Ethical research when abortion access is legally restricted.

Risks and benefits of some clinical research may be altered.

Brief Report: Challenges in Obtaining the Informed Perspectives of Stakeholders Regarding HIV Molecular Epidemiology.

BACKGROUND: HIV molecular epidemiology (HIV-ME) is now being used in a variety of ways, including molecular HIV surveillance to help identify and respond to emerging HIV transmission clusters as specified in the Ending the HIV Epidemic in the U.S. initiative. However, HIV-ME in general, and its use for cluster detection and response, in particular, raises significant ethical and social concerns, which have spurred vigorous debates. Nevertheless, there is a paucity of information regarding how these potential benefits and concerns are perceived among people living with HIV and people without HIV at an increased risk. SETTING: Virtual engagement with US participants. METHODS: We rigorously developed a brief informational video about HIV-ME and conducted a series of in-depth interviews with people living with HIV and people without HIV at an increased risk. RESULTS: Through extensive stakeholder engagement during the video development process and subsequent in-depth interviews (N = 24), several preliminary findings surfaced. In contrast to the high level of concern raised by some critics of HIV-ME, our data appear to show broad support for it. In addition, we observed conflation of perspectives about HIV-ME with concerns about HIV public health surveillance more generally. CONCLUSION: Our experiences reveal substantial communication challenges related to the nature of HIV-ME that need to be overcome to ensure that it is properly understood, which is necessary for meaningfully engaging stakeholders in discussions about its use. Moreover, ongoing, responsive, engagement efforts are critical. Additional systematic data are needed to help inform policy making and practice regarding HIV-ME.

Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials.

Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct.

Low-Dose Linezolid for Treatment of Patients With Multidrug-Resistant Tuberculosis.

Background: Linezolid has been prioritized for treating multidrug-resistant tuberculosis (MDR TB), but toxicity limits its use. We report treatment outcomes for MDR TB patients in California who received standard-dose linezolid vs those who switched to low-dose. Methods: We include culture-positive MDR TB cases treated with linezolid and receiving California MDR TB Service consultation during 2009-2016. Demographic, clinical, and laboratory data are analyzed using univariate analysis to compare patients who received linezolid of different dosing strategies. Analysis end points are linezolid treatment duration (measure of tolerability), treatment success (completion or cure), and adverse events (AEs). Results: Sixty-nine of 194 (36%) MDR TB patients met inclusion criteria. While all patients began linezolid treatment at 600 mg daily, 39 (57%) continued at this dosage (standard-dose), and 30 (43%) switched to 300 mg daily (29%) or intermittent dosing (14%) (low dose). Patients on standard-dose linezolid were treated for 240 days, compared with 535 for those on low-dose (P < .0001). Sixty-three patients (91%) achieved treatment success, 2 (2.9%) died, 1 (1.5%) failed treatment, 1 (1.5%) stopped treatment due to side effects, and 2 (2.9%) were lost or moved. Treatment success was higher (P = .03) in the low-dose group. Sixty-two patients experienced ≥1 hematologic (71%) or neurologic (65%) AE. Those on low-dose linezolid experienced significantly (P = .03) fewer AEs per linezolid-month after switching (0.32 vs 0.10). Conclusions: Patients who switched to low dose tolerated linezolid longer with better treatment outcomes and fewer recurring AEs.

Bedaquiline for multidrug-resistant tuberculosis and QTc prolongation in California.

BACKGROUND: Bedaquiline (BDQ) is recommended for the treatment of multidrug-resistant tuberculosis (MDR TB), however, it has the potential to prolong QTc interval. We assessed the frequency and severity of QTc prolongation in patients receiving BDQ in California. METHODS: Based on chart review for patients receiving BDQ as part of MDR TB therapy from January 2013-May 2019, we analyzed QTc values at six pre-specified time points during BDQ therapy (baseline, 2, 4, 8, 12, and 24 weeks), as well as peak QTc, time to peak QTc, and the clinical characteristics of patients who had QTc elevation >500 milliseconds (ms) during therapy. RESULTS: A total of 37 patients were treated with BDQ during the analysis period, with a total of 449 QTc measurements available for analysis. Most patients (89%) received at least one QTc-prolonging drug in addition to BDQ. Median QTc values at all pre-specified time points were <450 ms. Median peak QTc was 455 ms (interquartile range [IQR]: 437-486) and median time to peak was 57 days (IQR: 19-156). Four patients (11%) had a non-transient elevation in QTc to >500 ms, including one patient with profound hypokalemia and one receiving concurrent chemotherapy, but none had cardiac arrhythmia. Less than 10% of patient in our cohort had ECGs performed at all six pre-specified time points. DISCUSSION: BDQ was generally well-tolerated in a cohort of patients treated for MDR TB in California, with 11% of patients experiencing a non-transient QTc elevation >500 ms, and no episodes of arrhythmia. Frequent ECG monitoring during BDQ therapy presents a challenge for TB clinicians, even in well-resourced countries.

