Updated recommendations* on the conduct of clinical trials of medicinal products under the conditions of continued quarantine in Ukraine

Recommendations have been elaborated on the basis of valid regulatory requirements effective in Ukraine related to the conduct of clinical trials of medicinal products (hereinafter – CT) under the conditions of quarantine to prevent the spread of the acute respiratory disease COVID-19 and with due consideration of recommendations of the European Medicines Agency (ЕМА, Version 3 dated April 28, 2020).

1. Introduction

Activities of a sponsor, investigators and other persons involved in a CT should comply with requirements approved by the government at the national and local levels and should be based on the risk-benefit assessment criteria for study subjects, investigators and the quality of data received in the course of a CT.

Considering the need for adherence to the social distancing, if a study subject is not able to come to a trial site (hereinafter – TS), other measures may be taken, such as, home nursing, if possible, or telephone or video communication (telemedicine) which may be required to define adverse events and to ensure permanent medical aid and supervision. However, restrictions and risks of such methods as well as requirements to data protection of a CT and personal data of study subjects should be taken into account. Such alternative mechanisms should be duly documented and thereafter approved as substantial amendments under the established procedure.

Preference is given to any (new) applications for a CT for the treatment or prevention of the COVID-19 infecting and/or applications for substantial amendments to ongoing CTs which were necessitated by COVID-19. In accordance with the Law of Ukraine “On Incorporation of Changes to Certain Regulatory Acts of Ukraine on Assurance of the Treatment of Coronavirus Disease (COVID-19)” No. 539-ІХ dated March 20, 2020, approval of protocols of clinical trials of medicinal products for the treatment of coronavirus disease (COVID-19) and substantial amendments to them should be done within the term up to five calendar days.

It is necessary to review effects of coronavirus disease (COVID-19) on the possibility of continuation of ongoing CTs, opening of a new TS for an approved CT, possibility of involvement of staff and patients/healthy volunteers in a CT as a high-priority measure to ensure health and safety of study subjects. Obligatory use of personal protective equipment for doctors and study subjects should be anticipated.

2. Start of new CTs

A sponsor should critically evaluate expediency of the start of a new CT or enrollment of new study subjects in an ongoing CT. Additional risks for study subjects should be incorporated to a section of a protocol related to the risk-benefit criteria together with measures aimed at the risk minimization (see also “risk assessment” below).

In the case of the conduct of a CT of medicinal products used for the treatment of patients with coronavirus disease (COVID-19) or its complications, a CT protocol should provide for and consider conditions established by quarantine measures and Orders of the MoH of Ukraine. This is applicable to the selection of TSs and laboratories for performance of polymerase chain reaction tests (hereinafter – PCR)

(https://moz.gov.ua/article/news/viznacheno-perelik-likaren-dlja-gospitalizaciipacientiv-z-covid-19;

https://phc.org.ua/news/testuvannya-na-covid-19-v-ukraini-zdiysnyuyutschonaymenshe-49-laboratoriy).

The Public Enterprise “The State Expert Center of the Ministry of Health of Ukraine” (hereinafter – the Center) supports initiatives related to the review of materials of a CT of medicinal products for the treatment of coronavirus disease (COVID-19) with due consideration of the Law of Ukraine “On Incorporation of Changes to Certain Regulatory Acts of Ukraine on Assurance of the Treatment of Coronavirus Disease (COVID-19)” No. 539-ІХ dated March 20, 2020, in accordance with which “… the conduct of expert analysis of materials of clinical trials of medicinal products for the treatment of coronavirus disease (COVID-19) and substantial amendments to them, under the conditions of submission of such materials in Ukrainian or English, within the term up to five calendar days” and for this purpose it ensures prompt procedure of respective consultations.

We herewith also inform you that a sponsor/applicant and investigators should in advance foresee and describe in a protocol and other materials of a CT all possible measures to minimize risks, in particular, related to non-admittance of coronavirus disease (COVID-19) spread among study subjects, healthcare personnel etc.

