's epidemiological risk.

The sponsor must notify INFARMED within four months where any of the above measures are taken. This notification must be accompanied by:

  • a report that systematically documents the measures implemented and the resulting deviations from the protocol; and
  • an assessment of the implementation of the measures and their effect on the post-pandemic study.

However, in cases which involve substantial changes that do not require immediate intervention by the investigator and sponsor, the sponsor must submit these to INFARMED as substantial changes through the usual procedure.