Special Section: Clinical Research in Ukraine
Clinical Trials Continuity: Ukraine State Expert Center Perspective and Recommendations
Taisa Herasymchuk
State Expert Center, Ministry of Health, Ukraine
Sergii Rasputniak
State Expert Center, Ministry of Health, Ukraine
Victoriia Dobrova
National University of Pharmacy, Ukraine

efore the war, the field of clinical trials had developed steadily in Ukraine, framed in a strict legal framework oriented to the legislation of the European Union and based on the Declaration of Helsinki, ICH GCP, and EU Directive 2001/20 (the Clinical Trials Directive). The State Expert Center regularly conducted clinical trials inspections, and its inspectors took part in EU GCP Inspectors Working Group Workshops and participated as observers in EMA, FDA, and PMDA inspections.

The number of approved clinical trials had been increasing annually in Ukraine. These were mostly phase 2 and 3 clinical trials in oncology, neurology, psychiatry, gastroenterology, and orphan diseases. The number of subjects involved in clinical trials had also been increasing.

After the start of the war in February 2022, conduct of clinical trials became quite difficult, and in some cases impossible.

GCP Clinical Trials Continue in Ukraine

At the beginning of the war, 794 clinical trials were approved and in various stages in Ukraine. Since then, sponsors, principal investigators, and patients met challenging situations and uncertainties, in particular, ensuring trial subject safety, conducting site visits, providing investigational medicinal product (IMP), and collection and transfer of samples to specified laboratories.

In the first few months of the war, 38 protocols suspended the start of a new clinical trial; 199 protocols suspended patient recruitment, screening, or randomization; and 3 protocols prematurely terminated their clinical trial set. However, 355 studies remained active. Numerous applications for substantial amendments to trial protocols were received from March to June 2022.

Clinical trials continuity in Ukraine is possible during war due to effective communication between the sponsor and center and because of substantial amendments to trial protocols. Despite the war, the State Expert Center continues to perform all its routine functions, including ongoing coordination of clinical trial activities and regulatory dossiers, and conducting GCP webinars to improve the knowledge of local investigators, ethics committees, and sponsors.

Looking forward, efforts toward the center’s goal of gradually harmonizing Ukraine’s regulatory framework with EU Regulation 536/2014 (the Clinical Trial Regulation) continue despite the war.

The Role of the State Expert Center

Despite the difficulties, all clinical trials continuing are conducted in accordance with international ethical principles and their priority remains the same: ensuring the protection of the subjects’ rights, safety, and well-being. All clinical trials are planned, conducted, and reported in compliance with GCP principles. The State Expert Center and the Ministry of Health continue to support and ensure the conduct of clinical trials in Ukraine.

One function of the State Expert Center is the scientific evaluation of preclinical and clinical trials in Ukraine, and the Minister of Health issues authority to carry out secure clinical trials based on this tentative expert assessment.

A formal communication chain ensures full functioning among clinical trial regulators, sponsors, CROs, principal investigators, local ethics committees, and patients. In this chain, trial sponsors are responsible for all decisions and actions in these force majeure circumstances, including ensuring maximum safety of all trial participants and staff, compliance with the protocol and recording all protocol deviations, and justification for health insurance, to ensure the impartiality, reliability, and validity of trial results.

GCP seminars conducted by the State Expert Center have become an important supporting tool in disseminating current, practical information among the Ukrainian clinical research community during this conflict.

State Expert Center Recommendations

Realizing that deviations from clinical trial protocols are inevitable during the war, the center published recommendations for sponsors of clinical trials, sponsors’ representatives, investigators, ethics committees, heads of enterprises, institutions, and organizations involved with conducting clinical trials. Its main messages include:

  • Sponsor should analyze risks in the possibility of starting new clinical trials in new facilities, or in continued screening and recruitment in ongoing clinical trials.
  • Consider the possibility of patient transfer to another trial site in Ukraine and/or to a trial site in another country.
  • Communicate such transfers to the State Expert Center and impacted investigative ethics committees.
  • Take all possible measures to ensure the essential and continuous provision of investigational medicinal product to patients and trial sites, including direct delivery of IMP to participants’ homes and other logistic changes.
  • Report all protocol deviations related to patient safety to the State Expert Center and impacted investigative ethics committees.

The center also recommended that local ethics committees consider the following in their SOPs to optimize their work during the war: eSubmissions, online meetings (audio/video conferencing), changing membership when/where there is no quorum, and, in exceptional cases, applying the single opinion of one local ethics committee to several sites (when urgent decisions are needed).

The State Expert Center advises sponsors to maintain adherence to the sponsor guidelines developed by the European Heads of Medicines Agencies Clinical Trials Facilitation and Coordination Group on managing the impact of the war on clinical trials in Ukraine:

  • Take all possible measures to ensure continuous provision of investigational medicinal product to patients and trial site, including direct delivery of IMP to participants’ homes.
  • Report all protocol violations related to patient safety and other clinical aspects to ensure patient protection and secure reliable study data.
  • If it is impossible for the investigator or participants to visit the study site, optimize communication and safety monitoring via telemedicine and related technology: telephone contact, combination of remote and in-home visits, etc.
  • Logistical switch from central to local laboratories for better control of samples and patient safety parameter testing.
  • Sponsor may and shall implement actions pursuant to changes in the clinical trials protocol without waiting for the patient’s complete approval but will communicate these actions and get patient approval as soon as possible.

The State Expert Center also advises sponsors to follow EMA recommendations for local ethics committees and other enterprises, institutions, and organizations involved in clinical trials regarding other aspects of clinical study conduct during the martial law period. The sponsor’s main priority remains ensuring the rights and safety of all persons involved in the conduct of their clinical trials. The investigator must preserve the confidentiality of information regarding participants’ ethical rights.

Clinical Trial Participant Transfers

By May 2022, the center had received 155 notifications of transfer of 315 subjects to other trial centers. 196 subjects were transferred to trial sites abroad, in 22 countries as near as Poland and as far as Canada. The center began conducting inspections to verify compliance with GCP while transferring subjects in May 2002. Five such inspections were carried out, and no violations of regulatory requirements were found. Generally, these steps were followed when transferring a participant to a new site:

  1. Principal investigator from the current site contacted the sponsor.
  2. Sponsor analyzed risk and contacted the principal investigator from the new site to determine the possibility of accepting that subject there. Important considerations included availability of IMP, access to the patient records, CRF, etc.
  3. The current site investigator informed the participant of the transfer possibility.
  4. The participant contacted and arranged the visit with the new site’s investigator.
  5. Records were provided in extracted form from the current site to the participant to share with the new site; when this was not possible, the former investigator emailed documents to the new investigator.
  6. Informed consent was completed at the new site.
  7. Analysis of participant medical documentation and clinical inclusion/exclusion status was completed.
  8. Subjects continued to receive treatment and monitoring and investigators at the new site gained access to the eCRF. Both sites protected the confidentiality of records that could identify the subject in every process.
  9. The center and local ethics committees were notified about the transfer of the subject, and necessary amendments were submitted, in all cases.