Recent guidance from global regulatory authorities

• In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) issued guidance on the management of clinical trials in light of the COVID-19 pandemic. Among other things, the guidance takes a practical approach and states that increased protocol deviations as a result of COVID-19 do not need to be reported unless patients are at risk. For more information about the MHRA guidance, please see our separate client alert here.

• The Netherlands’ Central Committee on Research Involving Human Subjects (CCMO) issued guidance allowing for exceptional amendments to or deviations from the study protocol without prior approval and allowing study drugs to be delivered directly to trial subjects. The CCMO also announced the availability of fast-track approval procedures for clinical trials relating to the development of vaccines for COVID-19.

• In Italy, the Italian Medicines Agency (AIFA) issued a guidance containing various requirements and recommendations related to continuing clinical trial operations in light of the country’s COVID-19-related travel restrictions. Among other things: study sponsors are required to have hematological analyses carried out in public facilities close to the patients’ domicile; clinical trials with trial sites closed to the public should be suspended or transferred to the nearest trial facility; sponsors may directly reimburse additional expenses to patients due to the emergency situation; and sponsors may deliver the investigational medicinal products directly to patients rather than to the hospital pharmacy. For additional information, please see our separate client alert here.

Study conduct

• Study sites may face various obstacles related to the COVID-19 pandemic, including strained resources, reduced study personnel, and rapidly changing internal policies and procedures implemented to combat the spread of the virus. These obstacles could result in fewer devoted resources to clinical trials, delays, and protocol or good clinical practice (GCP) deviations.

• Companies may need to quickly adapt to shifting circumstances, including study sites’ and institutional review boards’ (IRBs) imposition of new restrictions or requirements on ongoing studies. For example, some study sites have barred further visits by clinical trial sponsors – including on-site monitoring – until further notice. Companies may need to propose alternative approaches, such as using video conferencing or other long distance means to perform tasks that would usually be performed in person. These changes may prompt submission of protocol amendments and/or revised informed consent forms to regulators and the IRB(s)/ethics committee(s) overseeing the study.

• For ongoing clinical trials or upcoming studies, study sponsors may need to determine whether they wish to implement additional screening of study subjects before enrollment or during site visit procedures (e.g., for fever or other symptoms). As additional testing kits and methods become available, companies may wish to consider whether screening for COVID-19 or the presence of the COVID-19 virus in study subjects is desirable. Once again, such additional testing would likely require amending the inclusion/exclusion criteria and other aspects of study protocols.

• Companies should consider whether study subjects who report testing positive for COVID-19 should be removed from ongoing studies, especially where the study drug may make it more difficult to treat the viral infection. In such cases, companies should consider how to safely and appropriately wind down study drug dosing for individual patients, as well as how to perform any necessary follow-up for such subjects. It may also be necessary to amend study protocols to specifically address what steps study staff should take in the event a subject tests positive for COVID-19 during an ongoing study.

Travel – restrictions and reimbursements

• As local and national governments impose travel limitations such as the nationwide travel restrictions imposed in Italy, companies could encounter subjects, vendors, or study staff who are unwilling or unable to travel to study sites. 

• Patient enrollment for clinical studies also may decline, particularly for studies that do not treat a serious or life-threatening disease. Patients may elect to wait for the COVID-19 pandemic to subside before traveling to potentially crowded hospitals and other study sites to participate in clinical trials for diseases or conditions that are less serious or do not have imminent consequences.

• While it may be too late for currently ongoing studies, companies could consider incorporating technologies for telemedicine, virtual study visits, and long-distance monitoring into their studies. Given the lack of clarity as to how long the COVID-19 pandemic will impact travel and patient willingness to participate, technologies that avoid the need for frequent in-person trips to study sites may help mitigate slowdowns in patient enrollment.

• Some companies are also considering revision to travel reimbursement policies for ongoing studies to provide for housing near study sites for the duration of the study, particularly if the study involves long-distance or international travel. Doing so may decrease the risk of dropouts and may help keep studies on schedule.

• As another strategy, some companies are considering the feasibility of shipping study drug directly to subjects’ houses rather than to study sites in an effort to limit subjects’ need to travel.

Clinical trial vendors

• Vendors performing clinical trial-related services may encounter issues that impact their operations, such as an increase in costs for materials or labor, or a decrease in available employees or contractors.

• Companies may wish to proactively contact their vendors to inquire about any anticipated risks or difficulties in carrying out agreed-upon services, as well as the vendors’ plans to mitigate such risks or difficulties, in order to anticipate potential delays and to prepare contingency plans. Doing so may also help lessen the risk that a vendor could invoke a force majeure clause to cease performance under applicable vendor agreements.

Clinical supply

• China is both a major provider of biopharmaceutical manufacturing services and one of the countries hit hardest by COVID-19 to date. Companies with China-based supply chains may experience delays or other hurdles that could slow or otherwise negatively impact ongoing or prospective clinical studies. Lack of sufficient clinical supply could cause protocol deviations that may result in problems with outcomes measurements or statistical analyses where dosing regimens are thrown off or insufficient subjects are dosed. Companies with limited inventory of investigational product should naturally start planning for how to continue studies in the face of potential interruptions in the supply chain.

