Much of the focus of the published 2011 symposium that inspired this work focused on the question, “When have you reduced risk enough to move from bench/animal studies to ‘first in-human’ studies?” Building applied research ethics related to nanotherapeutics requires bench and clinical scientists to have a clear vision about how to test nanotherapeutic safety, and it is clear that there is still much to be considered at the steps before “in-human” assessment. Herein, the perspective of the bench scientist is brought to bear on using in vivo and in vitro models to assess the safety of nanotherapeutics. Much of this work falls under the purview of the field of nanotoxicology that aims to understand the toxicological impact of engineered nanoscale materials. Engineered nanomaterials include a wide variety of materials that are manipulated and controlled on the nanoscale level where, typically, the nanoparticle or nanomaterial has some dimension that is less than 100 nm.

Approximately two billion people lack access to medicines globally. People living with HIV, cancer patients, those suffering from tuberculosis or malaria, and other populations in desperate need of life-saving medicines are increasingly unable to access existing preventative, curative, and life-prolonging treatments. In many cases, treatment may be unavailable or inaccessible for even some of the most common and readily treatable health concerns, such as hypertension. In the developing world, many of the factors that contribute to making the world’s most vulnerable and marginalized populations particularly susceptible to illness also operate to restrict their access to medicines. As a result of dramatic economic inequities and widespread poverty, it is not profitable for most originator pharmaceutical companies to develop new medicines for sale in developing markets or to lower the cost of existing drugs so that they are affordable for the majority of these populations.

A word, first, about the religious sensibility that I have found helpful to describe the care professionals owe to dying patients, particularly patients with advanced dementia.

That word is covenant. It is a biblical term; but, today, it covers such dubious devices as real estate covenants. A real estate covenant often operates below the moral level of a contract to wall some people out of a neighborhood. Classically understood, however, the word covenant helps probe the obligations of doctors to their patients more deeply than the notion of a contract. Covenants of the sort I have in mind and contracts appear to be first cousins; they both include an agreement and an exchange between parties. But, in spirit, contracts and covenants differ markedly. Contracts are external; covenants are internal to the parties involved. We sign contracts in order to discharge them expediently. Contracts are limited and time-bound — whether a contract to fix plumbing or to charge such and such for a medical procedure.

Physicians and patients rely on medical journals as trusted sources of medical information. Unfortunately, in multiple instances conflicts of interest have undermined the credibility of the medical literature.

The primary sources of conflict of interest at medical journals are authors, reviewers, editors (a category that includes editorial staff, editorial boards, and other advisory groups), and journals (a category that includes owners and publishers). Consider these examples.

The biomedical literature and popular media are full of upbeat reports about the health benefits we can expect from medical innovations using nanotechnology. Some particularly enthusiastic reports portray nanotechnology as one of the innovations that will lead to a significantly extended human life span. Extreme enthusiasts predict that nanotechnology “will ultimately enable us to redesign and rebuild, molecule by molecule, our bodies and brains….”

Nanomaterials have special characteristics that could contribute to improved patient care. But the same characteristics that make nanotechnology promising also present risks to humans exposed to nanomaterials. A failure to appreciate these risks could jeopardize the research effort. As others have pointed out, if nanomedical interventions produce unexpected human harm, a loss of public and government support for nanomedicine is likely to follow.

Like other forms of medical innovation, novel nanomedical interventions require human testing to evaluate their safety and effectiveness.

Our society is obsessed with health. At every second, everywhere, we are surrounded and overwhelmed by distressing calls on how vital it is to adopt a healthy lifestyle. While incorporating a healthy diet and physical exercise into our routines are the foremost commandments, everything from tobacco to refined sugars, trans fat, excessive alcohol, caffeine, and even eggs are declared public evils. Yet there is hope: medicines will save us! And indeed medicines exist available for all kinds of human afflictions. There are pills to help you relax and forget about stress, while some others, on the contrary, can keep you miraculously alert. There are pills that heal your most unbearable pains, physical or emotional, wherever their location — the head, back, quadriceps, heart, or soul. Though they may cause your stomach to burn, that is easily remedied by taking a complementary pill that will neutralize your stomach acidity with only some minor and negligible side effects elsewhere. There are also magic pills that promise you happiness, by giving you the power to thrive and the endurance to conquer the world. They ignite your hunger for achievement, but also for extra sugar and saturated fat.

