On 12 March, 2020, due to the COVID-19 outbreak and the consequent lockdown that is affecting non-essential services in Italy, including some health care services, the Italian Medicines Agency (AIFA) issued a guidance ("Guidance") to provide directions to sponsors, non-profit organisations, and contract research organizations (CROs) involved in clinical trials. The Guidance tackles criticalities that the sponsors are experiencing in clinical trials due to the restrictions to patients' access to the trial sites. AIFA sets out conditions for alternative arrangements in compliance with Good Clinical Practice (GCP) with a view toward ensuring therapeutic continuity in clinical trials to the benefit of the patients.
The Guidance covers all the various phases of the clinical trial, from the electronic submissions of applications and amendments, to the management of the clinical trial's activities – such as the delivery of the Investigational Medicinal Product (IMP) directly to the patients or the remote monitoring of the trial, including circumstances where the trial sites has been closed and trials must be temporary halted.
Submissions of applications and amendments
Submissions in electronic format are unaffected by the emergency. However, sponsors may delay the sending of paper documentation and digital supports, which shall be provided as soon as feasible. Submissions that must be performed exclusively in paper format are currently suspended. As an exception, paper submissions related to applications for trials concerning treatments of COVID-19 are instead admitted. Transition to the digital platform should be performed as soon as possible.
Ethics Committees (CEs) work to ensure service continuity. Meetings of Ethics Committees may be held by teleconference or other similar means. As the activity is managed at local level, we would recommend checking the operational aspects with the competent authority.
Management of trial activities outside the trial site
Under particular circumstances, trial activities may need to be conducted outside the trial site. Such exceptional circumstances may relate to:
- The sponsors' delivery of the IMP directly to the patients rather than to the hospital pharmacy as it is required by the applicable regulation.
- The conduct of certain diagnostic analysis or tests by medical facilities that are not specifically authorised for the concerned trial, as well as the performance of patients' visits or medications exceptionally at the domicile of the patient.
Under those circumstances, the sponsor shall submit to the competent Ethics Committee a substantial amendment for immediate implementation, highlighting the urgency of the matter.
The CRO and sponsor shall prepare a risk management plan and an action plan in the overriding interest of the patients in consideration of the urgent need to minimise contact between the patients and staff, and to avoid to unnecessarily overloading medical facilities.
Investigational medicinal product (IMP)
To the extent that it is feasible, trial sites shall provide a quantity of IMP that is suitable to satisfy the therapeutic needs for a longer period than the usual one. The ordinary rule shall be followed as far as possible, thus delivering the IMP to the hospital pharmacy, which shall receive, register, and store the product, supplying it to the trial site.
By way of derogation, due to the emergency situation, upon instruction of the managing director of the hospital pharmacy and of the principal investigator, the sponsor may be requested to perform direct shipment from the hospital pharmacy to the patients enrolled in the trials, even by means of dedicated couriers. It is understood that the hospital pharmacy shall maintain the supervision of the delivery process. The hospital pharmacy and the principal investigator shall be kept informed on a continued basis.
The conditions of the delivery and risk management plan shall take into account the nature of the IMP, the manner of administration, storage, and transportation modalities. Appropriate information shall be provided at a distance to the patients in replacement of the in-person meetings with the investigator at the trial site. Depending on the circumstances, the trial site may ensure that the communication is performed via teleconference or videoconference.
Traceability of any activity must be still ensured. To the extent feasible, compliance with the conditions set forth in the FAQ 10 of the EMA “Q&A: Good clinical practice (GCP) – GCP Matters” shall also be warranted. If the Clinical Research Associate (CRA) is not in a position to perform the final accounting of the IMP for the purpose of reconciliation, then this operation, if it cannot be postponed, can be performed by a pharmacist of the hospital pharmacy or by the study coordinator or data manager who has received apposite training. The IMP shall be returned directly by the hospital pharmacy.
Clinical tests to the patients
Haematological analysis must be carried out in public facilities that are located close to the patients' domicile. The performance of analysis by private facilities that are not recognised as authorised for clinical trials shall be carefully considered. They are admissible where this is the only way to protect patient safety. The use for regulatory purposes of data obtained from laboratory that are not authorised for the trial should be justified when the data are submitted.
Trial sites closed to the public
If a trial site is closed to the public, it is first necessary to assess whether the trial staff are able to guarantee continuity outside the trial site by adopting the above measures and arrangements. If this is not the case, either the trial should be temporarily halted or patients should be transferred to the nearest trial facility. If patients are transferred to another trial site, the relevant documentation and information, as well as the IMP, must be transmitted to the trial site that takes charge of the patients. Patients transferred to a backup medical facility that is not authorised for the trial at stake will not be admitted.
Monitoring of clinical trials
The sponsor shall consider in the risk management plan whether on-site monitoring visits are absolutely necessary or could be postponed, replacing the on-site visits (to the extent possible) by increased central monitoring. Exceptional modalities (e.g. teleconference or videoconferencing with the trial staff) can be implemented for data source verification provided that the activity is regulated by a Standard Operating Procedure (SOP) of the sponsor/CRO, and then that modality must be evaluated and approved by the trial site responsible for data protection.
Other monitoring methodologies involving more risky access to sensitive data – such as the video recording of source documents, or making available to the sponsor/CRO's monitor original documents in shared digital platforms – must always be approved by the party responsible for data protection of the trial site, but it is recommended to seek a specific opinion of the National Data Protection Authority (DPA).
Sponsor may directly conclude contracts with specialised agencies
The sponsor may directly engage specialised agencies for the provision of health care services (e.g., home nursing services) related to the clinical management of patients under the responsibility of the principal investigator.
This is admitted by way of exception during the current emergency circumstances for the COVID-19 infection. In derogation of the requirements set out in FAQ 11 of EMA “Q&A: Good clinical practice (GCP) – GCP Matters,” the sponsor may enter into service agreements with agencies or companies that are specialised in the concerned health care sector. All other requirements in the FAQ remain applicable, including the need:
- that the supervision is maintained by the principal investigator.
- that efficient communication is ensured between the personnel appointed by the sponsor and the principal investigator.
- that the personnel appointed are adequately trained and that the tasks and responsibilities are detailed in the contract and/or delegation log.
- that data protection of the concerned individuals is ensured.
Reimbursement of exceptional expenses
Due to the emergency situation, to the extent that patients incur in additional expenses for the application of the exceptional measures, the sponsor is allowed to directly reimburse such expenses to the patients, provided that the supporting documentation is collected and stored.