Changes on Ongoing Clinical Trials during the Covid-19 Pandemic

By Amalia Xeini, Associate, POTAMITISVEKRIS

In a dynamic environment, such as that of the pharmaceutical industry, R&D on new pharmaceutical products and therapies for the successful treatment of diseases is of strategic importance at both national and EU level^[1]. In this respect, pharmaceutical companies are investing significant funds in the research and development (R&D) of clinical trials.

A typical example of the key importance of clinical trials is, undoubtedly, the management and treatment of the new COVID-19 pandemic, caused by the coronavirus SARS-CoV-2. The COVID-19 pandemic is rapidly escalating putting national health care systems under continuously increasing pressure. It is obvious that under such difficult circumstances, the need for investment in R&D in terms of finding  a new medicine and/ or new vaccine against the COVID-19 pandemic is of high priority at both global and Union and national level. At global level more than 1.350 clinical trials have been already conducted and 450 in Europe in order to investigate medicines and more than 70 globally and 7 in Europe to investigate effective vaccines and their results are shortly expected.

In some Member States, it has been observed that the health-care system has already reached its limits. In this respect, certain actions are required to ensure the necessary simplifications needed to maintain the integrity of the ongoing trials, to ensure the rights, safety and wellbeing of trial participants as well as the safety of clinical trial staff during this global public health crisis.

At national level, EOF has announced instructions for conducting clinical trials in Greece, in  exception of the applicable framework, in order to discover the appropriate treatment for the COVID-19 pandemic. Given the above, pursuant to the announcement of EOF, the files of the clinical trials for COVID-19 disease in Greece (a) are submitted for approval to the competent Department of Clinical Trials of EOF and they are evaluated through an urgent procedure, as per the applicable legislation and (b) the positive opinion of the National Ethics Committee is required for their approval. Furthermore, in the event that the clinical trials are multinational according to the recommendation of the CTFG team, the VHP procedure is recommended[2]. It is to be noted that the clinical trials after their approval by the regulatory authorities (EOF-EED) and their uploading in EudraCT are automatically displayed in the EU Clinical Trials Register where all interested parties have public access (https://www.clinicaltrialsregregister.eu/). To facilitate their search, the title of the clinical trials shall include the term COVID-19.

The clinical trials[3] are divided into two main categories namely Interventional and Non-Interventional. The first category of clinical studies is the Interventional Clinical Studies, which are clinical trials on humans and aim to define and document the indications, safety and effectiveness of a drug under investigation while, at the same time, determining its side effects and clinical characteristics. The following criteria shall be followed to conduct an Interventional Clinical Study: (a) inclusion of the subject in a specific treatment strategy, b) decision to provide the drug along with the inclusion of the subject in the clinical study (c) diagnostic or follow-up procedures in addition to the usual clinical practice applied to the subjects^[4]. Each trial aims to document the safety and/or effectiveness of the tested drugs in full compliance with the Protocol. In general, the Interventional Clinical Studies have four phases. An application is submitted to EOF accompanied with all required supporting documents for the approval or modification of a Clinical Study (Test).

The second category of clinical studies is the Non-Interventional Studies^[5], which until recently, were carried out in Greece under Article 4 of Law 4523/2018^[6]. The conditions precedent are the following (a) the patients participated in the trial must have been already undergone treatment with the tested medicine, (b) the drug under trial to be provided to the subjects patients according to the treatment protocol and the conditions provided in its marketing authorization license and its approved indications, (c) the trial should have been conducted multinationally or in Greece, as per the relevant provisions of EU law, in at least three centers (health institutions or PHC units), (d) diagnostic or follow-up procedures should not be applied to subjects patients in addition to the usual clinical practice provided by the guidelines, (e) the principal investigator should have been a doctor occupied by the National Health System or faculty member or a physician in charge of a private hospital department, in which a Scientific Council or Scientific Committee should have been established and operated; (f) the drug should have been reimbursed by the Social Security Institution (g) if there was a registry for a particular disease, the lead researcher should inform the competent scientific team that manages the registry and record the study data, (h) the purpose of the study should have been the evaluation of the safety or effectiveness of the drug in daily clinical practice or its effects on the quality of life of patients receiving it[7]. Given the most recent abolishment of Article 4 of Law 4523/2018, a new framework for Non-Interventional Studies is expected to be announced. At this point, it is to be highlighted that under Article 100 of Law 4692/2020 (Government Gazette A '111/ 2.6.2020) there is an explicit exclusion of interventional and non-interventional clinical studies from the regulatory scope of the Research Ethics Committee (E .H.D.E.) of the Special Account for Research Funds of A.E.I., provided by article 21 of L. 4521/2018.

