Faculty Bibliography

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

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.

Transgender and gender-nonconforming (TGNC) youth who suffer from gender dysphoria are at a substantially elevated risk of numerous adverse physical and psychosocial outcomes compared with their cisgender peers. Innovative treatment options used to support and affirm an individual's preferred gender identity can help resolve gender dysphoria and avoid many negative sequelae of nontreatment. Yet, despite advances in these relatively novel treatment options, which appear to be highly effective in addressing gender dysphoria and mitigating associated adverse outcomes, ethical challenges abound in ensuring that young patients receive appropriate, safe, affordable treatment and that access to this treatment is fair and equitable. Ethical considerations in gender-affirming care for TGNC youth span concerns about meeting the obligations to maximize treatment benefit to patients (beneficence), minimizing harm (nonmaleficence), supporting autonomy for pediatric patients during a time of rapid development, and addressing justice, including equitable access to care for TGNC youth. Moreover, although available data describing the use of gender-affirming treatment options are encouraging, and the risks of not treating TGNC youth with gender dysphoria are evident, little is known about the long-term effects of both hormonal and surgical interventions in this population. To support ethical decision-making about treatment options, we encourage the development of a comprehensive registry in the United States to track long-term patient outcomes. In the meantime, providers who work with TGNC youth and their families should endeavor to offer ethically sound, patient-centered, gender-affirming care based on the best currently available evidence.

Patients have received experimental pharmaceuticals outside of clinical trials for decades. There are no industry-wide best practices, and many companies that have granted compassionate use, or 'preapproval', access to their investigational products have done so without fanfare and without divulging the process or grounds on which decisions were made. The number of compassionate use requests has increased over time. Driving the demand are new treatments for serious unmet medical needs; patient advocacy groups pressing for access to emerging treatments; internet platforms enabling broad awareness of compelling cases or novel drugs and a lack of trust among some that the pharmaceutical industry and/or the FDA have patients' best interests in mind. High-profile cases in the media have highlighted the gap between patient expectations for compassionate use and company utilisation of fair processes to adjudicate requests. With many pharmaceutical manufacturers, patient groups, healthcare providers and policy analysts unhappy with the inequities of the status quo, fairer and more ethical management of compassionate use requests was needed. This paper reports on a novel collaboration between a pharmaceutical company and an academic medical ethics department that led to the formation of the Compassionate Use Advisory Committee (CompAC). Comprising medical experts, bioethicists and patient representatives, CompAC established an ethical framework for the allocation of a scarce investigational oncology agent to single patients requesting non-trial access. This is the first account of how the committee was formed and how it built an ethical framework and put it into practice.

Patients who suffer from life-threatening illnesses or are stricken with conditions that could result in serious morbidity who have exhausted all appropriate treatments may choose to try, through the Food and Drug Administration's expanded access program, an investigational drug or device in development. The program has succeeded for decades in allowing patients to access potentially helpful but still experimental agents. Nevertheless, the administration of investigational drugs outside of clinical trials raises several ethical issues. Of particular concern are the validity of informed consent and the absence of a framework to ensure that experimental drugs are allocated justly and transparently. Although there are some safeguards to help protect the soundness of consent, little work to date has been done to guarantee that investigational medical products are allocated justly and transparently. We introduce a novel pilot project that seeks to address this issue.