Consideration and Disclosure of Group Risks in Genomics and Other Data-Centric Research: Does the Common Rule Need Revision?

Harms and risks to groups and third-parties can be significant in the context of research, particularly in data-centric studies involving genomic, artificial intelligence, and/or machine learning technologies. This article explores whether and how United States federal regulations should be adapted to better align with current ethical thinking and protect group interests. Three aspects of the Common Rule deserve attention and reconsideration with respect to group interests: institutional review board (IRB) assessment of the risks/benefits of research; disclosure requirements in the informed consent process; and criteria for waivers of informed consent. In accordance with respect for persons and communities, investigators and IRBs should systematically consider potential group harm when designing and reviewing protocols, respectively. Research participants should be informed about any potential group harm in the consent process. We call for additional public discussion, empirical research, and normative analysis on these issues to determine the right regulatory and policy path forward.

Ethical challenges in autism genomics: Recommendations for researchers.

Equitable and just genetic research and clinical translation require an examination of the ethical questions pertaining to vulnerable and marginalized communities. Autism research and advocate communities have expressed concerns over current practices of genetics research, urging the field to shift towards paradigms and practices that ensure benefits and avoid harm to research participants and the wider autistic community. Building upon a framework of bioethical principles, we provide the background for the concerns and present recommendations for ethically sustainable and justice-oriented genetic and genomic autism research. With the primary goal of enhancing the health, well-being, and autonomy of autistic persons, we make recommendations to guide priority setting, responsible research conduct, and informed consent practices. Further, we discuss the ethical challenges particularly pertaining to research involving highly vulnerable individuals and groups, such as those with impaired cognitive or communication ability. Finally, we consider the clinical translation of autism genetics studies, including the use of genetic testing. These guidelines, developed by an interdisciplinary working group comprising autistic and non-autistic individuals, will aid in leveraging the potential of genetics research to enhance the quality of life of autistic individuals and are widely applicable across stigmatized traits and vulnerable communities.

Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial.

B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA0 with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA0 rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.

Ethical, legal, and social implications of genetic risk prediction for multifactorial disease: a narrative review identifying concerns about interpretation and use of polygenic scores.

Advances in genomics have enabled the development of polygenic scores (PGS), sometimes called polygenic risk scores, in the context of multifactorial diseases and disorders such as cancer, cardiovascular disease, and schizophrenia. PGS estimate an individual's genetic predisposition, as compared to other members of a population, for conditions which are influenced by both genetic and environmental factors. There is significant interest in using genetic risk prediction afforded through PGS in public health, clinical care, and research settings, yet many acknowledge the need to thoughtfully consider and address ethical, legal, and social implications (ELSI). To contribute to this effort, this paper reports on a narrative review of the literature, with the aim of identifying and categorizing ELSI relating to genetic risk prediction in the context of multifactorial disease, which have been raised by scholars in the field. Ninety-two articles, spanning from 1977 to 2021, met the inclusion criteria for this study. Identified ELSI included potential benefits, challenges and risks that focused on concerns about interpretation and use, and ethical obligations to maximize benefits, minimize risks, promote justice, and support autonomy. This research will support geneticists, clinicians, genetic counselors, patients, patient advocates, and policymakers in recognizing and addressing ethical concerns associated with PGS; it will also guide future empirical and normative research.

A survey of pediatric hematologists/oncologists' perspectives on single patient Expanded Access and Right to Try.

Introduction: 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: A cross-sectional survey was developed and sent to pediatric hematologist/oncologists via St. Baldrick's Foundation's email distribution list. Results: Of 73 respondents (10.1% of those who received the survey), 56 met eligibility criteria and are included in the analysis. Over 80% (n = 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: 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.

Reactions to the National Academies/Royal Society Report on Heritable Human Genome Editing.

In September 2020, a detailed report on Heritable Human Genome Editing was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

Oversight of Right-to-Try and Expanded Access Requests for Off-Trial Access to Investigational Drugs.

For decades, the U.S. Food and Drug Administration (FDA) has provided an "expanded access" pathway that allows patients who meet qualifying conditions to gain access outside a clinical trial to an investigational medical product being tested to see if it is safe and effective for a specific use. The Right to Try (RTT) Act, enacted in 2018, created a second mechanism for off-trial, or non-trial, access to investigational drugs. In contrast to the expanded access pathway, the federal RTT pathway does not require the involvement of the FDA or an institutional review board (IRB). Given that physicians, drug manufacturers, and medical institutions now have a choice whether to assist individual patients through the expanded access or the federal RTT pathway, we review the differences between these options and discuss the benefits and burdens of IRB involvement in requests to access interventions through the pathways. We also suggest ways in which IRB oversight may be further improved.

Genetic discrimination: emerging ethical challenges in the context of advancing technology.

Genetic testing is becoming more widespread, and its capabilities and predictive power are growing. In this paper, we evaluate the ethical justifications for and strength of the US legal framework that aims to protect patients, research participants, and consumers from genetic discrimination in employment and health insurance settings in the context of advancing genetic technology. The Genetic Information Nondiscrimination Act (GINA) and other laws prohibit genetic and other health-related discrimination in the United States, but these laws have significant limitations, and some provisions are under threat. If accuracy and predictive power increase, specific instances of use of genetic information by employers may indeed become ethically justifiable; however, any changes to laws would need to be adopted cautiously, if at all, given that people have consented to genetic testing with the expectation that there would be no genetic discrimination in employment or health insurance settings. However, if our society values access to healthcare for both the healthy and the sick, we should uphold strict and broad prohibitions against genetic and health-related discrimination in the context of health insurance, including employer-based health insurance. This is an extremely important but often overlooked consideration in the current US debate on healthcare.

