Global Life Sciences Update

Considerations for Sponsors of Ongoing Clinical Trials in Light of COVID-19 (Part 1)

March 31, 2020

In this first Update, we provide:

an overview of useful guidelines issued by regulatory agencies in Europe and the U.S.
some practical considerations related to risk assessments that sponsors must conduct to determine next steps for their trials and patients
guidance on how a sponsor may tackle changes to its clinical trials due to COVID-19

1. COVID-19: Related Regulatory Guidelines on Clinical Trials

European Union (EU). The European Commission, the European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA) recently jointly published recommendations for sponsors on how to manage the conduct of clinical trials in the context of COVID-19. Their guidance covers, inter alia:

potential changes that sponsors might need to make in the distribution of a trial drug
changes that sponsors might want to consider in the monitoring of the trial
how sponsors may deal with potential protocol deviations

The EMA also issued draft guidance regarding implications of COVID-19 on methodological aspects of ongoing clinical trials. This draft guidance, open for a special short public consultation until April 25, 2020, sets out important points that sponsors of ongoing clinical trials should consider, including:

planning of how systematic deviations resulting from the measures and individual decisions related to the COVID-19 pandemic are captured
diligent collection of pandemic-related measures and potentially affected patients, including subpopulations to study the impact on the treatment effect in exposed/nonexposed and affected/nonaffected patients
conducting risk-assessment of COVID-19 potentially affecting patients and COVID-19 related measures affecting clinical trial conduct

While this guidance is useful, in the EU clinical trials are subject to authorization by the member states’ national competent authorities (NCAs). Any changes to the trial’s benefit-risk ratio or deviations from the protocol need thus to be reported to the relevant NCA(s) and/or Ethics Committee (EC) of the members in which the clinical trial is taking place. This would also include the reporting of potential risks of shortages or availability of investigational and other drugs dispensed as part of the trial.

In the EU, Switzerland and the United Kingdom, some NCAs have already issued guidance to sponsors conducting clinical trials on their territory, including:

Belgian Federal Agency for Medicines and Health Products
Danish Medicines Agency
Dutch Health and Youth Care Inspectorate
French National Agency for the Safety of Medicines and Health Products
German Federal Institute for Drugs and Medical Devices
Italian Medicines Agency (available in Italian only)
Spanish Agency for Medicines and Medical Devices (available in Spanish only)
Swiss Agency for Therapeutic Products and Swiss Ethics Committees
UK Medicines and Healthcare products Regulatory Agency

United States (U.S.). The Food and Drug Administration (FDA) issued a Final Guidance on the Conduct of Clinical Trials of Medical Products during the COVID-19 pandemic. The Guidance, which applies to trials of human drugs, biological products and medical devices, addresses potential changes to clinical trials resulting from, among other things, quarantines, site closures, travel limitations, interruptions to supply chain for the investigational product, and infection of patients and/or investigators.

FDA’s key directive is that the safety of trial participants is paramount. FDA advises that any changes made should be consistent with the protocol to the extent possible and should be fully documented with specific information about the relationship to COVID-19 in the clinical study report.

Specifically, the clinical trial report of all trials affected by the COVID-19 pandemic should include:

a discussion of contingency measures to manage trial conduct during disruption
a listing of all participants affected by a COVID-19-related disruption
analyses and corresponding discussions that assess the effect of implemented contingency methods on safety and efficacy results of the trial

FDA also advises sponsors, clinical investigators and institutional review boards (IRBs) to ensure that they develop policies and procedures for protecting trial patients and managing trial conduct during disruptions due to COVID-19. These policies and procedures should address, among other things, impact on the informed consent process, study visits and procedures, data collection, study monitoring, adverse event reporting and quarantine measures or COVID-19 itself.

China. During the COVID-19 pandemic, China has been encouraging investigator-initiated studies to explore effective therapies. The Ministry of Sciences and Technology (MOST) is taking the lead to oversee such studies. MOST requires that (i) the studies should be conducted on drugs that are already approved for market in China, (ii) the study drugs should have certain efficacious effects proven through in vitro or animal studies before being administered on humans and (iii) the studies should follow the approved label of the study drugs in terms of administration route and dosage. Notably, the National Medical Product Administration, the drug regulatory agency of China, has issued clinical trial approval for such studies, which it has never done in the past.

2. Evolving Environment, Evolving Risk Assessment

The first step a sponsor should take in light of potential COVID-19 disruptions to its trials is a risk assessment. This is because the risks and disruptions caused by the pandemic may affect the benefit-risk ratio of a clinical trial.

Generally, sponsors should perform an individual risk assessment for each ongoing trial and carefully consider how local conditions and guidance affect — or will affect — patient safety and data integrity. These risk assessments should be based on relevant parties’ input and should be documented.

Depending on the outcome of benefit-risk assessment, sponsors should take measures to maintain patient safety and data validity. In particular, sponsors should consider whether the benefit-risk ratio remains in favor of continuing the trial or whether measures should be taken to maintain a favorable benefit-risk ratio. When taking such measures, it is important that sponsors consider prioritization of critical tasks in the clinical trial and how these are best maintained. In case of a conflict between patient safety and data validity, safety must prevail.

3. Managing Changes to a Clinical Trial Due to COVID-19

Once the risk assessment has been conducted, sponsors may need to take certain measures or implement changes to the protocol to address the risks identified and mitigate their effect on patient safety and data integrity.

EU. In the EU, one practical way of dealing with measures that must be put in place immediately is “urgent safety measures” (Article 10(b), EU Clinical Trials Directive). Such measures may be taken without prior notification to the NCA and/or the EC. However, the sponsor must inform ex post the NCA and/or the EC of the member state(s) concerned of the new events, the measures taken and the plan for further action as soon as possible.

Ex post notification of urgent safety measures is independent of the obligation to notify early termination of the trial (Article 10(c), EU Clinical Trials Directive) and to notify adverse events and serious adverse reactions (Articles 16 and 17, EU Clinical Trials Directive).

For measures not required to be taken immediately, a substantial amendment to the protocol may be used for which prior approval of the NCA and/or the EC is required (Article 10(a), EU Clinical Trials Directive). Further guidance on the general requirements related to the authorization of clinical trials and changes to such authorizations, including urgent safety measures and substantial amendments, can be found in EudraLex — Volume 10 — Clinical trials guidelines, CT-1.

U.S. In its guidance, FDA makes clear that changes to a protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB/independent ethics committee (IEC) approval or before filing an amendment to the investigational new drug (IND) application or investigational drug exemption (IDE). However, sponsors are encouraged to engage with the relevant IRB or IEC as early as possible when urgent or emergent changes are anticipated and must report any such changes consistent with the regulations. FDA also directs sponsors to describe any such changes in detail, including the relationship to COVID-19, in clinical trial reports.

Effective communication with all stakeholders in the clinical trial is crucial to deal with potential disruptions as they arise.

China. Given the rising number of investigator initiated studies, companies should be more vigilant in adhering to their own policies in supporting such studies, and making sure proper regulatory approvals are in place to make sure they can legally access to the data generated from such studies. For ongoing trials sponsored by companies during the COVID-19 pandemic, they may face challenges in hospitals’ resource limitations and inability to follow the study protocols. Companies should keep in close communication with investigators for potential variations to study protocols and take additional measures to ensure data integrity.

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