Special Section: Clinical Research in Ukraine
The Lessons of War Inform Good Clinical Practice Guidelines
Viktoriia Dobrova
National University of Pharmacy, Ukraine
Mark Turner
University of Liverpool (UK)
Katrina A. Bramstedt
Roche, Switzerland
Sandor Kerpel-Fronius
Semmelweis University, Hungary
Beate Aurich
conect4children, France
Francis P. Crawley
Good Clinical Practice Alliance – Europe (GCPA)

Strategic Initiative for Developing Capacity in Ethical Review (SIDCER)


he ongoing war in Ukraine is teaching us invaluable lessons about the resilience of people and the impact of such events on clinical trials and research. It also reveals opportunities to improve guidance to protect people and ensure research quality during disruptions which can also include pandemics and natural disasters. One such opportunity arises from the ongoing revision of the ICH E6 Good Clinical Practice (GCP) Guideline as this document shapes clinical trial operations.

Clinical trials are a critical element of the development of medicines and medical technologies that are both effective and safe. Ukraine actively participates in research in the fields of cardiovascular disease, oncology, and rare/orphan disease, led by drug and device companies based in Japan, the EU, the US, and other countries in the modern, globalized world. Participation of patients and healthy volunteers in clinical trials in Ukraine contributes to research that potentially benefits future patients around the world.

Protecting research participants and the quality of research data are fundamental to global GCP and are key priorities for regulatory authorities, including research ethics committees. The local regulatory authority in Ukraine is collaborating with regulatory and health authorities such as the European Medicines Agency and the World Health Organization to identify solutions to the challenges imposed by the war. These learnings may provide useful lessons for similar situations elsewhere and contribute to the evolution of regulatory and clinical trial practice.

Impact of War on Research Integrity

Research integrity speaks to how well we trust and have confidence in the methods used for a study as well as its data outputs. Crises can trigger problems in research integrity. This 2018 article written by medical students in Syria sounded an alarm about the research problems in Syria caused by the war there. We now see similar problems and a similar situation in Ukraine.

War disrupts many of the critical elements that keep research moving and ensure integrity during peaceful times. Impacts on these critical elements include:

  • Professionals who were focused on research may transition to emergency or critical care and trauma instead.
  • Challenges arise with shipping, storing, and tracking of investigational medical product, specimens, and data.
  • Disruptions of research ethics committees may interrupt reviews and approvals.
  • Late or missed visits may become frequent and create data gaps.
  • Difficulties may arise with obtaining signatures, either on paper or in digital/electronic form.
  • Some participants have acquired situations or conditions which are exclusions to trial participation.
  • Staff burnout and fatigue occurs more frequently and persists longer, as medical staff often work without reasonable rest or break periods.
  • Utilities providing gas, electricity, and telephone services, transportation, and the physical security of research sites can be compromised.

Each of these presents unique challenges to maintaining GCP, and the time needed to problem solve or possibly change course can often cause study delays. Flexibility in guidance that allows clinical trial processes to continue while maintaining trial data integrity is vital.

Responsibility to Maintain Research Integrity

Ukraine has a strong, well-developed clinical research infrastructure and hosted a large number of clinical trials prior to the war. Many clinical trials are also being conducted in nearby countries and the surrounding region. Maintaining clinical trial activities at GCP quality under the current circumstances requires trial staff in Ukraine to work in close cooperation with colleagues in neighboring countries, especially Poland. Together, sponsors and investigators are responsible for ensuring research integrity and compliance with GCP guidelines. In the setting of very difficult conditions, numerous sponsors have responded to assist research participants and team with tools such as:

  • Providing a 24/7 multilingual telephone hotline to maintain communication between research teams, participants, and their families.
  • Establishing direct contact between research operations and experts in related fields (such as bioethics) to evaluate and address dilemmas.
  • Building a searchable Q&A database continuously populated with questions and their answers to facilitate timely, consistent operational responses across clinical teams.
  • Creating subgroups and teams for specific subtopics such as supply and distribution, data integrity, vendor management, etc.

Resources to Support Research Integrity

Many people in Ukraine participate in clinical trials as a substitute or replacement for healthcare. This creates the risk of therapeutic misconception. Thus, it is critical that patient-facing clinical trial documents and discussions with patients reinforce that the primary reason for clinical research is the generation of data for the benefit of future patients. The clinical trial data generated in Ukraine today aims to leave a robust scientific legacy for future research.

Resources available to help researchers and sponsors navigate these challenges include:

Proposed ICH E6 GCP Principles

The regulatory authority of Ukraine issued recommendations describing approaches that can be used to avoid noncompliance with the study protocol or ICH GCP. Their general rule is to use flexibility to support investigators and to learn from insights that investigators and sponsors gained from the COVID-19 pandemic: 1) the safety of research participants is paramount; 2) the best approach is flexibility.

The Good Clinical Practice guidelines described in ICH E6 are currently under revision and scheduled to be open for Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice public consultation until September 2023. The revision aims to create a framework that emphasizes quality and that can guide implementation under different circumstances while allowing for more efficient integration of new technologies and modernized clinical trial designs. The principles of quality and ethics feature prominently in the new draft as components of protecting participants and assuring the reliability of results. Highlights of the principles proposed in the draft revision include:

  • Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and which are consistent with good clinical practice and applicable regulatory requirement(s).
  • Informed consent is an integral feature of the ethical conduct of a trial. Clinical trial participation should be voluntary and based on a consent process that ensures participants are well-informed.
  • Clinical trials should be scientifically sound for their intended purpose and based on robust and current scientific knowledge and approaches.
  • Quality should be built into the scientific and operational design and conduct of clinical trials.
  • Clinical trial processes, measures, and approaches should be proportionate to the risks to participants and to the reliability of trial results.

The principles don’t specify how to perform informed consent. But they make clear that, however consent is done (electronically, in person, on paper, etc.), participants must be well-informed about the potential benefits and risks of the study. This would include assent from children as well as parental permission in accordance with participant age and local regulations.

Another principle is that studies need an objective, independent review to determine whether the study is scientifically sound for its intended purpose. There are different purposes for different study phases or types (e.g., phase 1 or phase 2, pragmatic or explanatory, etc.). Protocol review should consider the differences in study design and their unique ethical complexities.

The current conflict is sending an urgent call to maintain continuity in clinical trials during a crisis. Including the need to consider clinical trial continuity before, during, and after the trial in the revised ICH guideline would provide needed guidance for considering how to apply these guidelines during times of war or other disasters. The European Federation of Pharmaceutical Industries and Associations (EFPIA) has cataloged numerous pharmaceutical company support systems that promote clinical trial continuity in the setting of the current conflict.

Armed conflict, pandemics, and natural disasters disrupt normal clinical trial operations, displace or move human and other physical resources, and create time delays and pressures—ripe settings for research integrity problems. Honoring the ethical duty of maintaining research integrity through GCP compliance requires thoughtful, agile, targeted responses that give research teams the proper tools to foster data integrity and patient safety in every circumstance.

Disclosures: Katrina Bramstedt is an employee of Roche and a stockholder in Roche. Roche conducts clinical trials in Ukraine and Russia.