The world has been thrown off its stride by the 2019 novel coronavirus SARS-CoV-2 and the resulting disease, “COVID-19.” At the time of this Alert, the full impact of SARS-CoV-2 and COVID-19 is still unknown. As an example, many institutions and companies know that the virus and current containment efforts will disrupt their ongoing clinical trials and other research activities—such as by necessitating changes to study protocols, slowing enrollment, or halting studies altogether—but are not yet sure of the extent or consequences of this disruption. Institutions, in particular, are also struggling with how to address a need for urgent IRB review of SARS-CoV-2/COVID-19-related research studies, especially at a time when the institutions face competing priorities, and gathering a group of IRB members in the same room may be practically difficult, unsafe, or even prohibited.
While helping institution and company clients navigate these challenges, we have developed a list of issues that the virus may present in regard to ongoing research studies, new SARS-CoV-2/COVID-19-related research studies, and expanded access treatment uses of investigational products for COVID-19 patients. The list of issues that follows is not exhaustive and best practices continue to evolve. Nevertheless, it hopefully provides a helpful check point to identify topics that your institution or company may need to consider in the days ahead as we all continue to come to terms with the COVID-19 pandemic and its effects on the research enterprise.
Issues to Consider Regarding Ongoing Research Studies
Below is a list of issues for institutions and companies to consider in relation to the impact of SARS-CoV-2/COVID-19 on their ongoing clinical trials and other research studies. We expect that federal agencies—particularly the Office for Human Research Protections (“OHRP”) and Food and Drug Administration (“FDA”)—may issue additional guidance in the days ahead relevant to many of these topics.
- Evaluating whether to suspend some research studies. Institutions facing the possibility of burdened resources and staff, as well as an influx of SARS-CoV-2/COVID-19-related protocols, may wish to evaluate whether other, non-essential research studies should be suspended, particularly given the potential risks of in-person study appointments during the pandemic. Companies, for their part, may wish to evaluate whether to suspend certain of their research studies that may provide little or no direct benefit to participants. The challenge for institutions and companies, and for IRBs reviewing their plans, will be to determine the criteria used to determine which research studies to suspend. Factors such as the health of the participants, the possible treatment benefit of the intervention or investigational drug/device, the setting or frequency of study visits, the potential need to reallocate personnel and other resources, and the risks of transitioning participants off the study protocol will all need to be weighed.
- Identifying reporting obligations in the event of a suspension. If an institution directs that a study be paused indefinitely due to SARS-CoV-2/COVID-19 (e.g., due to resource constraints or other concerns regarding managing risks), it should consider any consequential reporting obligations to federal funding agencies (e.g., NIH), ClinicalTrials.gov, industry sponsors or other private funders, and participants. To the extent a suspension is directed by the IRB of record, reporting obligations to federal oversight agencies (e.g., OHRP and/or FDA) also need to be considered. Likewise, if a company suspends a study due to SARS-CoV-2/COVID-19, it may also have reporting obligations to federal oversight agencies (e.g., FDA), ClinicalTrials.gov, institutions, IRBs, participants, and others (e.g., patient communities).
- Addressing immediate hazards to research participants without prior IRB review and approval. Given the nature of the COVID-19 pandemic, circumstances may arise in which an ongoing research study may present an “immediate hazard” to participants such that changes to the research protocol or procedures responsive to the pandemic (e.g., using telehealth appointments or home visits, shipping study drug instead of dispensing it in person, eliminating certain study procedures, changing the eligibility criteria, or allowing blood draws and other testing at remote facilities) may be warranted without prior review and approval by the IRB as contemplated by the Common Rule and FDA’s IRB regulations. Institutions should discuss with their IRBs what changes to existing research, if any, will be required to be submitted to the IRB for pre-review and how to communicate that effectively to the research community.
- Providing clear communication regarding ongoing studies and points of contact. Companies should consider proactively reaching out to their trial sites to communicate regarding the impact of SARS-CoV-2/COVID-19 on particular studies or at a minimum to provide contact information for the sites to communicate with the company on COVID-19related issues.
