Faculty Bibliography

After witnessing extraordinary scientific and regulatory efforts to speed development of and access to new COVID-19 interventions, patients facing other serious diseases have begun to ask "where's our Operation Warp Speed?" and "why isn't Emergency Use Authorization an option for our health crises?" Although this pandemic bears a number of unique features, the response to COVID-19 offers translatable lessons, in both its successes and failures, for non-pandemic diseases. These include the importance of collaborating across sectors, supporting the highest-priority research efforts, adopting rigorous and innovative trial designs, and sharing reliable information quickly. In addition, the regulatory response to the pandemic demonstrates that lowering standards for marketing authorization can result in increased safety concerns, missed opportunities for research and treatment, and delays in determining what works. Accordingly, policymakers and patient advocates seeking to build on the COVID-19 experience for non-pandemic diseases with unmet treatment needs should focus their efforts on promoting robust and efficient research designs, improving access to clinical trials, and facilitating use of the Food and Drug Administration's existing Expanded Access pathway.

Deciding whether to grant an expanded access request for a child whose sibling is enrolled in a gene therapy trial involves a number of complex factors: considering the best interests of the child, the psychosocial and economic impact on the family, and the concerns and obligations of researchers. Despite the challenges in coming to a substantively fair outcome in cases of discordant eligibility, creating a procedurally fair decision-making process to adjudicate requests is essential.

Convalescent plasma is an investigational product, not approved by the Food and Drug Administration for any use, that has been administered for the prevention and treatment of epidemic infections, including Ebola and most recently COVID-19. On 3 April 2020, Food and Drug Administration authorized an Expanded Access Program for treatment use of convalescent plasma in hospitalized COVID-19 patients, with Mayo Clinic as the coordinating site for this nationwide effort. Expanded Access, historically referred to as ''compassionate use,'' is a regulatory pathway that allows patients to use an investigational product outside of a clinical trial when four conditions are met: the patient has a life-threatening or serious disease, no comparable or satisfactory alternative treatment options are available, clinical trial enrollment is not possible, and non-trial use does not pose a threat to timely clinical development. Food and Drug Administration can authorize Expanded Access through requests for single patients, intermediate-size patient populations, and widespread treatment programs. The convalescent plasma Expanded Access Program was the largest in US history, leading to infusion of more than 94,000 patients. In comparison, the largest prior Expanded Access Programs-for lamivudine (HIV) and gefitinib (cancer)-each provided unapproved drugs to approximately 30,000 patients outside of clinical trials. Expanded Access Programs of this size are unusual and dwarf most clinical trials. However, Expanded Access Programs are intended for treatment, not research. Therefore, even when they involve sizable patient populations, they lack features of rigorous trial design, including control groups and randomization. Nevertheless, Expanded Access Program data have been considered pivotal by both the Food and Drug Administration and European Medicines Agency, often in the context of rare disease and the collection of safety data, and it was primarily the convalescent plasma Expanded Access Program data that led Food and Drug Administration to issue an emergency use authorization for that product. Although Expanded Access Programs are by regulation not supposed to hinder clinical trials, large Expanded Access Programs can create circular challenges, as when a lack of trial opportunities makes an Expanded Access Program an important pathway for initial access to an investigational product, but then the Expanded Access Program becomes a barrier to launching new trials. In this session, we will discuss the statistical, ethical, and regulatory issues that arise in the context of Expanded Access Programs, using the convalescent plasma Expanded Access Program as a case study in contrast to clinical trials, with a focus on issues arising in the context of a global pandemic. We will first discuss biostatistical considerations for extracting realworld evidence from Expanded Access Program data, as well as the role of these data in supplementing results from clinical trials. We will also consider the perspective of the patient in deciding whether to enroll in an Expanded Access Program versus clinical trial, including the opportunity for personal benefit or harm, potential for participation to impact the greater good, and the patient understanding of an unproven investigational treatment. Then, we will address the gatekeeping role of clinicians, institutions, and regulators, to ensure that Expanded Access Programs do not interfere with clinical trials. Finally, we will address patient pathways for accessing investigational drugs, especially in the context of a global pandemic, and the capacity for collecting rigorous data via these mechanisms, while prioritizing rigorous trials

INTRODUCTION/UNASSIGNED:Physicians in the United States play an essential role guiding patients through single patient pre-approval access (PAA) to investigational medical products via either the Food and Drug Administration (FDA)'s Expanded Access (EA) or the federal Right To Try (RTT) pathways. In this study, we sought to better understand pediatric hematologist/oncologists' attitudes about seeking PAA, on behalf of single patients, to investigational drugs outside of clinical trials. METHODS/UNASSIGNED:A cross-sectional survey was developed and sent to pediatric hematologist/oncologists via St. Baldrick's Foundation's email distribution list. RESULTS/UNASSIGNED: = 46) had prior experience with single patient PAA. Respondents were most concerned about the unknown risks and benefits of investigational drugs and financial implications of PAA for patients. One hundred percent and 91.1% of respondents indicated a willingness to support patients through EA and RTT pathways, respectively. When asked about their most recent experience with PAA, 40 out of 46 indicated that they used the FDA's EA pathway to seek PAA and 4 out of 46 indicated that they used the RTT pathway. Of 44 respondents who had used the EA or RTT pathway, 43 indicated that the biotechnology or pharmaceutical company they solicited granted access to the requested product. CONCLUSION/UNASSIGNED:Survey results support other findings suggesting a need for additional physician support and education about PAA and that physicians may have unequal access to information about investigational drugs and concerns about financial implications of PAA for their patients.

This article examines the origins and context of mandatory bicycle helmet laws in the United States. Localities began to enact such laws in the early 1990s, having experimented with helmet laws for motorcycles previously. As cycling became increasingly popular in the 1970s and 1980s because of a variety of historical trends, from improved cycle technology to growing environmental consciousness, cycling-related injuries also increased. Bicycle safety advocates and researchers alike were particularly troubled by head injuries. National injury surveillance systems and a growing body of medical literature on bicycle-related injuries motivated a number of physicians, cyclists, children, and other community members to advocate helmet laws, which they argued would save lives. Controversy over these laws, particularly over whether they should apply universally or only to children, raised public health ethics concerns that persist in contemporary debates over bicycle helmet policies. (Am J Public Health. 2020;110:1198-1204. doi: 10.2105/AJPH.2020.305718).

Aim: The US FDA has two nontrial pre-approval access pathways: expanded access (EA) and right to try (RTT). Reports of successful RTT use are scarce, and the FDA has not yet published RTT usage data, yet proponents tout its utility. In the face of this discrepancy and a lack of transparency of usage statistics, our aim is to add to the limited understanding of RTT usage. Materials & methods: We searched crowdfunding campaigns referencing 'expanded access', 'right to try' or 'compassionate use' since 2018. Results: We identified 26 EA campaigns, 29 RTT campaigns and two referencing both. Twenty one EA campaigns described being approved to receive access to the requested experimental medical product versus one RTT campaign. Conclusion: RTT is associated with poor understanding of nontrial pre-approval access. These campaigns suggest RTT is not offering a practical alternative to EA. Cost remains a significant barrier to these patients.