Also in the process of elaboration of a protocol of a CT of a medicinal product for the treatment of coronavirus disease (COVID-19) in order to select a TS a sponsor/applicant should take into account more than 200 backup Treatment and Prevention Institutions (mostly departments for infectious diseases and hospitals for infectious diseases) defined by the MoH of Ukraine and the National Health Service of Ukraine (Decree of the Chief State Sanitary Doctor of Ukraine No. 7 dated March 27, 2020) for hospitalization of patients with coronavirus disease (COVID-19) for the period of effect of measures taken to prevent the spread of the disease (https://nszu.gov.ua/e-data/dashboard/likarni-covid).

When using these recommendations, a sponsor/investigators should additionally consider other legislative acts of Ukraine which may be implemented due to the spread of coronavirus disease (COVID-19) and measures taken for its containment in Ukraine.

3. Changes in ongoing CTs

In its assessment of risks a sponsor should decide whether the below measures are the most expedient during the quarantine. Measures, as a rule, should be agreed with investigators and may be as follows:

• Change of physical visits to a TS (decrease of personal contacts of persons enrolled in a CT) for telephone contacts or video visiting (telemedicine), re-scheduling or cancellation of visits. Visits to a TS should take place only in specific cases
• Suspension of a CT in some or all TSs, if this does not impact the condition of study subjects
• Suspension or time delaying of enrollment of new study subjects in a CT
• Extension of a CT
• Postponing of a CT or inclusion of new approved TSs, which have not been included yet
• Closure of a TS. In the case, if it is not expedient at all to continue participation for a TS, a sponsor should decide whether it is worth to close a TS and how it may be done without harm for the safety and health of study subjects already enrolled in a CT, as well as with preservation of the CT data integrity
• Transfer of study subjects to other TSs as far as possible from risk zones or closer to their homes (if cannot be avoided, to TSs approved for this CT or to new TSs which will be approved). Exceptional nature of a situation should be justified based on the risk-benefit ratio assessment for each study subject individually. As a rule, initiation of new TSs for the period of quarantine is not anticipated, unless other decision cannot be made for a study subject.

If there is an urgent need for a study subject to visit a TS, opening of a new TS may be performed as urgent safety measures and with a submitted application for substantial amendment in relation to the approval of an additional TS in accordance with the Procedure for Conducting Clinical Trials of Medicinal Products and Expert Evaluation of Materials Pertinent to Clinical Trials, approved by the MoH Ukraine Order No. 690 dated September 23, 2009, as amended (hereinafter – the Procedure).

Exceptional situation may occur in the case, if it is vital for a study subject to remain in a CT and a TS in which he/she was enrolled is closed due to the quarantine or in relation to the re-profiling of a Treatment and Prevention Institution (hereinafter – TPI) for the period of quarantine. In such cases transfer of a study subject may take place to the nearest TS approved for the conduct of a certain CT. It is important for a study subject and investigators (admitting and those who transfer a study subject) to agree on the transfer and that an admitting TS has opportunities to obtain access to previously collected information/collected data of a certain transferred study subject and that any electronic CRF may be duly adjusted (an admitting investigator will have access to CRF), which allows an admitting TS to incorporate new data on this study subject. It is important to take into account and agree on the respective transportation of a study subject. A sponsor, Ethics Committees at Treatment and Prevention Institutions (hereinafter – LEC) of the both TSs and the Center should be informed on such measures.

Urgent laboratory, instrumental and other diagnostic studies may need to be performed for the safety of a study subject. In the case, if a study subject cannot come to a TS, it is admissible that laboratory and other diagnostic studies to be performed in a local laboratory (or a respective clinical institution for the performance of other studies), in such that has been authorized to perform such studies on a regular basis (e.g., complete blood count, biochemical blood assay, hepatic function panel, ECG, etc.), if this may be performed within local restrictions and with keeping respective distance under the conditions of quarantine. Responsible investigators should inform a sponsor on such cases. Results of such examinations may be used when making decision on the safety. If this is a final result of a CT and samples may not be delivered to a central laboratory, tests should be performed locally, and thereafter explained, evaluated and indicated in a CT Report (a form of a report should comply with guidance ICH E3).