- Considering re-review by the IRB or changes to informed consent. For any ongoing research that will continue, researchers, companies, and IRBs will need to consider whether the risks of the study are altered by the COVID-19 pandemic such that re-review by the IRB is warranted and/or changes to the informed consent should be made. For example, if a particular study drug under investigation has immunosuppressive qualities, is a more explicit review by the IRB and discussion of the risks of participating during the COVID-19 pandemic warranted? For ongoing research that requires in-person meetings, do the potential risks attendant to social interaction need to be considered by the reviewing IRB and included in any informed consent form? Do previously enrolled participants need to re-consent where it is determined that new risks are raised by virtue of the COVID-19 pandemic, or should changes be implemented on a prospective basis only?
- Determining how to communicate changes to informed consent. To the extent companies, researchers, or IRBs determine that changes to an informed consent for ongoing research are warranted, they may consider whether this is best accomplished by modifications to the risk section of the existing consent form, or whether providing a separate risk information sheet related to SARS-CoV-2/COVID-19 is sufficient.
- Assessing the impact of SARS-CoV-2/COVID-19 on validity of study results. Researchers and IRBs will need to consider whether, for research that continues, the COVID-19 pandemic affects the validity of the study results or otherwise undermines the trial design in a manner that needs to be controlled for in connection with the research. For example, will the risks in attending study visits created by the COVID-19 pandemic make it more likely that the sickest participants will withdraw from the study before completion? Or will the uneven distribution of the COVID-19 pandemic across the globe and its effect on particular research sites undermine efforts to enroll participants from varied locations and backgrounds?
Challenges Presented by New SARS-CoV-2/COVID-19-Related Research Studies
In addition to affecting existing unrelated research, COVID-19 will increasingly be the subject of new studies focused on the illness itself and on the SARS-CoV-2virus, and on potential diagnostic tests, treatments, and vaccine candidates. Below is a list of issues to consider for institutions and companies conducting or funding these new studies.
- Determining whether the proposed activity in fact constitutes research and/or a clinical investigation. The Common Rule specifically excludes public health surveillance activities from the definition of research. These activities include collection and testing of information or biospecimens by—or as requested, ordered, required, or authorized by—a public health authority as necessary for the authority to monitor, assess, or investigate disease outbreaks, to provide awareness, and to set priorities during a public health crisis. Institutions and IRBs may need to develop guidance for investigators as to the scope of this public health surveillance exclusion. Regardless, if an activity involves a drug or device regulated by FDA, such as vaccines and in vitrodiagnostic tests (including laboratory developed tests), FDA regulations governing clinical investigations may apply.
- Determining whether research or a clinical investigation falls within a category for which a Secretarial or FDA waiver of certain regulatory requirements has been granted or for which the regulations permit exceptions. Under the Common Rule, agency heads have authority to waive some or all of the regulatory requirements for specific research or classes of research as long as alternative procedures will be followed that are consistent with the ethical principles set forth in the Belmont Report. On the application of a sponsor, FDA has similar authority to waive regulatory requirements for IRBs and IRB review. It remains to be seen whether HHS or other Common Rule agencies or FDA will issue such a waiver specifically in connection with SARS-CoV-2/COVID-19. However, in some cases an existing waiver, such as HHS’ waiver of informed consent requirements in connection with certain planned emergency research, which tracks FDA’s regulatory exception from informed consent requirements for similar research, may be relevant (assuming all criteria are met).
- Identifying an IRB and/or IRB consultants with expertise in SARS-CoV-2/COVID-19 or, more generally, in infectious disease. When IRB review is required, both the Common Rule and FDA IRB regulations require IRBs to be sufficiently qualified through (among other things) the experience, expertise, and knowledge of their members to review proposed research. The regulations also permit IRBs to seek consultation from individuals with competence in special areas when needed. In the context of research on SARS-CoV-2 andCOVID-19, expertise in the virus or illness itself, in infectious disease generally, in epidemiological and other public health research, and in law may be important for an IRB that will review new protocols. If existing internal IRBs do not have this expertise or cannot identify appropriate consultants to provide it, institutions may need to consider entering an IRB reliance arrangement to utilize another organization’s IRB or an independent IRB with relevant expertise.