It is to be noted that all clinical studies conducted worldwide are registered in the database www.clinicaltrials.gov, in which, based on the transparency of the procedures, all the necessary information for each study is available as well as the guidelines from the EMA organization for conducting clinical studies in EU Member States.

The impact of COVID-19 on ongoing trials needs to be considered. The evaluation of this should take into account national recommendations and measures including travel restrictions and confinements of trial participants and trial staff as well as the availability of trial staff to perform visits, notify serious adverse events and, more generally, follow the protocol. The ability to confirm eligibility and to conduct key safety assessments and trial evaluations is of significant importance. However, the limitations and risks of such methods and the requirements for data protection should be taken into account and any potential amendments need to be adequately documented. Below are some typical questions and answers for the changes and impact on ongoing trials during COVID-19, in terms of harmonized EU-level recommendations provided by EMA and HMA[8]:

1. What are the most appropriate measures to be taken for ongoing trials during COVID-19?

1. In order to ensure that strictly necessary visits are performed at sites during COVID-19, there should be either replacement of physical visits into phone or video visits, or postponement or total cancellation of visits;
2. A temporary cease of the trial at specific or all trial sites;
3. Interruption or slowing down of recruitment of new trial participants in an ongoing trial needs to be reassessed;
4. Extension of the duration of the trial;
5. Postponement of trials or of activation of sites that have not yet been initiated;
6. Closing of sites. In case it is not feasible for a site to continue participation at all, the sponsor should consider if the trial site should be closed and how this can be done without violating any of the rights, safety and well-being of trial participants and data validity.

2. Shall sponsors continue the safety reporting with respect to ongoing trials?

Sponsors shall continue safety reporting in adherence to EU and national legal frameworks[9]. When per protocol physical visits are reduced and/or postponed, it is significant that the principal investigators shall continue collecting AE from the trial participants through other options, e.g. by phone calls, as appropriate.

3. Shall the sponsor and principal investigator continue to communicate with the authorities?

As per guidance by EC CT-18, for ongoing trials, a single submission by the same sponsor is acceptable in case of substantial amendments as well as of urgent safety measure. The following shall be met: (a) assessment of whether an amendment is to be regarded as ‘substantial’. A change is substantial when it has a potential impact on the safety or physical integrity of the clinical trial participant, or on the scientific value of the trial[10]. Substantial amendments relate to amendments of documents/information that are part of the clinical trial application dossier, b) Submission of information is only obligatory if the amendment is a substantial amendment. Directive 2001/20/EC does not require notification, or immediate submission of information on non-substantial amendments. In other words, the only communication mechanism of substantial changes to information in the protocol or clinical trial dossier is through the submission of a substantial amendment. In any case, the sponsor shall maintain appropriate records, in a timely manner, of all changes in the trial master file. Communication shall be clearly marked with the indication ‘COVID-19’.

4. Will there be any changes regarding  the Informed Consents?

Unless linked to the implementation of urgent safety measures, changes in informed consent procedures shall be reviewed and approved by the relevant ethics committee in advance. The informed consent procedure in all trials needs to remain compliant with the trial protocol as well as with EU and national legal framework, taking into consideration any differentiations. In case a sponsor plans to initiate a trial aiming to test new treatments for COVID-19, alternative procedures shall be followed to obtain informed consent, in case the physical consent is not appropriate as trial documentation.

5. Will there be any Protocol amendments?

The COVID-19 situation is likely to introduce more protocol deviations than normal. It is expected that the sponsor manages such protocol deviations in accordance with the standard procedures. The sponsor shall perform an analysis of the number and type of deviations periodically to assess whether a protocol amendment or other modifications are needed. A proportionate approach will be taken by the GCP inspectors when said deviations are reviewed, recognizing that the best interest of the trial participants is maintained, and the trial participants are not put at any risk.

In view of the above, it should be noted that any simplification measures and actions proposed for ongoing trials during COVID-19 shall be based on benefit-risk considerations taken nationally and locally by the authorities, with priority given to the impact on the health and safety of the trial participants.