All planned changes should be balanced and do not cause overload for staff of a TS during COVID-19 pandemic, if investigators are involved in the medical aid for patients with COVID-19.

Adherence to a CT protocol should be assured in the same manner to make the current risk-benefit assessment for a CT and study subjects possible. A sponsor should duly evaluate effects of protocol changes on the interpretation of clinical data, and the common database may be discussed later.

4. Safety reporting

Taking into account current situation with coronavirus infection, the Center considers that it is acceptable to report on cases of SUSARs and DSURs in the course of CTs of medicinal products in accordance with requirements of the Section XII of the Procedure to the e-mail of the Preclinical and Clinical Trial Materials Expert Evaluation Department  clinic@dec.gov.ua or in a paper format to the following address:

14, Anton Tsedik st., 03057, Kyiv.

It is expected that a sponsor will continue reporting on the safety in accordance with requirements of the Section XII of the Procedure with consideration of recommendations of the guidance ICH R2 and R3. If in accordance with a protocol physical visits are shortened or delayed, it is important that an investigator continues collection of data on adverse events/adverse reactions (hereinafter – AE/AR) reported by a study subject using alternative means of telephone contacts or using video communication (telemedicine).

5. Risk assessment

The safety of study subjects is of primary importance. Due to problems related to COVID-19, risks of enrollment of study subjects in a CT should be compared with the expected benefit for them and the population (principle 2.2 ICH GCP).

All decisions on the CT adjustment should be based on the risk assessment performed by a sponsor (ICH GCP, Section 5.0). It is expected that a sponsor will perform such risk assessment for each individual ongoing CT, and an investigator for each study subject and will implement measures which identify priority of the safety of a study subject and data reliability. In the case of a conflict between these two notions, the safety of a study subject always prevails. Such risk assessments should be based on incorporated data of respective parties and documented on a regular basis. It is important that a sponsor in its risk assessment takes into account the priority of clinical tasks within a CT and possibility of their best performance.

A sponsor should overvalue risks depending on the development of a situation. Such overvalue should be documented as well.

It is distinctly possible that in the case of enhancement of the pandemic local situation will result in local changes in the risk assessment, therefore a need may occur for implementation of additional measures and the risk assessment may need to be performed which will be focused on a certain investigator (and a sponsor should be notified thereof).

In relation to study subjects taking part in ongoing CTs and may be defined as the COVID-19 risk group or who take part in a CT in which the treatment is used which may increase such risk, the potential effect of COVID-19 on these groups of study subjects should be mandatorily taken into account when deciding on the start or continuation of such CTs.

If the risk assessment results in actions which impact a CT, the Center and a LEC should be informed by a sponsor as per the Procedure. When a new case may seriously affect the risk-benefit ratio of this CT, a sponsor and investigator should take urgent measures to protect study subjects from direct threat. These urgent safety measures may be taken without a prior notification submitted to a LEC and the Center, however, at once upon the implementation of these measures, as soon as this becomes possible, information should be submitted to the Center and a LEC. In this notification from a sponsor respective information on a reason, measures taken and plan of further actions should be provided.

If changes possibly influence the safety or health of participants and/or scientific value of a trial, however, do not require from a sponsor or investigator urgent measures, they should be submitted as applications for substantial amendments to materials of a study. Such substantial amendments to CT materials are incorporated in accordance with the Section Х of the Procedure. A sponsor should take into account the limited potential of experts and submit only complete applications of high quality containing required changes.

If information is related to COVID-19, it is recommended to clearly indicate any relation with COVID-19 in submitted documents.

6. Communication between a sponsor, TSs and study subjects

Changes in the conduct of a CT should be agreed with investigators of a TS. It is important that changes and consequences of their effect to be clear, including labeling of amended documents with change tracking to support their incorporation at a TS. Agreements may be documented as e-mail correspondence.

