The State Enterprise "State Expert Center of the Ministry of Health of Ukraine" (hereinafter, the Center), based on the current regulatory requirements for conducting clinical trials of medicinal products in Ukraine and taking into account the recommendations of the regulatory authorities of EU countries, the European Medicines Agency (EMA, Version 1 of 20.03.2020) and the U.S. Food and Drug Administration (FDA, March 2020), provides answers to typical questions on the possibility of applying emergency measures in the course of clinical trials of medicinal products by sponsors/applicants in the context of the spread of the COVID-19 coronavirus.
Question 1: Is it possible to deliver investigational products directly to the patient (from the investigational site or a central depot) when the patient cannot visit the investigational site?
The sponsor of the clinical trial (hereinafter – CT) must assess the risks associated with delivery of the investigational medicinal product(s) (hereinafter – IMP) to the patient, in compliance with the requirements of subparagraphs 5.14.3 – 5.14.5 of paragraph 5.14 of section 5 of the “Guideline. Medicinal Products. Good Clinical Practice. Guideline ST-N MOHU 42-7.0:2008”, approved by MoH order of 16.02.2009 No. 95, as amended (ICH GCP). The sponsor must evaluate the existing risks against the established controls and, if necessary, take appropriate action, taking into account the characteristics of the medical and statistical variables and the statistical design of the trial, in order to identify systemic issues that may affect the safety of the subjects or the reliability of the CT results (para. 5.0.4 of ICH GCP). The sponsor must follow its standard operating procedures drawn up after the risk assessment. To ensure delivery of the IMP directly from the trial site, it is advisable to use the capacities of healthcare facilities/investigators. If another service is engaged for IMP delivery, additional agreements must be concluded and the informed consent must be amended in accordance with the established procedure. Alternative methods of IMP delivery must not jeopardize the disclosure of the subjects' personal data, confidential data, or the blinding of data processing. Responsibility for controlling the prescription of the IMP remains with the authorized investigator. Additional personnel involved in IMP delivery must receive appropriate training, taking into account the storage requirements and, if necessary, the method of use, and their duties must be specified in the agreement and/or the delegation log.
Question 2: Can subjects visit other trial sites if the healthcare facility where they participate in a clinical trial is closed?
The sponsor and investigators should consider that it may become necessary to transfer a subject from one trial site to another trial site approved in the established manner for conducting the given clinical trial. In such cases, it is important that subjects are informed of such a transfer in a timely manner and give their consent to it. The sponsor and both trial sites (investigators) agree on this process, which must be appropriately documented. The trial site to which the subject is transferred should be able to enter new data into the eCRF and access the subject's previously collected data.
If the trial site cannot continue conducting the clinical trial and it is not possible to transfer the subjects to another trial site approved in accordance with the established procedure, the sponsor should consider temporarily suspending the clinical trial at that site to ensure patient safety and data reliability. Patients must be withdrawn from the clinical trial and transferred to standard treatment according to their condition.
Question 3: Can trial subjects undergo tests (per the protocol) at the laboratory nearest to their place of residence without visiting the trial site, or by a laboratory technician’s home call?
If the subject cannot come to the trial site, the authorized staff of the research team (investigator/sub-investigator) may visit the subject at their place of residence to perform clinical and/or diagnostic tests according to the clinical trial protocol. Tests may also be performed in other laboratories designated by the sponsor/investigator in the established manner, taking into account the laboratories' capability to perform such tests.
Question 4: Can investigators in individual cases visit trial subjects at home to conduct examinations and collect samples? Can trial subjects visit a doctor at their place of residence for assessment of certain clinical parameters (for example, BP, heart rate, etc.) instead of a visit to the trial site?
The investigator agrees with the sponsor on the possibility of transferring visits of study subjects to the trial site, scheduling them for other dates in the visit schedule within the clinical trial, taking into account the approved examination plan where possible.
If the subject cannot come to the trial site, it is possible for authorized personnel of the research team (investigator/sub-investigator) to visit the subject at their place of residence to perform clinical and diagnostic tests in accordance with the protocol.
Question 5: Can the methodology for measurement/assessment using home healthcare medical devices, including digital devices, be changed?
Any change in the measurement/assessment methodology involving medical devices must be duly agreed with the sponsor, documented, and explained.
Question 6: On the use of telemedicine in conducting clinical trials.
If a participant cannot attend the site visit, the use of remote communication tools (telemedicine) may be used as an additional method to ensure medical supervision of the participant’s condition and to assess manifestations of adverse events. However, the limitations and risks of such methods and data protection requirements must be taken into account, and such alternative measures must be duly agreed with the sponsor, documented and approved in the established manner.
Question 7: Regarding the use of remote (distance) obtaining of consent to participate in clinical trials and signing the electronic Informed Consent Form.
The advisability of starting a new clinical trial or including new trial participants in an ongoing study must be critically assessed by the sponsor and investigators.
Protocol deviations remain unacceptable, and no new patients should be enrolled in clinical trials without proper assessment of their eligibility, including performance of the planned tests, and obtaining written informed consent in accordance with national requirements.
If subjects cannot re-sign the informed consent form in a timely manner, the investigator must provide them with verbal information about the changes (updates) to the informed consent in accordance with the established procedure (Appendix 2 to the Procedure for Conducting Clinical Trials of Medicinal Products and Expert Evaluation of Clinical Trial Materials, approved by MoH order of 23.09.2009 No. 690, as amended (hereinafter – the Procedure)). The informed consent of these subjects or their representatives will need to be obtained later, but as soon as possible. At the same time, visits by subjects to trial sites with the sole purpose of obtaining updated informed consent should be avoided. If updated informed consents are required to implement urgent changes in the conduct of clinical trials, other ways of obtaining such updated informed consents may be acceptable during the quarantine period. For example, contacting subjects by telephone to obtain verbal informed consents supplemented by confirmation by e-mail. Any informed consent obtained in this way must be documented and confirmed by carrying out the usual informed consent procedure at the first opportunity, when the subject is at a visit directly at the trial site.
Question 8: Is remote (distance) verification of source data possible?
The sponsor is recommended to update clinical trial monitoring plans, giving preference to centralized monitoring and remote monitoring by monitors that does not require evaluation of source data. To the extent possible, source data verification should be postponed until access to the primary medical records is restored. During remote monitoring, optimal precautions must be taken to comply with regulatory requirements on preserving the anonymity of trial subjects and the confidentiality of information belonging to the sponsor (item 1.21 of ICH GCP). Sponsors should agree with the monitors/investigators on the conditions for conducting such monitoring, but this should not create an additional burden for the monitors.
Thus, the safety and rights of trial subjects are the top priority during their participation in clinical trials. In view of the quarantine measures introduced in the country, it is necessary to take into account the recommendations on conducting clinical trials published on the Center's website (https://dec.gov.ua/announcement/do-uvagy-zayavnykiv-ta-doslidnykiv/).
All deviations from the protocol at the trial site must be noted and explained by the investigator in the primary medical records and reported to the sponsor and to the ethics committee at the healthcare facility. The sponsor/applicant informs the Center of such deviations. Subsequently, the sponsor may make substantial amendments to the trial materials. Such substantial amendments to the clinical trial materials are made in accordance with Section X of the Procedure.
