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May 7, 2020 Pharmacovigilance

Clinical Trials in the Midst of COVID-19, Part One: European Medicines Agency (EMA)

Hanneke Dominicus Consultant

Disclaimer

As of April 23, 2020

Each health authority within the EU has information regarding COVID-19 (coronavirus) on its website. In this blog we will try to guide you through some of these recommendations and measures. Please note that information changes rapidly. Always check the applicable websites (EMA, Health Authority in your country, Inspectorate, etc.) if you need more information.

 “There was a subject in the trials that had a cough and I asked the sponsor what to do. The sponsor said the patient should be tested before being kept in the ongoing clinical trial”

What would you do as a sponsor or as an investigator? Should the patient have an obligatory COVID-19 test? And what about the patient herself?

The World Has Changed

During this COVID-19 pandemic, many clinical trial management professionals involved in ongoing, ‘normal’ (i.e., non-COVID-19 related) clinical trials are faced with situations they had not previously considered and are not  addressed in the safety management plan or in the trial protocol.  These documents were written with the pre-COVID-19 situation in mind; but now, the conduct of your trials is affected by the 1.5-meter society, or even by a lockdown. Various challenges exist which result in restrictions of visits to healthcare facilities, increased demands on healthcare services and changes to the availability of trial staff. Participants may also be required to self-isolate, which introduces difficulties for Investigators to maintain their medical oversight.

These challenges will have an impact on the conduct of trials, such as the completion of trial assessments, completion of trial visits, and the provision of Investigational Medicinal Products (IMPs). There may be a need for critical laboratory tests, imaging, or other diagnostic tests to be performed for trial participant safety. Due to local restrictions, e.g. lockdown, this may be impossible.

Due to these circumstances, we will see the impact of the COVID-19 pandemic in clinical study reports and other clinical trials documents for years to come.

  • What are authorities saying about this and what are the consequences for your trial?

Although we are facing this pandemic, so far, no regulatory or other competent authorities have forbidden all clinical trials. However, Sponsors must adjust their trial execution and implement measures to make sure their trial and their trial results remain valid. Our experts around the world are on top of regulations due to this pandemic and are capable to assist in making your clinical trial still successful.

In this blog series,  we will guide you through the EMA and FDA documents that have been published since the outbreak of COVID-19. We will first discuss guidance from the EMA, then guidance from the FDA, and then conclude on eventual differences. Initiating trials on non-COVID-19 products will be difficult and protocols should be adjusted. In this blog, we focus on ongoing trials. Please keep in mind to always follow the local regulation as well.

EMA Guidance for Non-COVID-19 Related Clinical Trials During this Pandemic

On March 27th, 2020, the EMA issued a new, updated version of the Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) pandemic. This document has already been updated once since the outbreak of COVID-19 and more updates are expected to follow.

Overall, the safety reporting aspect is the easiest part because nothing has changed. Of course, you may have to find alternative ways to collect safety data, e.g. by phone instead of during a visit, but in general, a lot may have to be done. Always remember, for all situations, subject safety comes first. Therefore, Sponsors should continuously (re)perform a risk assessment of each ongoing trial, as the situation develops. The principal investigator should continuously (re)perform a risk assessment of each subject in the trial. Measures should be taken to maintain subject safety and data validity. These risk assessments should be based on relevant parties’ input and should be documented on an ongoing basis.

Initiating New Non-COVID-19 Trials: Adding New Participants

The EMA has already repeatedly questioned the feasibility of starting new trials, opening new sites, and including new participants.

  • Does this mean you should not start your planned trial?

Clinical trials aiming to find a treatment for COVID-19 should and will be started and several are already ongoing. However, starting other clinical trials is less feasible for various reasons, not to speak of assessor capacity at the authorities which will be primarily used for COVID-19 related trials and other COVID-19 related activities.

The EMA stressed that prospective protocol waivers remain unacceptable and patients should not be included in trials without proper eligibility assessment, including performance of planned tests, and written informed consent according to national laws and regulations.

The feasibility of starting a new clinical trial or including new trial participants in an ongoing trial should therefore be critically assessed by Sponsors. Additional risks to participants have to be addressed in the risk-benefit section of the protocol along with risk mitigation measures.