Moreover, an investigator should in a timely manner inform study subjects on changes in the CT conduct which are related to them (e.g., cancellation of visits, changes in laboratory studies and delivery of investigational medicinal products (hereinafter – IMP), etc.).

7. Changes in the procedure of the informed consent obtainment

The procedure of the informed consent obtainment (hereinafter – IC) in all CTs should comply with terms and conditions of a CT protocol, provisions of the Declaration of Helsinki and the Procedure.

A sponsor should consider the current load on healthcare personnel and thoroughly evaluate expediency of the enrollment of new subjects to ongoing CTs. The absolute priority should be given to the conduct of a CT aimed at the prevention or treatment of coronavirus disease (COVID-19) and diseases related to COVID-19 or a CT related to serious diseases which do not have satisfactory treatment options. In the case if a sponsor plans to initiate a CT in order to test a new treatment option for COVID-19, it is necessary to find alternative procedures to obtain the IC, since it is quite possible that a potential study subject cannot leave an isolation unit and to provide the consent in a regular manner (to personally sign and indicate the date). The use of personal protective equipment should be obligatorily foreseen in the course of the procedure of the IC obtainment and preservation of an IC Form document.

However, it is necessary to take into account the following specific approaches related to patients with COVID-19.

If it is not possible to obtain the written consent from a potential study subject (e.g., due to the physical isolation, due to COVID-19), a trial participant may provide the verbal consent in the presence of an independent witness. In such cases a witness should be obliged to sign and indicate the date in the IC document, and an investigator should indicate information how an independent witness was chosen in the source documentation (Section IV, clause 1.2 of the Procedure).

Moreover, a situation may occur when a study subject and a person who receives the consent sign and date the separate IC Form. In any case all respective records related to such procedure should be kept in the Investigator File at a TS. Thereafter, when it becomes possible, the signed and dated in a regular manner IC Form should be received from a study subject as soon as possible.

If a potential study subject with COVID-19 lacks the ability to provide the consent due to the severity of his/her condition or when minors are enrolled in a trial, the consent should be obtained from legal representative(s) in accordance with the Procedure (Section IV, clauses 1.2 and 3.1).

In life-threatening situations when it is not possible to preliminary obtain the IC of a study subject (or his/her legal representative(s)), it should be obtained later as permitted in accordance with the Procedure (Section IV, clause 1.3.2. of the Procedure). In such cases an investigator should record in the source documentation why the consent of a study subject for the enrollment in a CT could not have been obtained with indication of a reason and further steps to obtain the IC and informing a patient on a CT.

For other ongoing CTs a necessity may occur for repeated consent of study subjects who are already enrolled in a CT. However, the need for TS visiting by study subjects in order only to receive the repeated IC should be avoided. If repeated consents are required to implement new urgent changes in the conduct of a CT (mainly foreseen due to COVID-19-related reasons), alternative ways of obtainment of such repeated ICs during the pandemic should be considered, a study subject should be contacted by telephone or using video communication (telemedicine) and the verbal consent and supplement confirmation should be received via e-mail. Approved updated Information Sheet and IC Form should be provided to study subjects via e-mail, by regular mail or by a courier prior to the obtainment of the repeated IC. The procedure of the IC obtainment in such a way should be documented and confirmed using common procedures of the IC obtainment as soon as possible when study subjects return to a TS.

8. Changes in the distribution of an investigational medicinal product

Recommendations are related to an IMP, concomitant medicinal products and controller medicinal products as well as accompanying materials which are usually provided at visits and are indicated in a CT protocol. Changes in their distribution may be required to avoid unnecessary visits to a TS, as well as in order to assure the respective treatment for study subjects. A sponsor should evaluate IMP-related risks and consider any alternative mechanisms of the organization of their delivery and storage conditions.

Such measures cause different practical thoughts, in particular, whether an IMP can be stored by a study subject at home, how the stability of an IMP will be preserved during the transportation (especially the temperature regimen and preservation of the “cold chain”), how its accounting and intended purpose compliance assessment will be organized (as specified in a CT protocol).

