Table 1 Main recommendations of EMA and AIFA during the COVID-19 pandemic

Changes to ongoing trials, safety reporting and risk assessment

Safety reporting

Risk assessment

Sponsors should include in their risk assessment the most appropriate measures needed during COVID-19:

• Conversion of physical visits to phone or video visits, postponement or complete cancellation of visits.

• Interruption or slowing down of recruitment of new trial participants;

• Extension of trial duration;

• Transfer of trial participants to investigational sites away from risk zones, or closer to their home, to sites already participating in the trial, or new ones.

• Acceptable to perform laboratory, imaging or other diagnostic tests (e.g. blood cell count, liver function test, X-ray, CT, MRI, ultrasonography, ECG etc.), at a local laboratory or relevant clinical facility authorised/certified. These analyses can be used for safety decisions.

Sponsors must continue safety reporting. Investigators must continue collecting adverse events through alternative means, e.g. by phone or telemedicine visits.

Promoters must define risk assessment plans and implement suitable actions. An accurate tracking of all deviations from study procedures and the rapid implementation of emergency measures must be ensured through notified amendments:

• Temporary suspension of enrolment and/or treatment or change in trial procedures to limit visits to those absolutely needed (if possible, also providing for an extension of trial duration).

• Specific procedures can be performed directly at the patient’s home by experimental center staff or by third parties; these may include both clinical procedures (e.g. registration of adverse events, vital signs, etc.), and the administration of non-self-administering therapies (e.g. infusions).

Compliance with personal data protection rules remains applicable, such as the need for investigator’s supervision and maintenance of efficient communication between personnel in charge, investigator and patient.

• Laboratory and/or instrumental examinations (e.g. CT, MRI, X-ray) can be performed at facilities close to the subject’s home.

Communication with authorities

Priority is given to any (new) clinical trial application for the treatment or prevention of COVID-19, and/or substantial amendment applications to existing clinical trials necessary as a result of COVID-19.

Preliminary evaluation of COVID-19 treatment studies will be carried out by AIFA Scientific Technical Commission (CTS). After CTS approval, trials will be evaluated by the AIFA competent authority (Clinical Experimentation Office) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani (INMI) in Rome (appointed as the National Ethics Committee). An accelerated time-frame is expected for the evaluation of COVID-19 studies.

Agreement with and communication between sponsors, trial sites and trial participants

Changes to trial procedures should be clearly communicated by the Sponsor and agreed upon by the investigators.

Suitable remote communication mechanisms between the interested parties must be provided.

It is recommended that adequate documentation about all communications be maintained.

Changes to informed consent

Alternative procedures to obtain informed consent: phone or video-calls to obtain oral consent, to be documented in trial participants’ medical records, supplemented with e-mail confirmation.

Any validated and secure electronic system already used in the trial for obtaining informed consent can be used as per usual practice if in compliance with national legislation.

Alternative procedures to obtain informed consent must be considered: telephone contact, followed by confirmation e-mail or validated electronic system (previous DPO authorization). Written consent must be obtained as soon as the situation permits. DPO must identify technical and organizational measures to prove the acquisition of a valid consent.

Changes in the distribution of the investigational medicinal products

Changes in the distribution of IMP may be necessary to prevent avoidable visits to sites and to provide trial participants with needed treatments. Sponsors must assess the risks relating to the product and consider any alternative shipping and storage arrangements. The continuation of treatment should be under adequate supervision of the investigator.

AIFA allows the experimental center to supply, during patient visit to the center, a drug quantity that covers a longer period of time than that normally estimated by protocol and with an expiration date that goes beyond the treatment period provided in order to avoid the risk of patients taking an expired drug.

Drug delivery to a family member or to a delegated caregiver is also permitted if the patient has difficulty in reaching the experimental center.

The clinician must constantly ensure that the drugs are taken correctly.

Drug delivery from the hospital Pharmacy directly to the patient’s house is allowed through dedicated couriers. The Pharmacy of the experimental center must supervise the process and inform the investigator as per correct trial management and according to the risk plan provided by the sponsor, considering type of IMP, method of distribution, conservation and transport.

Documentation related to IMP delivery must be stored at the experimental site to guarantee the confidentiality of the data.

Changes to monitoring

A risk-based approach to monitoring should be taken, focusing on certain sites, data points and processes that are critical to ensure the rights, safety and well-being of trial participants and the integrity of the trial (and trial data).

a) On-site monitoring. The cancellation or postponement of on-site monitoring visits and the extension of the period between monitoring visits are likely to be necessary.

b) Centralised monitoring and central review of data collected can supplement and temporarily replace on-site monitoring.

c) Off-site monitoring including phone calls, video visits, e-mails or other online tools can be used to discuss trial progress and participant status with the investigator and site staff, to resolve problems, review procedures and facilitate remote site selection and investigator training.

d) Remote source data verification (SDV) will currently only be considered necessary for very few trials when in line with national law.

It is essential that robust follow-up measures are planned and can be rapidly implemented when the situation normalizes.

Sponsors must define risk assessment plans and implement actions that take into account the need to reduce unnecessary contact during the COVID-19 period, evaluating whether on-site monitoring visits can be deferred or replaced by the introduction and/or strengthening of the centralized monitoring.

Exceptional and alternative methods are accepted for SDV, such as telephone contact or, better, video conferences with the experimental site staff. Remote monitoring methods may be taken into consideration when appropriately justified by the intent to protect the rights and well-being of the subjects enrolled in the trial. It is essential for promoters to plan robust follow-up measures to assess and eventually fill in the gaps due to the reduced frequency of in-site monitoring or to the use of alternative measures.

Reimbursement of exceptional expenses

Urgent safety measures may create unplanned expenses that should be borne by the sponsor, preferably directly. If these expenses have to be borne initially by the trial participants, these should typically be compensated subsequently by the sponsor via the investigator.

AIFA recommends that the promoter reimburses documented costs incurred by patients for the implementation of urgent measures.