Faculty Bibliography

Policies have been developed to protect vulnerable populations in clinical research, including the US federal research regulations (45 Code of Federal Regulations 46 Subparts B, C, and D). These policies generally recognize vulnerable populations to include pregnant women, fetuses, neonates, children, prisoners, persons with physical handicaps or mental disabilities, and disadvantaged persons. The aim has been to protect these populations from harm, often by creating regulatory and ethical checks that may limit their participation in many clinical trials. The recent increase in pragmatic clinical trials raises at least two questions about this approach. First, is exclusion itself a harm to vulnerable populations, as these groups may be denied access to understanding how health interventions work for them in clinical settings? Second, are groups considered vulnerable in traditional clinical trials also vulnerable in pragmatic clinical trials? We argue first that excluding vulnerable subjects from participation in pragmatic clinical trials can be harmful by preventing acquisition of data to meaningfully inform clinical decision-making in the future. Second, we argue that protections for vulnerable subjects in traditional clinical trial settings may not be translatable, feasible, or even ethical to apply in pragmatic clinical trials. We conclude by offering specific recommendations for appropriately protecting vulnerable research subjects in pragmatic clinical trials, focusing on pregnant women, fetuses, neonates, children, prisoners, persons with physical handicaps or mental disabilities, and disadvantaged persons.

Several requirements and regulations have been issued to promote clinical trial transparency through prospective registration of trials, disclosure of results, access to trial reports submitted to regulatory agencies and access to anonymised patient-level data. -Clinical trial results are disseminated through articles. Yet, many present outcome reporting bias. -Open-access to trial data will help to deter outcome reporting bias. However, this is not enough to clinicians

'Calling' a code can be an ambiguous undertaking. Despite guidelines and the medical literature outlining when it is acceptable to stop resuscitation, code cessation and deciding what not to do during a code, in practice, is an art form. Familiarity with classic evidence suggesting most codes are unsuccessful may influence decisions about when to terminate resuscitative efforts, in effect enacting self-fulfilling prophesies. Code interventions and duration may be influenced by patient demographics, gender or a concern about the stewardship of scarce resources. Yet, recent evidence links longer code duration with improved outcomes, and advances in resuscitation techniques complicate attempts to standardise both resuscitation length and the application of advanced interventions. In this context of increasing clinical and moral uncertainty, discussions between patients, families and medical providers about resuscitation plans take on an increased degree of importance. For some patients, a 'bespoke' resuscitation plan may be in order.

Life expectancy statistics predict that in a couple of decades women will enjoy a mean life of 90 years. Assuming a median age for the onset of menopause of 51, women will spend about 40 years in menopause. Harvesting and freezing ovarian cortical tissue at a younger age to permit future transplantation for postponing menopause and its sequelae could become a possible option. However, both medical and ethical issues need to be addressed before this can be offered as a treatment for menopause.

Whistleblowers remain essential as complainants in allegations of research misconduct. Frequently internal to the research team, they are poorly protected from acts of retribution, which may deter the reporting of misconduct. In order to perform their important role, whistleblowers must be treated fairly. Draft regulations for whistleblower protection were published for public comment almost a decade ago but never issued (Dahlberg 2013). In the face of the growing challenge of research fraud, we suggest vigorous steps, to include: organizational responsibility to certify the accuracy of research including audit, required whistleblower action in the face of imminent or grave harm to subjects, strengthened legal protections against retaliation including prompt enactment of Federal whistleblower protections and consideration of criminalizing the most egregious cases of research misconduct.