Clinical trials during the COVID‍-‍19 pandemic and joint action CT-CURE

The EU guidance document under COVID-19 pandemic

The European Medicines Agency (EMA), together with the European Commission and the Heads of Medicines Agencies (HMA), has produced a guidance document for clinical trials during the COVID-19 pandemic, “Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic".

Note that the simplification measures proposed in the document will only take place during the current public health crisis until the withdrawal of the guidance, when there is agreement on the period for the COVID-19 outbreak in the EU/EEA has passed.

The document was updated with references to Regulation (EU) No 536/2014 on 10 February 2022.

Possible USM situations

Urgent situations that occur with regard to COVID‍-‍19 may be handled as Urgent Safety Measures (USM). This means that the measure can be initiated without first being approved by the Swedish MPA. Although the authority shall, as always, be informed about any Urgent Safety Measures without delay.

The Swedish MPA emphasises that the patient safety is of the outmost importance, therefore shall all planned measures in relation to deviations be based on thorough risk assessments.

Safety reporting

Sponsors are expected to continue safety reporting in adherence with the EU and national legal frameworks (Directive 2001/20/EC, CT-3, and Regulation (EU) No 536/2014). When the number of physical visits is reduced or postponed per protocol, it is important that the investigators continue to collect adverse events from the trial subjects through alternative means, for example by telephone conversations or video visits, depending on what is appropriate.

For more information, see section 4 of the guidance document.

Thorough documentation of deviations

Under the current circumstances with the coronavirus outbreak, protocol deviations may occur due to that trial subjects are not able to perform planned trial visits or that sponsor personnel are not able to visit the trial sites.

The Swedish MPA is of the opinion that a protocol deviation which may occur as a consequence of the coronavirus outbreak is not by definition necessarily a serious breach. However, the authority encourages sponsors to document deviations thoroughly and decide if these need to be reported as serious breaches to the Swedish MPA in line with the regulations LVFS 2011:19, Chapter 8, Article 11 on clinical trials on medicinal products for human use, or Article 52 in Regulation (EU) No 536/2014.

More information on reporting serious deviations can be found in the EMA guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol.

Amendments/‌modifications

The safety of the trial subjects is of the utmost importance. It is up to the sponsor to assess if the amendment/modification to a clinical trial is substantial and is needed in relation to the current trial protocol. The amendment/modification should then be sent to the Swedish MPA as a submission of a substantial amendment, in line with LVFS 2011:19, Chapter 7, or as a substantial modification in accordance with Chapter III in Regulation (EU) No 536/2014.

The substantial amendments/modifications that shall be made are recommended to be listed and shall be clearly justified, and the consequences for the subjects’ safety and the scientific value of the trial shall be clearly described in the application.

Highlight in the cover letter to the substantial amendment/modification application that the amendment is made due to the current situation with the coronavirus outbreak.

If the trial is conducted in accordance with EU Directive 2001/20/EC, also state “COVID-19” in the email/Eudralink subject field. This will enable the Swedish MPA to prioritise the submission.

If the trial is performed in accordance with Regulation (EU) No 536/2014, it is appropriate that "COVID-19" is included in the title of the trial at the initial application submission, as well as when the application for substantial modification is uploaded in the CTIS (Clinical Trials Information System).

More information and examples of substantial amendments/modifications can be found in section 6 of the guidance document.

Monitoring

The Swedish MPA receives questions about the possibility to perform the entire or parts of the monitoring visit remotely during the coronavirus pandemic.

Given the current circumstances, the Swedish MPA would like to advice clinical trial sponsors to perform and document an updated risk analysis and to update the monitoring plan. For example, it is possible to postpone monitoring visits if the sponsors document the rationale grounds for their decisions, and/or to increase the central data monitoring (collected electronically) and to have continuous contact with participating clinics by phone/email.

In the EU guidance document on the management of clinical trials during the COVID-19 pandemic, the following options for remote source data verification (SDV) are included:

• Sharing pseudonymised copies of trial related source documents.
• Direct, controlled remote access to trial patients’ electronic medical records.
  Note that direct access is not permitted in Sweden according to the Patient Data Act (2008:355) definition.
• Video review of patients’ medical records with clinical site team support, without sending any copy to the monitor and without the monitor recording, copying, or photographing images during the review.
  Note that it is important to ensure that the network used is not public and that private digital units shall not be used.

As described in the guidance document, remote SDV may be considered only during the COVID‍-‍19 pandemic related public health crisis and when in line with EU and national law (or temporary national emergency measures).

Remote SDV may be considered for trials involving COVID-19 indication or serious or life-threatening conditions, trials involving particularly vulnerable participants (such as children and adults incapable of giving their information consent), pivotal trials and trials where the absence of SDV for critical data may likely pose unacceptable risks to participants' safety or the reliability/integrity of trial results.

Remote SDV should then focus on the quality control of critical data such as primary efficacy data and important safety data. The document also clarifies that this applies during a limited time period.