The primary objective of all changes in the distribution is the provision of trial participants with IMPs, concomitant and/or controller medicinal products as well as accompanying materials, when needed, in accordance with a CT protocol and in order to avoid interruptions in the administration of an IMP and treatment, to assure positive risk-benefit balance and protection of rights, safety and well-being of study subjects and integrity of data collected in the course of a CT. Continuation of the use of an IMP should be duly managed by a responsible investigator.

Changes in the distribution of an IMP may include provision to a study subject more number of IMPs than it is usually specified per visit. The purpose is to provide a study subject with required IMPs for a longer period of time and to avoid visits to a TS by him/her. This may be performed under the conditions when the use of an IMP takes place under proper supervision of a responsible investigator. When conducting a CT it is recommended to support the required backup of all IMPs and other medicinal products to ensure their continuous use in the case of their improper distribution. In the case of urgent lack of an IMP in some TSs or as a result of transfer of study subjects from one TS to another, a necessity may occur to re-distribute IMPs between TSs in accordance with the GMP, Annex 13 (Section 47). This should be considered only in cases when direct distribution of IMPs for TSs by regular distributor may not take place or under exceptional circumstances when a study subject is transferred from one TS to another. A sponsor should evaluate whether TSs can process and manage such process of the re-distribution, especially in the case of restricted storage conditions. When conducting re – distribution the written procedure should be followed which has been established in cooperation with a qualified authorized person or a person in charge of the IMP distribution, and a TS should be provided with sufficient information to warrant safe performance of such process.

Proper accompanying documentation on the IMP transfer should be kept in study files of parties concerned.

Together with decrease in the number of physical visits to a TS, it may be required to deliver an IMP directly to a study subject during C                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    OVID-19 pandemic to avoid the risk of the infection extension/contamination.

To ensure delivery of an IMP to a study subject directly from a TS, it is desirable to use powers of a TPI/investigators/co-investigators.

If, due to the COVID-19 pandemic, a trial site is not able to handle the additional burden of IMP shipment to subjects, the IMP may as an exception be shipped to the subjects by an independent distributor under the contract concluded with the sponsor. In such case it is necessary to conclude supplementary agreements and incorporate changes to the IC under the established procedure. Such ways of delivery of an IMP should not jeopardize disclosure of personal data of study subjects, confidential data and data processing blinding. A responsible investigator and a sponsor remain in charge of management of the IMP prescription. Staff members additionally involved in the IMP delivery should undergo respective training considering requirements for storage, route of administration. Their obligations should be defined in an agreement and/or delegation of authorities log. Delivery of an IMP with involvement of any courier service without concluding a contract (according to the abovementioned conditions) between it and the sponsor is prohibited.

All procedures of delivery should ensure timely receipt of an IMP directly by a study subject or his/her legal representative. Provision of an IMP to a third person (neighbor, etc.) is prohibited. An investigator should receive confirmation of all deliveries of an IMP and conformation of their acceptance by study subjects using telephone/video communication or via e-mail. An investigator remains in charge of the proper administration of an IMP by a study subject.

9. Peculiarities of the monitoring

Certain responsibilities of a sponsor – the CT monitoring to ensure the quality of a CT should be re-evaluated. Alternative proportional monitoring mechanisms may be temporarily required. The major priority in the course of review of any changes is the protection of rights, safety and well-being of CT participants.

The scope of the monitoring at a TS, if it remains possible, should consider national and local restrictions, urgency (e.g., verification of outgoing data may be often postponed) and the presence of staff at a TS, and should be conducted only upon agreement with a responsible investigator and management of a TPI. Also it is necessary to take into account overload of staff and a TS as a result of implementation of any alternative measures to ensure acceptable balance between the proper monitoring, potential and abilities of a TS.

Adjustment of the monitoring measures may include the following combinations:

а). On-site monitoring.

Cancellation or re-scheduling of monitoring visits at a TS and extension of intervals between them may possibly be required. Investigators should be informed thereof in advance.

Additional monitoring measures at a TS may include limited, on-site oriented monitoring to define a TS with a higher risk.

