Due to the COVID-19 emergency and the consequent lockdown that is affecting most non-essential services in Italy, including some healthcare services, on 12 March 2020 the Italian Medicines Agency (AIFA) issued guidance for sponsors, non-profit organisations and contract research organisations (CROs) involved in clinical trials.
The guidance tackles urgent needs that sponsors are experiencing in clinical trials due to restrictions on patients' access to trial sites. The AIFA has set out conditions for alternative arrangements that comply with good clinical practice (GCP) with a view to ensuring therapeutic continuity in clinical trials to the benefit of patients.
The guidance covers all phases of clinical trials, including:
- electronic submissions of applications;
- amendments to activity management;
- delivery of investigational medicinal products (IMPs) directly to patients; and
- remote monitoring of trials, including circumstances where trial sites have been closed and trials must be temporary halted.
Submission of applications and amendments
Electronic submissions have been unaffected by the COVID-19 emergency. However, sponsors may delay sending paper documentation and digital supports, which will be provided as soon as possible.
Submissions that must be performed exclusively in paper format are currently suspended. As an exception, paper submissions relating to applications for trials concerning COVID-19 treatments are admitted. Transition to the digital platform should be performed as soon as possible.
Ethics committees are ensuring the continuity of services. Meetings of ethics committees may be held by teleconference or other similar means. As activities are managed on a local level, operational aspects should be checked with the competent authority.
Trial activity management outside trial sites
In certain circumstances, trial activities may need to be conducted outside a trial site, including:
- the sponsors' delivery of investigational medicinal products (IMPs) directly to patients instead of to a hospital pharmacy as required by the applicable regulation; and
- 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 the dispensing of medications at the patient's domicile.
Under such circumstances, the sponsor will submit a substantial amendment for immediate implementation to the competent ethics committee, highlighting the urgency of the matter.
CROs and sponsors must prepare a risk management plan and an action plan in the overriding interest of the patients which considers the urgent need to minimise contact between patients and staff and to avoid unnecessarily overloading medical facilities.
To the extent that it is feasible, trial sites will provide a quantity of IMPs that meets the therapeutic needs for a longer period than usual.
Where possible, IMPs will be delivered to hospital pharmacies, which will receive, register and store the product and supply it to a trial site.
By way of derogation, due to the emergency, on instruction from the managing director of the hospital pharmacy and the principal investigator, sponsors 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 hospital pharmacies will maintain the supervision of the delivery process. Hospital pharmacies and principal investigators must be kept informed continually.
The conditions of delivery and risk management plan must consider the nature, administration, storage and transport of IMPs.
Appropriate information will be provided at a distance to the patients instead of face-to-face meetings with investigators at a trial site. Depending on the circumstances, trial sites may conduct all communication via teleconference or videoconference.
All activities must be traceable and to the extent possible, must comply with FAQ 10 of the European Medicines Agency (EMA) "Q&A: Good clinical practice (GCP) – GCP Matters".
If the CRA is unable to perform the final accountancy of the IMP for reconciliation purposes, this operation, if it cannot be postponed, can be performed by a pharmacist from the hospital pharmacy or by a study coordinator or data manager who has received apposite training. The IMP will be returned directly by the hospital pharmacy.
Haematological analysis must be carried out in public facilities which are located close to the patients' domicile. The performance of analysis by private facilities that are not authorised for clinical trials must be carefully considered. They are admissible if this is the only way to protect patient safety. The use for regulatory purposes of data obtained from laboratories that are not authorised for the trial should be justified when the data is 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 can guarantee continuity outside the trial site by adopting the above measures and arrangements. If not, either the trial should be temporarily halted or patients should be transferred to the nearest trial facility. Where 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.
The transfer of the patients to a backup medical facility that is not authorised for the relevant trial is not permitted.
Sponsors must consider in their risk management plans whether on-site monitoring visits are necessary or could be postponed, replacing to the extent that is possible the on-site visits by increased central monitoring.
Exceptional methods (eg, teleconferencing or videoconferencing with trial staff) can be implemented for data source verification provided that the activity is regulated by the standard operating procedures (SOPs) of the sponsor or CRO and evaluated and approved by the trial site's data protection authority (DAP).
Other monitoring methods involve more risky access to sensitive data, as the video recording of source documents or making available to the sponsor or CRO monitor original documents in shared digital platforms must always be approved by the trial site's DPA. However, it is recommended to seek the opinion of the national DPA (ie, Garante).
Sponsors' direct conclusion of contracts with specialised agencies
A sponsor may directly engage specialised agencies for the provision of healthcare services (eg, home nursing services) relating to the clinical management of patients under the responsibility of the principal investigator.
This is admitted by way of exception during the current COVID-19 emergency. In derogation of the requirements set out in FAQ 11 of the 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 healthcare sector. Any other requirements in the FAQ remain applicable, including that:
- supervision is maintained by the principal investigator;
- efficient communication is ensured between the personnel appointed by the sponsor and the principal investigator;
- the personnel appointed are adequately trained and the tasks and responsibilities are detailed in the contract or delegation log; and
- data protection of the concerned individuals is ensured.
Reimbursement of exceptional expenses
Due to the ongoing COVID-19 emergency, where patients incur additional expenses for the application of exceptional measures, sponsors may directly reimburse such expenses to patients, provided that supporting documentation is collected and stored.