The Pathway Forward: Insights on Factors that Facilitate Research with Pregnant Women.

The near-routine exclusion of pregnant women from clinical research has resulted in evidence gaps that endanger the health of pregnant women and their future offspring. Although existing literature documents numerous obstacles along the clinical trial pathway that can stymie research involving pregnant women, there is little guidance on how to facilitate such research. This qualitative study aims to fill that void by examining the experiences of individuals involved in conducting, approving, or overseeing research involving pregnant women at one academic institution. The study identifies factors throughout the clinical pathway-from protocol development, to IRB review, and ultimately trial execution-that likely contribute to the successful conduct of research with pregnant women. Attention to those factors, coupled with agreement among stakeholders that research with pregnant women should and can be done ethically and legally, is critical to shifting the narrative from "why we cannot" do such research to "how we can."

Ethical Considerations Concerning Amnioinfusions for Treating Fetal Bilateral Renal Agenesis.

Congenital bilateral renal agenesis has been considered a uniformly fatal condition. However, the report of using serial amnioinfusions followed by the live birth in 2012 and ongoing survival of a child with bilateral renal agenesis has generated hope, but also considerable controversy over an array of complex clinical and ethical concerns. To assess the ethical concerns associated with using serial amnioinfusions for bilateral renal agenesis, we assembled a multidisciplinary group to map the ethical issues relevant to this novel intervention. The key ethical issues identified were related to 1) potential risks and benefits, 2) clinical care compared with innovation compared with research, 3) counseling of expectant parents, 4) consent, 5) outcome measures, 6) access and justice, 7) conflicts of interest, 8) effects on clinicians, 9) effects on institutions, and 10) long-term societal implications. These ethical issues should be addressed in conjunction with systematic efforts to examine whether this intervention is safe and effective. Future work should capture the experiences of expectant parents, women who undergo serial amnioinfusions, those born with bilateral renal agenesis and their families as well as clinicians confronted with making difficult choices related to it.

Research with Pregnant Women: New Insights on Legal Decision-Making.

U.S. researchers and scholars often point to two legal factors as significant obstacles to the inclusion of pregnant women in clinical research: the Department of Health and Human Services' regulatory limitations specific to pregnant women's research participation and the fear of liability for potential harm to children born following a pregnant woman's research participation. This article offers a more nuanced view of the potential legal complexities that can impede research with pregnant women than has previously been reflected in the literature. It reveals new insights into the role of legal professionals throughout the research pathway, from product conception to market, and it highlights a variety of legal factors influencing decision-making that may slow or halt research involving pregnant women. Our conclusion is that closing the evidence gap created by the underrepresentation and exclusion of pregnant women in research will require targeted attention to the role of legal professionals and the legal factors that influence their decisions.

Ethics, regulation, and beyond: the landscape of research with pregnant women.

Scarce research with pregnant women has led to a dearth of evidence to guide medical decisions about safe and effective treatment and preventive interventions for pregnant women and their potential offspring. In this paper, we highlight three aspects of the landscape in which pregnant women are included or, more frequently, excluded from research: international ethics guidance, regional and national regulatory frameworks, and prevailing practices. Our paper suggests that, in some cases, regulatory frameworks can be more restrictive than international ethics guidance, and that even when regulations permit research with pregnant women, practical challenges-as well as the prevailing practices of stakeholders, such as ethics review committees and investigators-may lead to the generalized exclusion of pregnant women from research.

Digoxin therapy for cor pulmonale: A systematic review.

OBJECTIVE: Right heart failure is associated with increased mortality and morbidity. The optimal treatment for patients with RV failure is not established. The aim of this study is to conduct a systematic review of the literature to assess the relative benefits and harms of digoxin therapy in patients with RV failure. METHODS: We performed a literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) on Nov. 4, 2014. We did not use publication type, period or language restrictions to the search strategy. Exclusions included: trials that excluded patients with RV failure, included patients requiring mechanical or intravenous inotropic support, review papers and case reports. The primary outcome was long-term efficacy outcomes of digoxin in right heart failure. Two reviewers screened titles and abstracts of identified citations independently and in duplication using calibration exercises and standardized screening forms. RESULTS: The search strategy identified 4097 citations, and 4 studies were included in this analysis (n=76 patients). Of the four studies, two assessed improvements in RVEF, two studies compared exercise capacity indexes, and one assessed symptoms with digoxin compared with placebo. No study assessed mortality outcomes. Overall, there was no statistically significant improvement in RVEF, exercise capacity, NYHA class, heart failure score, or body weight. CONCLUSIONS: There are few studies evaluating Digitalis use for RV failure, which are limited to patients with cor pulmonale. In these patients, Digitalis use provides no improvement in RVEF, exercise capacity, or NYHA class. Randomized clinical trials are needed to address this question.

Advancing HIV research with pregnant women: navigating challenges and opportunities.

