Arthur Caplan

SeriesEngineered whole organs and complex tissues

End-stage organ failure is a key challenge for the medical community because of the ageing population and the severe shortage of suitable donor organs available. Equally, injuries to or congenital absence of complex tissues such as the trachea, oesophagus, or skeletal muscle have few therapeutic options. A new approach to treatment involves the use of three-dimensional biological scaffolds made of allogeneic or xenogeneic extracellular matrix derived from non-autologous sources. These scaffolds can act as an inductive template for functional tissue and organ reconstruction after recellularisation with autologous stem cells or differentiated cells. Such an approach has been used successfully for the repair and reconstruction of several complex tissues such as trachea, oesophagus, and skeletal muscle in animal models and human beings, and, guided by appropriate scientific and ethical oversight, could serve as a platform for the engineering of whole organs and other tissues.

Randomised controlled trials for Ebola: practical and ethical issues

2 months ago, when the numbers known to have died from Ebola in west Africa could still be counted in hundreds, WHO made an important statement about investigational drugs and vaccines. This crisis is so acute, WHO declared, that it is ethical to offer interventions with potential benefits but unknown efficacy and side-effects, though every effort should be made to evaluate benefits and risks and share all data generated. The need for drugs and vaccines was urgent then. With cases now rising exponentially and health systems overwhelmed, it is even greater today. Vaccine safety trials are underway in the USA and the UK, and poised to roll out to Africa soon. But treatments for those with infection are required too. Besides playing a direct part in containing the epidemic, interventions that could improve outcomes for the sick would help to rebuild the confidence of affected communities in health services, a critical step if Ebola is to be overcome. A fast-track initiative for evaluating investigational drugs was launched in September, 2014.1 But although the question of whether unproven treatments should be offered at all is now settled, the question of how they should be deployed and tested is not. Still at issue is whether such treatments should be made available only in the context of randomised controlled trials (RCTs) in which patients receive either a new intervention and conventional care, or conventional care alone or with a placebo. Advocates of this RCT approach2 state that as this experimental design will create the most robust evidence for the future, and is what regulators are used to, it is the only approach that should be considered. We disagree. While we concur that RCTs provide robust evidence, and support their use where this is ethical and practical, we do not believe that either consideration is likely to be satisfied in the context of this epidemic. The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment. Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability. The first objection to RCTs in which investigational drugs plus conventional care are compared purely with conventional care is ethical. Such randomisation is ethical when there is equipoise—when there is genuine uncertainty about whether an untested treatment has benefits or risks that exceed those of conventional care. Equipoise is a useful principle, but it can break down when conventional care offers little benefit and mortality is extremely high. This is precisely the problem with Ebola: current conventional care does not much affect clinical outcomes and mortality is as high as 70%. When conventional care means such a high probability of death, it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk. No-one insisted that western medical workers offered zMapp and other investigational products were randomised to receive the drug or conventional care plus a placebo. None of us would consent to be randomised in such circumstances. In cancers with a poor prognosis for which there are no good treatments, evidence from studies without a control group can be accepted as sufficient for deployment, and even for licensing by regulators, with fuller analysis following later. There is no need for rules to be bent or corners to be cut: the necessary procedures already exist, and are used. The second objection is practical. Even if randomisation were ethically acceptable, it might not be deliverable in the context of health-care systems, and indeed wider social order, that are breaking down as in Liberia, Guinea, and Sierra Leone. Populations who are terrified by the progress of the epidemic, and who lack trust in health-care and aid workers, and in public authorities in the aftermath of civil wars, cannot be expected to offer informed consent to such randomised trials. It is also unclear that any capacity exists to impose controlled conditions during a raging epidemic. Insisting on RCTs could even worsen the epidemic, by undermining trust in the Ebola treatment centres that are central to containing it. Randomisation is not, moreover, the only way to gather reliable information about the safety and effectiveness of potential Ebola therapies. Indeed, other methods might be more appropriate for achieving the key objective, which is to identify drug regimens that improve outcomes over existing methods of care, quickly, so that WHO can recommend their use and lives can be saved. One viable approach would be to try different treatments in parallel and at different sites, following observational studies that document mortality under standard care. This approach could effectively triage treatments into those with great benefits that should be rolled out immediately, those with no effect that should be discarded quickly, and those with promise needing follow-up in randomised trials. These trials can be designed adaptively, meaning that patient enrolment can be altered as efficacy data emerge, minimising the numbers of individuals who get ineffective treatments and increasing the numbers getting those that show benefits. This is not different from phase 2 studies as currently conducted and accepted by regulatory authorities for other diseases. It will also enable quick follow-up trials of combinations of antivirals and new treatments that have already shown evidence of activity. A different type of RCT might also become an option once more than one drug has shown efficacy—even efficacy in animal models. Then, patients could ethically be randomised to one investigational drug or another. No-one would get only standard care. We accept that RCTs can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history. The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.

