Research that is executed in part or in whole through remote modalities, such as telemedicine and health care providers who visit participant homes, is increasingly commonplace yet complicated. Decentralized research raises novel questions regarding whether and which institutions are engaged in research under the Common Rule and who is a subinvestigator according to United States Food and Drug Administration (FDA) regulations. Mark Barnes, MRCT Center Faculty Director, overviewed the concept of engagement in research subject to the Common Rule and proposed a model to redefine the concept of engagement. David Peloquin, MRCT Center Senior Advisor, overviewed the investigator and subinvestigator designations in research subject to FDA regulations.
The European Union (“EU”) General Data Protection Regulation (“GDPR”) and its effect on research activities was the first topic addressed by the R3 at its initial meetings in 2018. In the four years since those meetings, there have been many developments that have continued to cause complications for trans-Atlantic research. These have included, among others, the invalidation of the EU-U.S. Privacy Shield in June 2020 by the Schrems II decision, Brexit, the release in 2021 of new Standard Contractual Clauses by the European Commission, and the introduction of data transfer impact assessments as a prerequisite for many cross-border transfers of personal data.
On March 25, 2022, the European Commission and the United States announced that they have agreed in principle on a new Trans-Atlantic Data Privacy Framework, intended to foster trans-Atlantic data flows and address the concerns raised by the Court of Justice of the European Union in the Schrems II decision. The discussion at the convened R3 considered these recent developments and identified potential solutions to ease trans-Atlantic research while complying with GDPR.
The core activities of clinical trials are typically conducted at physical locations referred to as “sites.” Traditionally, these sites are hospitals or academic medical centers. While these traditional sites remain important fixtures in the clinical trial landscape, new models including “decentralized” or even “site-less” clinical trials have emerged. David Peloquin, MRCT Center Senior Advisor and Partner at Ropes & Gray LLP, provided an overview of the clinical trial site landscape and how it has changed over time, with a particular focus on the emergence of stand-alone sites, as such sites present unique regulatory issues. He then provided several examples of these stand-alone sites and presented a handful of recent regulatory enforcement cases before moving into a discussion of the relevant legal risks and considerations.
In an increasingly connected world, clinical trials and other research activities are no longer state- or country-specific. Not surprisingly, the globalization of research activities creates any number of legal and compliance challenges for stakeholders involved in the development, authorization, and commercialization of medicinal products, including under data privacy regulations that continue to evolve.
This hybrid meeting addressed some of the most pressing of these challenges. We addressed issues that go to the heart of the General Data Protection Regulation (“GDPR”) of the European Union (“EU”), such as what constitutes a restricted international data transfer, the appropriate lawful basis to legitimize the processing of personal data in the context of clinical trials and secondary research, and the designations of parties participating in research as controllers and processors. We also discussed potential solutions to problems that continue to challenge the research community. The research community has been awaiting further guidance on the topic of the GDPR and research from the European Data Protection Board (“EDPB”) for several years. The research community must thus navigate several complex issues in the absence of relevant regulatory guidance.
This meeting consisted of a series of panels made up of experts from the life sciences industry, government, and academia to address key challenges faced by the research sector under the GDPR and data privacy regulations in other geographies, including the Personal Information Protection Law of the People’s Republic of China (“PIPL”).
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The administration of an investigational product via Expanded Access is not meant to answer questions about the product’s safety and effectiveness; rather, it is intended to treat an individual patient with a serious or immediately life-threatening disease or condition for which no satisfactory alternative therapy exists. In the absence of robust guidance for assessing requests for expanded access, physicians and sponsors are left without a critical understanding of the legal, ethical, and financial considerations that ought to influence expanded access determinations.
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Clinical trials are closed prematurely for a variety of reasons, including for scientifically-driven reasons of efficacy, safety, and futility wherein there is no justification for continuing to enroll participants. The majority of clinical trials, however, terminate early as a result of operational issues—such as inadequate recruitment, commercial product viability, insufficient funding or resources, or de-prioritization by an investigator, institution, or sponsor. The decision to terminate a trial raises complex ethical questions regarding the appropriate communication with and responsibilities owed to participants.
Efficacy and safety of medicines can vary depending on a number of intrinsic and extrinsic factors, such as an individual’s genetic background, ethnicity, lifestyle, and age. In appreciation of these differences and in the interest of generating generalizable knowledge—the participant population enrolled in a clinical trial ought to be representative of the general population. Despite this normative ideal, underrepresentation of gender, sex, ethnic, and racial minorities in clinical trials persists.
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Presently, there is no operational framework to guides investigators in designing, and IRBs in evaluating, recruitment methodologies and payment proposals to international research participants. This lack of guidance has been a cause for concern amongst regulators, trialists, advocacy groups, and research participants –especially when conducting clinical trials in low-and middle-income countries (LMICs).
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This meeting of the MRCT Center Bioethics Collaborative will explore the ethical considerations underscoring the challenge of informed selection of clinical trials. We will examine the responsibilities of various stakeholders within the clinical trial ecosystem, and we will discuss potential solutions.
The current landscape of clinical trial identification, referral, selection, and enrollment depends largely upon access to clinical trial information by a multiplicity of stakeholders. Unfortunately, access to this information is fragmented. Treating physicians do not routinely discuss clinical trials with their patients; investigators recommend enrollment in the clinical trials in which they or their institution are involved, but often not others; institutional IRBs evaluate the potential benefit/risk calculus for a given trial without consideration of the entire landscape of competitive trials; institutions do not consistently provide patients with instructions or guidance on navigating patient advocacy and trial registry websites, nor do they refer patients to external resources (e.g., patient advocacy groups and disease advocacy organizations) to help navigate the choice among alternative trials; existing clinical trial databases are often incomplete and complex, and they do not convey information in ways that help patients and providers choose among available trials. As a result, patients’ knowledge of their clinical trial options is often incomplete, and enrollment decisions are based on limited information.
Patients can, and often want to, be empowered with clinical trial information that is understandable and accessible. But institutional walls appear to have created artificial boundaries around the choice of clinical trials. We have not equipped patients to compare the suitability of the clinical trial(s) offered by their physicians with those offered down the block or across the river, concordant with their own preferences. As availability of electronic information increases (and with the appreciation that more information is not necessarily better information), our current systems may be improved to better uphold the foundational ethical principles of clinical research. These principles—respect for persons, beneficence, and justice—and their application to how we offer, and how patients select, clinical trials deserve review.
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The MRCT Center Return of Individual Results Work Group has formulated key principles and recommendations on the return of individual results to research participants from clinical trials in which the participants were enrolled (see above). A number of unanswered questions, however, related to return of individual results to research participants persist. For example, who should communicate urgent results and urgent incidental findings to individual research participants? The lead or site investigators? The referring health care provider? The study sponsors? This meeting explored the pragmatic considerations underlying the return of individual results to research participants and axes of communication.