OBJECTIVE: Concerns about including pregnant women in research have led to a dearth of evidence to guide safe and effective treatment and prevention of HIV in pregnancy. To better understand why these evidence gaps persist and inform guidance for responsible inclusion of pregnant women in the HIV research agenda, we aimed to learn what HIV experts perceive as barriers and constraints to conducting this research. METHODS: We conducted a series of group and one-on-one consultations with 62 HIV investigators and clinicians to elicit their views and experiences conducting HIV research involving pregnant women. Thematic analysis was used to identify priorities and perceived barriers to HIV research with pregnant women. RESULTS: Experts discussed a breadth of needed research, including safety, efficacy, and appropriate dosing of: newer antiretrovirals for pregnant women, emerging preventive strategies, and treatment for coinfections. Challenges to conducting research on pregnancy and HIV included ethical concerns, such as how to weigh risks and benefits in pregnancy; legal concerns, such as restrictive interpretations of current regulations and liability issues; financial and professional disincentives, including misaligned funder priorities and fear of reputational damage; and analytical and logistical complexities, such as challenges recruiting and retaining pregnant women to sufficiently power analyses. CONCLUSION: Investigators face numerous challenges to conducting needed HIV research with pregnant women. Advancing such research will require clearer guidance regarding ethical and legal uncertainties; incentives that encourage rather than discourage investigators to undertake such research; and a commitment to earlier development of safety and efficacy data through creative trial designs.

Just compensation: a no-fault proposal for research-related injuries.

Biomedical research, no matter how well designed and ethically conducted, carries uncertainties and exposes participants to risk of injury. Research injuries can range from the relatively minor to those that result in hospitalization, permanent disability, or even death. Participants might also suffer a range of economic harms related to their injuries. Unlike the vast majority of developed countries, which have implemented no-fault compensation systems, the United States continues to rely on the tort system to compensate injured research participants-an approach that is no longer morally defensible. Despite decades of US advisory panels advocating for no-fault compensation, little progress has been made. Accordingly, this article proposes a novel and necessary no-fault compensation system, grounded in the ethical notion of compensatory justice. This first-of-its-kind concrete proposal aims to treat like cases alike, offer fair compensation, and disburse compensation with maximum efficiency and minimum administrative cost. It also harmonizes national and international approaches-an increasingly important goal as research becomes more globalized, multi-site trials grow in number, and institutions and sponsors in the United States move to single-IRB review.

Respect and dignity: a conceptual model for patients in the intensive care unit.

Although the concept of dignity is commonly invoked in clinical care, there is not widespread agreement--in either the academic literature or in everyday clinical conversations--about what dignity means. Without a framework for understanding dignity, it is difficult to determine what threatens patients' dignity and, conversely, how to honor commitments to protect and promote it. This article aims to change that by offering the first conceptual model of dignity for patients in the intensive care unit. The conceptual model we present is based on the notion that there are three sources of patients' dignity-their shared humanity, personal narratives, and autonomy-each of which independently warrants respect. The article describes each source of dignity and draws on examples to illustrate how clinician attitudes, actions, and behaviors can either contribute to, or detract from, expressions of respect for patient dignity.

Moral gridlock: conceptual barriers to no-fault compensation for injured research subjects.

The federal regulations that govern biomedical research, most notably those enshrined in the Common Rule, express a protectionist ethos aimed at safeguarding subjects of human experimentation from the potential harms of research participation. In at least one critical way, however, the regulations have always fallen short of this promise: if a subject suffers a research-related injury, then neither the investigator nor the sponsor has any legal obligation under the regulations to care for or compensate the subject. Because very few subjects with research-related injuries can meet the financial or evidentiary requirements associated with a successful legal claim to recover the costs associated with their injuries, most injured subjects must shoulder the burden of those expenses alone. For 40 years, national advisory panels have concluded that this result is out of step with the Common Rule's otherwise protectionist promise. When the Department of Health and Human Services released an Advance Notice of Proposed Rulemaking (ANPRM) in 2011, suggesting potential changes to the Common Rule, the time seemed ripe to address research-related injuries. The ANPRM, however, makes no mention of compensation for research-related injuries, and the federal government once again seems poised to stop short of addressing what has arguably become the most longstanding, frequent, and consistent plea for regulatory reform of research: protections for injured subjects. This article asks why, despite decades of federal-level panels recommending no-fault compensation for research-related injuries, the United States has so strongly resisted change. I suggest that a central reason for our current impasse is that, despite consensus among federal advisory committees that there is an obligation to compensate injured subjects, the committees have not coalesced around a moral justification for that duty. Although multiple justifications can support and even strengthen a single ethical obligation, the reverse has occurred in this context. I demonstrate that the committees' articulation of multiple ethical principles - including humanitarianism, professional beneficence, and compensatory justice - results in incongruent obligations that favor different kinds of compensation systems. This outcome, which I call "moral gridlock," makes it extremely difficult to determine what kind of compensation scheme to implement. Recognizing that each moral argument for compensation creates a slightly different trajectory is, however, an important first step in moving toward a more systematic approach to compensating injured research subjects.