Deep brain stimulation of the nucleus accumbens for the treatment of addiction

Despite novel medications and other therapeutic strategies, addiction to psychotropic substances remains one of the most serious public health problems worldwide. In this review, beginning with an introduction of deep brain stimulation (DBS), we highlight the importance of the nucleus accumbens (NAc) in the context of the reward circuitry and addictive behavior. We will provide a short historic overview of other neurosurgical approaches to treat addiction and describe the experimental and preclinical data on DBS in addiction. Finally, we call attention to key ethical issues related to using DBS to treat addiction that are important for future research and the design of clinical trials.

The OHRP and SUPPORT

A group of medical ethicists and pediatricians asks for reconsideration of the recent Office for Human Research Protections decision about informed consent in SUPPORT.

Accepting Brain Death

The cases of Jahi McMath and Marlise Munoz have reopened public debate about brain death. But the law and ethics have long recognized that deferring to medical expertise regarding the diagnosis of brain death is the most reasonable way to manage the process of dying.

Selecting the Right Tool For the Job

There are competing ethical concerns when it comes to designing any clinical research study. Clinical trials of possible treatments for Ebola virus are no exception. If anything, the competing ethical concerns are exacerbated in trying to find answers to a deadly, rapidly spreading, infectious disease. The primary goal of current research is to identify experimental therapies that can cure Ebola or cure it with reasonable probability in infected individuals. Pursuit of that goal must be methodologically sound, practical and consistent with prevailing norms governing human subjects research. Some maintain that only randomized controlled trials (RCTs) with a placebo or standard-of-care arm can meet these conditions. We maintain that there are alternative trial designs that can do so as well and that sometimes these are preferable to RCTs.

No time to waste—the ethical challenges created by CRISPR CRISPR/Cas, being an efficient, simple, and cheap technology to edit the genome of any organism, raises many ethical and regulatory issues beyond the use to manipulate human germ line cells

The term “CRISPR” has gained a lot of attention recently as a result of a debate among scientists about the possibility of genetically modifying the human germ line and the ethical implications of doing so. However, CRISPR is not just a method to edit the genomes of embryonic cells, as the public discussion might have implied; it is a powerful, efficient, and reliable tool for editing genes in any organism, and it has garnered significant attention and use among biologists for a variety of purposes. Thus, in addition to the discussion about human germ line editing, CRISPR raises or revives many other ethical issues, not all of which concern only humans, but also other species and the environment. > … CRISPR raises or revives many other ethical issues, not all of which concern only humans, but also other species and the environment CRISPRs are short DNA sequences with unique spacer sequences that, along with CRISPR‐associated (Cas) proteins, constitute an adaptive immune system in many bacteria and archaea against invading bacteriophages [1]. By using short RNA molecules as a template, Cas makes highly sequence‐specific cuts in DNA molecules that can be exploited to insert genes or to precisely modify the nucleotide sequence at the cut site. CRISPRs were first identified in the 1980s, but it is only during the past few years that scientists realized their potential to edit the genomes of any organism, from microorganisms to plants to human cells and, most controversially, human embryos. The CRISPR/Cas system is not a breakthrough technology in the sense that it enables genome editing; biologists have been using transcription activator‐like effector nucleases (TALENs) and zinc finger nucleases (ZFNs) to edit genomes for some time. However, those technologies are expensive, technically challenging, and time‐consuming, as they require protein engineering to target specific DNA …