Remote SDV should only be carried out if adequate data protection, including data security and protection of personal data even if pseudonymised, is ensured. Refer to Annex 1 in the guidance document, for controls that, where applicable, can protect trial participants’ rights while permitting remote SDV.

The Swedish Patient Data Act and the National Board of Health and Welfare regulation HSLF-FS 2016:40 complement the General Data Protection Regulation in EU. It is the responsibility of the caregiver to demonstrate that the data protection rules are followed. Health care workers shall follow the instructions from the caregiver for the handling of the patient’s personal data. It does not require name or social security number to make a patient’s data personal data.

There are no provisions in law or regulation allowing the caregiver to permit direct access to patients’ electronic medical records for monitoring in clinical trials according to the Patient Data Act definition (Chapter 5). Direct access in this context means in simplified terms that the monitor, for example gets digital access to data in a patient‍´‍s medical record by a personal login.

A caregiver may, if the caregiver first performs a test in accordance with the rules on confidentiality, separate and disclose personal data about a patient on paper or digitally on IT media (Patient Data Act, Chapter 5, Article 6). In this case there must be a decision of disclosure in place and a confidentiality testing that precedes the disclosure. To make such digital disclosure, the caregiver is required to take security measures to protect the information about the patient. For disclosure over an open network, the information of the patient must be protected from unauthorized disclosure and unauthorized access by, for example encryption and secure login (HSLF‍-‍FS 2016:40, Chapter 3, Article 15).

If the sponsor foresees that remote SDV is needed to be able to perform the clinical trial, this should be specified in the initial protocol application to the Swedish MPA or, in case of ongoing trials, submitted via a substantial amendment. The application shall reveal how the sponsor practically will solve the monitoring and this shall correspondingly be clearly described in the patient information. It is also important to assure that the participating trial sites have technical possibilities and resources to be able to perform the monitoring.

Handling of IMP

The regulation presupposes that the investigational medicinal product (IMP) is being delivered to the trial site and then handed over to the patient. However, during the current circumstances, the Swedish MPA understands there might be situations with a need for delivering the IMP directly to trial subjects in their private homes.

Some important aspects to consider are:

• The integrity of the trial subjects must be protected.
  The identity of the subject must be kept unrevealed to the sponsor. All delivery of IMP to a trial subject’s home must therefore be performed from the hospital/clinic or from a pharmacy involved in the trial.
• Product quality.
  The deliveries must fulfill the temperature storage requirements specified for the product.
• Control of each product throughout the entire chain.
  It must be ensured that the correct IMP and quantity is delivered to the correct subject. The IMP must not be delivered to a mailbox, outside the door or equivalent. The delivery handling shall be documented.
• Patient safety.
  Home delivery must not replace a planned investigator contact.

The above aspects can be handled as Urgent Safety Measures.

More information on the handling of investigational medicinal products, non-investigational medicinal products (NIMP)/auxiliary medicinal products (AxMP) and other products or devices that the subjects, according to the investigative protocol, need can be found in section 9 of the guidance document.

Note that risk-proportional labeling requirements for approved investigational and auxiliary medicinal products are set out in Article 67 of Regulation (EU) No 536/2014.

New COVID-19 treatments – CT‍-‍CURE

EU Member States have taken an initiative to speed up the investigation of multinational trial applications with the aim of testing new medicinal drug treatments during COVID-19 (does not apply to vaccines).

The joint action is called CT-CURE and means that the investigation phase of the applications for the Member States is significantly shortened depending on the type of application compared with maximum timelines according to Regulation (EU) No 536/2014.

Note that the sponsor's response time when supplementary information is requested is not shortened. More information about this fast-track assessment for trial applications can be found at the website of CT-CURE. Information is also found on the European Commission website.

In order to take maximum advantage of these coordinated multinational assessments with short, fixed timelines for the various assessment phases, it is recommended that the sponsor submit complete applications (Part I and Part II) in all Member States concerned, and in the cover letter express a wish to be included in the CT-CURE project.

Note that only submitting application for clinical trials under Regulation (EU) No 536/2014 is covered by the accelerated assessment period.

If the application for a substantial modification refers to a new COVID-19 investigational medicinal product that is added to an already ongoing trial, for example in trials with adaptive platform design, this may be included in CT-CURE after transferring of the ongoing trial to the new regulatory framework under Article 98 of Regulation (EU) No 536/2014.

More information on the transfer of trials is provided in the Commission's Questions and Answers, section 11.

Sponsors are welcome to seek advice nationally (RIC@lakemedelsverket.se) or centrally (EMA, for fast-tracked advice send email to 2019‍-‍nCoV@ema.europa.eu).

General questions about CT-CURE are answered via email to registrator@lakemedelsverket.se or
eu4health_ct-cure@fagg-afmps.be (EU project coordinator).

Related information

More information is available on the EMA website.