- Creating a SARS-CoV-2/COVID-19 special IRB panel. In order to focus resources and help prioritize SARS-CoV-2/COVID-19 protocols, and where available expertise permits, it may be useful to consider whether to establish a special IRB or IRB panel to review only such protocols and to do so on a more ad hoc and urgent basis to ensure efficiency of review. Additionally, institutions may want to consider whether a separate institutional pre-review should be established and tied to overall institutional decision-making regarding the deployment of resources during a pandemic and overall scientific merit review. This can help ensure that the special IRB panel will only receive for review potential protocols that the institution has deemed are scientifically meritorious and worthy of investment of the necessary institutional resources.
- Ensuring that ethical principles and related regulatory requirements continue to be followed despite potential pressure to speed or shortcut usual research or research review processes. In times of public health crisis, the potential for human subjects violations and the need to keep underlying ethical principles in mind may be greater than ever. In the absence of an applicable Secretarial or FDA waiver or agency guidance that may be issued, regulatory requirements continue to apply. Among the areas that may warrant particular care by institutions, IRBs, researchers, and companies in the context of SARS-CoV-2/COVID-19 research are attending to protections for vulnerable populations while ensuring equitable subject selection and thoughtful research design, avoiding coercive subject compensation structures, and ensuring adequate informed consent including discussion of potential risks of participation.
Expanded Access Use for COVID-19 Patients
In addition to research on new potential COVID-19 treatment regimens, institutions are beginning to treat patients with investigational drugs through expanded access treatment protocols under either single patient or treatment INDs.
- Considering whether to proceed without an expanded access agreement. Institutions should consider whether, assuming companies do not insist on an agreement documenting the arrangement, institutions are similarly comfortable moving forward with receiving the investigational product without negotiating a written agreement.
- Assessing using a simple Memorandum of Understanding as an alternative. If institutions or companies have specific terms they feel are important to document in a written agreement before receiving or providing an investigational product (e.g., quantity of drug and length of time for which it will be provided, any cost associated or whether it will be provided free of charge, timely notification by the company to the institution if the drug will no longer be available so that expectations can be managed and other options considered, and any terms around information that the company may expect to be reported by the institution), a simple Memorandum of Understanding may be possible. We are preparing a sample MOU for institutions and companies to consider as a relatively simple template for documenting the transmission of investigational products for COVID-19 treatment use that aims to meet the needs of both companies and institutions. We will circulate that to our clients and colleagues shortly.
Aside on the Development of New Tests, Vaccines, and Treatments
Although our comments here focus primarily on considerations in the context of conducting clinical trials and other interventional human subjects research, it is worth noting that important considerations also exist for in-house research or clinical laboratories engaged in developing new diagnostic tests, vaccines or potential treatments for COVID-19. Specific FDA and CMS requirements may need to be navigated carefully. For research laboratories in particular, to the extent identifiable (or re-linkable) human specimens are being utilized in the development of new diagnostic tests, the research laboratories may want to have a proactive conversation with the reviewing IRB of record to ensure that a plan is in place for addressing any potential positive results in a manner that is compliant with CLIA and any related state laboratory regulations. For clinical laboratories, understanding when an IDE will be needed and the extent to which FDA may require pre-approval before the test is available is key. Notably, the FDA has taken recent steps to reduce the burden of the Emergency Use Authorization (“EUA”) process for CLIA-certified laboratories developing diagnostics for SARS-CoV-2/COVID-19, permitting the use of validated tests during the time the laboratory organizations are pursuing EUA approval, and exercising enforcement discretion where states elect to assume responsibility for the development and performance of SARS-CoV-2/COVID-19 testing by CLIA-certified laboratories within their jurisdiction.
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We will continue to monitor SARS-CoV-2/COVID-19 developments and the ongoing implications it may have on institutions and companies.