Euthanasia in Belgium and the Netherlands On a Slippery Slope

20. Kuiken A. Was haar leven nog leefbaar? Trouw. January 11, 2014. http://www.trouw.nl/tr/nl/4516 /Gezondheid/article/detail/3575826/2014/01/11 /Was-haar-leven-nog-leefbaar.dhtml. Accessed July 6, 2015. 21. Bolt EE, SnijdewindMC,Willems DL, van der Heide A, Onwuteaka-Philipsen BD. Can physicians conceive of performing euthanasia in case of psychiatric disease, dementia or being tired of living [published online February 18, 2015]? J Med Ethics. doi:10.1136/medethics-2014-102150. 22. van Tol D, Rietjens J, van der Heide A. Judgment of unbearable suffering and willingness to grant a euthanasia request by Dutch general practitioners.Health Policy. 2010;97(2-3):166-172. 23. Muller MT, Onwuteaka-Philipsen BD, van derWal G, van Eijk J, RibbeMW. The role of the social network in active euthanasia and physician-assisted suicide. Public Health. 1996;110 (5):271-275.

Rising rates of vaccine exemptions: Problems with current policy and more promising remedies

Parents of school-age children are increasingly claiming nonmedical exemptions to refuse vaccinations required for school entry. The resultant unvaccinated pockets in many areas of the country have been linked with outbreaks of vaccine-preventable diseases. Many states are now focused on reducing rates of nonmedical exemptions by making exemption processes more restrictive or burdensome for the exemptor. These strategies, however, pose ethical problems and may ultimately be inadequate. A shift to strategies that raise the financial liabilities of exemptors may lead to better success and prove ethically more sound. Potential areas of reform include tax law, health insurance, and private school funding programs. We advocate an approach that combines this type of incentive with more effective vaccination education.

The Ethical Challenges of Compassionate Use

Granting access to drugs, vaccines, biologics, and devices that have not yet been approved by governmental regulatory authorities is a growing challenge for physicians, public officials, patient advocacy groups, institutional review boards (IRBs), and patients.1 Although the issue of rapid access to investigational agents is not new, tracing back to the early days of the human immunodeficiency virus pandemic, the pace of requests has increased. This is attributable to many factors, including greater awareness of compassionate use on the part of patients and their physicians; more information available through the Internet and websites describing clinical trials; an increase in promising interventions, including genetic markers, immunotherapies, and recombinant vaccines; threats from potential epidemics such as Ebola, cholera, and influenza; and an increased willingness to try novel agents by patients who are chronically ill or dying. Requests for rapid access to agents still under investigation fall into 2 categories—requests for groups of persons with the same disease and requests by individuals. The former are often described as requests for expanded access, the latter as requests for compassionate use. Regulatory bodies in various countries have created various programs for providing greater access to requests from groups, including the creation of expanded-access programs and emergency use waivers for patients who do not qualify for clinical trials. Compassionate use requests have proven to be more difficult to resolve. Compassionate use requests can occur at any time in the research process—from product testing in animals, to early human safety trials, to the period nearing the end of clinical trials. Requests can come from patients who are dying, those facing disability and pain for which no approved agent has proven effective, those in the midst of lethal disease outbreaks and those newly affected, those who are chronically ill, and those who have limited access to therapies.2 Until recently, the main strategy for patients seeking compassionate use was to try to locate a possible treatment for their disease, often but not always with the help of their physician. Once a potential therapy is found, patients seeking compassionate use might try to make direct contact with the researcher testing the agent, most often at a private company, or to use a connection with an individual to make a request to a corporate official. Sometimes patients try to interest the traditional media in their plight or launch campaigns using social media to draw attention with the hope that public pressure might be brought to bear on the private parties who own the agent to provide it.3 In the United States, some have claimed that the key obstacle for those seeking compassionate use is the Food and Drug Administration (FDA). Even though the application process can be cumbersome, the FDA grants approval for 99% of compassionate use requests.4 The major pathway for patients is to secure approval by a company moving the agent through the regulatory approval process. Unless that happens, the FDA plays almost no role in responding to compassionate use requests. However, granting compassionate use requests can at times compete with development of the agent for a larger group of patients. Companies have no legal obligation to offer access to experimental treatments, are often uncertain how to respond to requests, and may be uncomfortable in determining how to respond fairly to requests from the well connected or those using social media campaigns.1 Historically, evaluating compassionate use requests depended exclusively or predominantly on assessments from company employees.