The monitoring plan at a TS should be adjusted and include alternative measures (such as those stated in the clause b), c) and d) below);

b). Centralized monitoring and central review of data collected.

Centralized monitoring of data received by electronic systems of data collection (e.g., e-RF, central laboratory or ECG/CT/MRI, e-PRO, etc.) may supplement and temporarily substitute monitoring at a TS using remote assessment of current and/or accumulated data collected on time at a TS;

1. c) Off-site

Additional monitoring measures outside a TS may include telephone/video visits, e-mail messages or other online tools for discussion of the CT status with an investigator and his/her team. This activity may be used to receive information on the course of a CT, to exchange information on the solution of certain problems, to review procedures, status of study subjects and to facilitate remote selection of TSs and trainings for investigators;

1. d) Remote source data verification.

Currently the remote Source Data Verification (SDV) is justified only in specific cases, in particular, in the course of a CT regarding the treatment and prevention of COVID-19 or at final stages of data processing prior to database lockdown in key (pivotal) trials studying serious and life-threatening states without the available satisfactory treatment options. One should concentrate on the quality control of critical data, such as source efficacy data and significant safety data. Important secondary efficacy data may be monitored simultaneously under the conditions that this does not lead to the necessity for the obtainment of access to additional documents and does not increase the load on TS staff.

A sponsor should identify the level and nature of the remote Source Data Verification which he/she considers to be necessary for each CT in this exceptional situation and should thoroughly evaluate possible additional load on staff and technical means in the course of alternative monitoring options.

In these several cases responsible investigators should personally decide whether a situation in their TS allows using the following options for remote Source Data Verification:

• Provision within the frameworks of the monitoring of copies of source documentation transformed into anonymous form (depersonalized) (this may be done in electronic form, if performed by members of a study team)
• Direct duly managed remote access to electronic medical records of study subjects
• Video review of medical records supported by members of a study team. Herewith, a monitor does not get any copy, and images are not recorded in the course of the review.

For CTs of medicinal products related to the treatment of COVID-19 which is planned to be submitted for expert analysis to the Center, remote Source Data Verification should be described in a protocol, Informed Consent Form and, if required, other related documents.

It is essential for further measures to be planned and ready for implementation when a situation normalizes. This should probably include enhanced on-site control during the period sufficient for assurance that the impact of the shortened control may be eliminated, and problems may be resolved or duly documented for notification in a CT Report.

All these measures should not create additional overload on a study team. Investigators should not be succumbed to excessive pressure in order to perform remote Source Data Verification. The medical aid and care are still the priority for investigators which should be provided for study subjects and other patients.

10. Changes in the conduct of an audit of a clinical trial

It is recommended to postpone the conduct of sponsor’s audits. In emergency, as agreed with a responsible investigator and management of a TPI, an audit may be conducted at a TS directly, as well as a remote audit, if such audit is essential in order to study serious abnormalities in the course of a CT, serious adverse reactions, etc.

11. Clinical trial protocol deviation

Due to unavoidable increase in CT protocol deviations, a sponsor should manage such deviations in accordance with its standard operational procedures and periodically analyze their number and types for the assessment of necessity for incorporation of respective amendments to a CT protocol.

Such substantial amendments to materials of a CT should be incorporated in accordance with the Section Х of the Procedure.

12. Expense reimbursement

For implementation of urgent measures related to the protection of study subjects who take part in a CT, in relation to the spread of coronavirus disease (COVID-19) and measures taken for its non-spreading in Ukraine, additional unexpected expenses may occur which should be reimbursed by a CT sponsor. All additional financial compensations for TPIs/investigators/co-investigators should be documented and performed in accordance with valid regulatory acts of Ukraine.