A pilot trial of pembrolizumab plus prostatic cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate cancer.

BACKGROUND: Monotherapy with immune checkpoint inhibitors has generally been unsuccessful in men with advanced prostate cancer. Preclinical data support the notion that cryotherapy may improve immune-mediated and anti-tumor responses. The objective of this study was to assess the safety and feasibility of whole-prostate gland cryotherapy combined with pembrolizumab and androgen deprivation in men with oligometastatic hormone-sensitive prostate cancer. METHODS: This single-institution, pilot trial recruited 12 patients with newly diagnosed oligometastatic prostate cancer between 2015 and 2016. Patients underwent whole-prostate cryoablation combined with short-term androgen deprivation (eight months) and pembrolizumab (6 doses). The primary clinical endpoints were the number of patients with a PSA level of <0.6 ng/mL at one year and the frequency of adverse events. Other outcome measures included progression-free survival and systemic therapy-free survival. Exploratory analyses included PD-L1 protein expression. RESULTS: Forty two percent (5/12) of patients had a PSAs of <0.6 ng/mL at one year though only 2 of these patients had recovered their testosterone at this time point. Median progression-free survival was 14 months, and median systemic therapy-free survival was 17.5 months. PD-L1 expression was not detectable by IHC in patients with evaluable tissue. All adverse events were grade ≤2, and there were no apparent complications from cryotherapy. CONCLUSIONS: Whole-prostate cryoablation combined with short-term androgen deprivation and pembrolizumab treatment was well tolerated and no safety concerns were observed in men with oligometastatic prostate cancer. Though local disease appeared effectively treated in the majority of men, the regimen only infrequency led to sustained disease control following testosterone recovery.

How Should Physicians Respond When They Learn Patients Are Using Unapproved Gene Editing Interventions?

Hundreds of gene therapies are currently in various stages of research and development. A subset of these involve gene editing technologies such as CRISPR. In this hypothetical case, a patient with chronic pain has initiated a CRISPR-based intervention obtained from a clinic in the Cayman Islands. His physician doubts it is approved by the US Food and Drug Administration and worries about its safety. The case presents ethical questions about potential violations of US regulations regarding the sale of products intended to affect human health, patients' lack of understanding about risks of unproven drugs, and suboptimal support for and management of patients with chronic pain. We discuss how physicians should address these questions.

Single-Patient Expanded Access Requests: IRB Professionals' Experiences and Perspectives.

BACKGROUND: U.S. physicians may treat a patient with an investigational drug outside of a clinical trial by using the expanded access (EA) pathway or the recently created federal right to try (RTT) pathway. The EA pathway requires physicians to get prior permission from the U.S. Food and Drug Administration (FDA) and, except in emergency cases, institutional review board (IRB) approval. The perspectives of IRB professionals on the review of single-patient EA requests have not been empirically studied. METHODS: We used a cross-sectional online survey to ascertain IRB professionals' perspectives on IRB experiences with and preparedness for review of single-patient EA requests, as well as their attitudes about the importance of IRB review of such requests. Email invitations were sent to 234 IRB professionals connected to the SMART IRB platform. Approximately half of the survey questions used a Likert scale to assess respondents' agreement with specific statements. RESULTS: Eighty-three respondents completed the survey (36.4% response rate, with 228 deliverable e-mail invitations). Of the respondents, 73.5% were affiliated with an academic medical institution; 78.3% of respondents agreed that it is important for a designated member of an IRB to review single-patient EA requests before investigational drugs are used by patients. The majority indicated that local review of the EA request was important and that a single designated reviewer was sufficient (rather than full board). Further, 86.6% felt that their IRBs were prepared to review these requests, and 9.2% indicated that not all the single-patient EA requests reviewed by their IRBs in 2017 were approved. CONCLUSIONS: A large majority of IRB professionals affiliated with the SMART IRB platform who responded to this survey felt IRB review of single-patient EA requests is important and that their IRBs were prepared to handle such requests.

Federal Right to Try: Where Is It Going?

Policy-makers, bioethicists, and patient advocates have been engaged in a fierce battle about the merits and potential harms of a federal right-to-try law. This debate about access to investigational medical products has raised profound questions about the limits of patient autonomy, appropriate government regulation, medical paternalism, and political rhetoric. For example, do patients have a right to access investigational therapies, as the right-to-try movement asserts? What is government's proper role in regulating and facilitating access to drugs that are still in development? In this review, we analyze the history of the right-to-try movement, review the arguments put forth by supporters and opponents of the legislation, and consider the movement's consequences. Two possible scenarios may emerge. One is that the right-to-try pathway may fail to meaningfully increase patient access to investigational products. Alternatively, certain companies may attempt to rely on the federal right-to-try legislation to sell investigational products, taking advantage of the provision that allows for direct costs, as there is currently no clear mechanism for enforcement or monitoring of cost calculations.