So, the EMA is discouraging and the FDA even halted Phase I and observational studies. Please look at your local authorities. In the Netherlands, with some exceptions, the Inspectorate ‘does not expect’ Phase I studies to continue or start. In the UK, the MHRA announced it has written to all Sponsors conducting Phase I clinical trials to confirm they have conducted a risk assessment for the potential impact of COVID-19 on their studies.

Ongoing Non-COVID Clinical Trials

  • Can you proceed with your ongoing trial?

For ongoing trials, compliance with the trial protocol should be ensured to such an extent that an ongoing benefit-risk assessment for the clinical trial and its participants is still possible. The impact of protocol changes on clinical data interpretability needs to be properly assessed by the Sponsor, and the overall evidence generation package could be subsequently discussed within scientific advice with regulatory authorities. A relevant guidance on the implications of Coronavirus on methodological aspects of ongoing clinical trials by the CHMP Biostats working party was published on March 25th, 2020. This document is open for public consultation until April 22nd, 2020. In this document, several recommendations are included, such as: pre-plan how systematic deviations resulting from the measures related to the COVID-19 pandemic are captured; preferably do not stop data collection (safety data collection should go on). It also contains contemplations on re-starting usual trial operations, and how to statistically deal with necessary additional analyses and potential sources of bias such as missing values. When looking at the final trial results, you will have to acknowledge that there are three phases in your trial now: pre, during, and post COVID-19 pandemic. This will lead to extra analyses.

  • What can you do to manage these new risks?

There are several possibilities to manage the new risks. You may change physical visits to phone calls. Investigators who decide to do this should inform the Sponsors and, if needed, the competent authorities. Who and when to inform will depend on the impact of those measures.

Measures could consist of:

  • Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites
  • A temporary halt of the trial at some or all trial sites
  • Suspension or slowing down of recruitment of new trial participants
  • Extension of the duration of the trial
  • Postponement of trials or activation of sites that have not yet been initiated
  • Closing of sites
  • If unavoidable, transfer of participants to other investigational sites, away from risk zones, or closer to their home. Initiation of new trial sites is generally not expected
  • Where a trial participant is unable to attend the site, other measures, such as home nursing, if possible given social distancing needs, or contact via phone or telemedicine means, may be required to identify adverse events and ensure continuous medical care and oversight. However, the limitations and risks of such methods and the requirements for data protection should be taken into account and such alternative arrangements need to be adequately documented.
  • In case the trial participant cannot reach the site to have these performed, it is acceptable that laboratory, imaging or other diagnostic tests are done at a local laboratory (or relevant clinical facility for other tests) authorized/certified (as legally required nationally) to perform such tests routinely (e.g. blood cell count, liver function test, X-ray, ECG etc.), if this can be done within local restrictions on social distancing.

Reporting and Permission of Changes

  • Who and when do you have to contact regarding changes to your study procedures?

If there is an urgent need to open a new trial site for critical trial visits, for example outside the hospital, this may be implemented as an urgent safety measure first, with a substantial amendment application submitted later as for the approval and initiation. Any permanent changes in principal investigator (in case of indisposition) should be submitted to the National Competent Authority and Ethics Committees, as appropriate and as soon as possible.

Trial halt, even if only temporary, can potentially compromise the overall well-being and best interest of trial participants; all measures need to be considered and taken to avoid this.

EMA, the European Commission, and the Heads of Medicines Agencies strongly support the efforts of the Good Clinical Practice Inspectors’ Working Group for developing a harmonized EU/EEA-level guidance to mitigate the negative effects of the COVID-19 pandemic on the conduct of clinical trials.

Major changes in the conduct of a trial should follow the local regulations and be approved by Ethics Committees. Discussion with relevant competent authorities is encouraged and COVID-19 related guidance should be consulted.

Again, the safety of the participant is of primary importance, and risks of involvement in the trial, in particular with added challenges due to COVID-19, should be weighed against anticipated benefit for the participant and society (ref: principle 2.2 of ICH GCP).

Click here to continue with part two of this series. 

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