13. The conduct of bioequivalence studies with enrollment of healthy volunteers under the conditions of the spread of coronavirus disease COVID-19

A sponsor/applicant/investigators within the frameworks of the conduct of bioequivalence studies and under the conditions of the COVID-19 spread must apply the following measures (but not limited to them):

– Determination of bioequivalence study sites and conditions taking into account the requirements of the Decree of the Cabinet of Ministers of Ukraine of July 22, 2020 № 641 “On introduction of quarantine and stepping up anti-epidemic measures in the area with a significant spread of acute respiratory disease COVID-19 caused by coronavirus SARS-CoV-2’, as amended (when the “red” or “orange” level of epidemic danger is assigned to the region where the study is planned, this study must be postponed until the level of epidemic danger has been downgraded);

– Allowing the potential study participants, who have negative results of the SARS-CoV-2 test of nasopharyngeal biomaterial using PCR method for confirmation of the absence of SARS-CоV-2 infection within 48 hours before the screening, and for whom after the signing of the IC Form a non-contact thermometry, questioning regarding the sanitary and epidemiological environment for the last 14-21 calendar days will be performed, to undergo screening procedures;

– Only subjects, who have negative results of the test of nasopharyngeal biomaterial using PCR method for confirmation of the absence of SARS-CоV-2 infection within 48 hours prior to the start of each study period (a hospitalization for carrying out all necessary procedures according to the requirements of the study protocol) and have been undergone a non-contact thermometry and physical examination are allowed to participate in each next study period (the Day 0);

• Performance of PCR tests for healthcare professionals of a TS who take part in a CT and are in contact with volunteers, as well as sponsor’s representatives (monitors of the clinical stage of a study) in accordance with internal procedures.

All taken measures being a CT protocol deviation should be indicated in source documents and clarified, whereof a sponsor/applicant informs the Center and thereafter substantial amendments may be incorporated to materials of a CT in accordance with the Section Х of the Procedure. Such changes may be a part of a generalized amendment (non-urgent).

A sponsor/applicant and investigators should in advance foreseen and describe in a protocol and other CT materials all potential risk minimization measures, in particular, related to the non-admittance of COVID-19 spread among study subjects, medical personnel, if a CT of medicinal products is planned to be conducted in order to prove their bioequivalence and for the conduct of CTs of medicinal products for the treatment of coronavirus disease (COVID-19).

14. On the operation of Ethics Committees at Treatment and Prevention Institutions

In accordance with the Law of Ukraine “On Incorporation of Changes to Certain Regulatory Acts of Ukraine on Assurance of the Treatment of Coronavirus Disease COVID-19” No. 539-ІХ dated March 20, 2020, “… the conduct of expert analysis of materials of clinical trials of medicinal products for the treatment of coronavirus disease (COVID-19) and substantial amendments to them, under the conditions of submission of such materials in Ukrainian or English, within the term up to five calendar days” was accepted. A LEC should be governed by this provision of law.

Taking into account the stated above, it is recommended for LECs to take all possible respective measures to ensure continuous operation in accordance with their Regulations under the conditions of COVID-19 outbreak and to adhere to the quarantine regimen for COVID-19 non-admittance, however with due consideration and use of personal protective equipment by LEC members.

At the same time operation of a LEC during the quarantine should be extended due to the following recommendations:

• UNESCO – Statement on COVID-19: Ethical Considerations from a Global Perspective (https://unesdoc.unesco.org/ark:/48223/pf0000373115),
• CIOMS – International ethical recommendations on health-related studies involving humans (https://cioms.ch/wpcontent/uploads/2018/12/Final-CIOMS-EthicalGuidelinesUkrainian.pdf)

and regulatory agencies:

• FDA – Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic (https://www.fda.gov/media/136238/download)
• EMA – Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf
• MHRA – Managing clinical trials during Coronavirus (COVID-19)

(https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus- covid-19).

A LEC should adjust its standard operational procedures in the part of implementation of respective measures related to the conduct of CTs of medicinal products and review of CT materials under the conditions of coronavirus disease (COVID-19) outbreak.

Thus, the safety and rights of study subjects is the major priority during their participation in CTs.

Due to quarantine measures taken in the country it is necessary to consider recommendations on the CT conduct made public at the website of the Center (https://dec.gov.ua/announcement/do-uvagy-zayavnykiv-ta-doslidnykiv/).