• The U.S. Centers for Disease Control and Prevention (CDC) has stated, on a COVID-19 FAQ web page, that “because of poor survivability of [similar coronaviruses, including SARS-CoV and MERS-CoV] on surfaces, there is likely very low risk of spread from products or packaging that are shipped over a period of days or weeks at ambient temperatures. Coronaviruses are generally thought to be spread most often by respiratory droplets. Currently there is no evidence to support transmission of COVID-19 associated with imported goods and there have not been any cases of COVID-19 in the United States associated with imported goods.” Even so, the CDC has also noted that it may be possible that a person can get COVID-19 by touching a surface or object that has the virus.

Other clinical trial considerations

• Other issues to consider include potential company liability for subjects who contract COVID-19 during the study. For this reason, study sponsors may want to review the subject injury provisions contained within the Clinical Trial Agreements and in informed consent forms.

• Public companies working on filings with the U.S. Securities Exchange Commission (SEC) may wish to include a discussion of COVID-19 and the potential for disruption of clinical development programs, clinical and commercial supply, or other risks that may impact their business.

• Institutions conducting U.S. federally-funded clinical studies will need to make determinations on the allowability of unforeseen costs, such as travel cancellation fees, insurance costs, and remote work costs. Where IRBs decide that certain studies involving in-person contact with participants must pause, or where other factors destabilize project timelines and deliverables, documentation and communication with federal contracting officers and program officers will be important. Recipients of U.S. federal grants and cooperative agreements must notify the funding agency as soon as “problems, delays, or adverse conditions which will materially impact the ability to meet the objective of the Federal award” are known. Recipients of U.S. federal contracts for research and development also may have rights under the “Excusable Delays” contract clause in Federal Acquisition Regulation (FAR).

Clinical development of countermeasures to combat the pandemic

• In addition to their ongoing clinical trials, many pharmaceutical and biotechnology companies have started working on a number of different fronts to develop vaccines and other countermeasures to combat the pandemic, including seeking Emergency Use Authorizations (EUAs) from the U.S. Food and Drug Administration (FDA) to authorize marketing of drugs as medical countermeasures, bypassing the regular drug approval process.

• Under section 564 of the Federal Food, Drug, and Cosmetic Act (FDCA), the FDA Commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent a disease or condition – such as COVID-19 – when there are no adequate, approved, and available alternatives. While the issuance of an EUA is discretionary (see FDA guidance), the efficacy standards are lower with companies only needing data to show the product “may be effective” – a standard determined on a case-by-case basis using a risk-benefit analysis. In determining whether the known and potential benefits of the product outweigh the known and potential risks, FDA looks at the totality of the scientific evidence to make an overall risk-benefit determination. Such evidence, which FDA states could arise from a variety of sources, may include (but is not limited to): results of domestic and foreign clinical trials, in vivo efficacy data from animal models, and in vitro data. FDA will also assess the quality and quantity of the available evidence, given the current state of scientific knowledge.

• Additionally, to further incentivize the development of such countermeasures, the U.S. Department of Health and Human Services (HHS) issued a Notice of Declaration under the Public Readiness and Emergency Preparedness Act to provide certain liability immunity for qualified activities related to the manufacture, testing, development, distribution, administration, or use of a medical countermeasure to COVID-19. The immunity protection extends to a drug covered by an Investigational New Drug (IND) or a device covered by an Investigational Device Exemption (IDE) that “is the object of research for possible use for diagnosis, mitigation, prevention, treatment, or cure, or to limit harm of a pandemic or epidemic or serious or life-threatening condition caused by such a drug or device.”

• Companies and research institutions developing medical countermeasures against COVID-19 should work closely with regulators to ensure they are maintaining the right balance between accelerating delivery of new therapies while maintaining appropriately rigorous standards for clinical testing. When proposing innovative ways to expedite their development programs, product sponsors will need to assure regulatory bodies that the data obtained from an accelerated clinical development pathway will be of sufficiently high quality to adequately support a finding of safety and effectiveness.

• For example, when seeking EUAs for vaccines and other therapies, sponsors should consider working with health care providers to formulate feasible plans for collecting data that FDA will be able to interpret. They should also consider other long-term plans for studying their therapies under IND programs and for confirming their intent to progress to full product licensure or approval.

• As of March 15, FDA has not granted an EUA for any vaccine or other biologic or drug to prevent, treat, or mitigate COVID-19. It appears, however, that FDA has started considering untraditional approaches to speeding the development of such therapies. For example, we have seen reports that FDA may allow clinical trials to proceed in parallel with the sponsor’s efforts to develop a rodent model for the disease and to perform animal testing investigational agents to treat COVID-19.

• It also appears that FDA may allow medical countermeasure sponsors to pursue accelerated approval by showing an effect on surrogate endpoints — proxies for showing that a product can prevent or treat a disease. Such surrogate endpoints may consist of composite outcome measurements of the normalization of fever and other symptoms of patients with COVID-19. Other surrogate endpoints may be focused on the increase in antibodies capable of fighting the virus.
   

*       *       *       *       *

As the COVID-19 pandemic continues to gain force, it will have a greater impact on the operations of research institutions, pharmaceutical, biotechnology, and medical device companies, especially in the context of their clinical development activities. We will continue to monitor the landscape and will provide further updates as the situation evolves.