In recent years, the government, advocacy organizations, the press, and the public have pressured universities, academic medical centers, and physicianinvestigators to do more to ensure that their financial interests and relationships do not conflict with their duties to conduct high-quality research and protect the safety and welfare of clinical trial participants. A number of factors underlie the increased focus. First, private sector funding of clinical research has grown both in absolute terms and as a proportion of overall funding. In 2008, the pharmaceutical, medical device, and biotechnology industries’ domestic research and development expenditures constituted approximately 60.9% of funding for biomedical research in the United States; the next largest funder, the National Institutes of Health, funded 27.9%. Private industry spent $58.6 billion on research in 2007, up from $40 billion in 2003, an increase of 25% after adjusting for inflation.

America is aging. But even more striking than the rise in the proportion of the population over age 65 is the unprecedented number of individuals who are living into their eighties and nineties. While many people remain robust well into advanced age, the dramatic increase in the number of the oldest old has brought with it an epidemic of Alzheimer’s disease and other dementias. Dementia is a highly prevalent condition — currently 5.4 million Americans have Alzheimer’s disease, a number which may rise to 16 million by 2050 if there is no breakthrough in the prevention or treatment of the disease — but it disproportionately affects those over age 85, striking between one-third and one-half of this cohort. Developing a reasonable approach to the medical care of older people with dementia will be essential in the coming decades.

In my career as a primary care physician and as a palliative care consultant, I have assisted many patients to die with their full consent. None of them wanted to die, and all would have chosen other paths had their disease not been so severe and irreversible. To a person, none of these patients thought of themselves as “suicidal,” and they would have found that label preposterous and demeaning. In fact, the kind of personal disintegration that the label implies is just what is trying to be prevented by those choosing this possibility. So on behalf of patients who have chosen this option, I reject the title of this debate as it unnecessarily tars the discussion with the suggestion of mental illness. In my primary care practice, I have also met many patients who were “suicidal” in the mental health sense of the word, and rest assured I have assisted none of them to die. In fact, I have at times had them involuntarily hospitalized to prevent them from carrying out their wishes.

Why do physicians have financial conflicts of interest? They arise because society expects physicians to act in their patients’ interest, while simultaneously, financial incentives encourage physicians to practice medicine in ways that promote their own interests or those of third parties. Because physicians’ clinical choices, referrals, and prescriptions affect the fortune of third parties (providers, medical facilities, insurers, drug firms and suppliers of ancillary services), these third parties may offer physicians financial incentives to make income-driven clinical choices. In the past, physicians and scholars typically conceived of conflicts of interest as an ethical issue to be resolved according to individual judgment or professional and organizational norms. However, society can mitigate or eliminate conflicts of interest by changing financial and organizational arrangements in medicine. Conflicts of interest, therefore, are as much matters of public policy and management as individual choices or social norms.

Do we have a legal and moral right to health care against others? There are international conventions and institutions that say emphatically yes, and they summarize this in the expression of “the right to health,” which is an established part of the international human rights canon. The International Covenant on Social and Economic Rights outlines this as “the right of everyone to the enjoyment of the highest attainable standard of physical and mental health,” but declarations such as this remain tragically unfulfilled. According to recent figures, roughly two billion people lack access to essential drugs or to primary health care. Millions are afflicted by infections and illnesses that are easily avoidable or treatable. In the developing world many children die or grow stunted and damaged for lack of available treatments. Tropical diseases receive little or no attention by the major pharmaceutical companies’ research departments. Is this a massive violation of the right to health? And if so, why does it attract so little attention? Is it because our supposed commitment to human rights and the rule of law is hypocritical and hollow? Or is it because the right to health is a special case of a right, so that these tragedies are no violation at all? Jennifer Prah Ruger summarized this puzzle when she wrote: “one would be hard pressed to find a more controversial or nebulous human right than the right to health.” In this essay I discuss three different theories of a right to health care. I conclude by offering my own reconstruction of one such theory.

Risk is the most often cited reason for ethical concern about any medical science or technology, particularly those new technologies that are not yet well understood, or create unfamiliar conditions. In fact, while risk and risk-benefit analyses are but one aspect of ethical oversight, ethical review and risk assessment are sometimes taken to mean the same thing. This is not surprising, since both the Common Rule and Food and Drug Administration (FDA) foreground procedures for minimizing risk for human subjects and require local IRBs to engage in some sort of risk-benefit analysis in decisions to approve or deny proposed research. Existing ethical review and oversight practices are based on the presumption that risk can be clearly identified within the planned activities of the protocol, that metrics can reasonably accurately predict potential hazards, and that mitigation measures can be taken to deal with unintended, harmful, or catastrophic events.

The idea that physicians should accept recommendations from learned colleagues on how to practice medicine is probably as old as medicine itself, but beginning around 1990, it took on new urgency in the face of rising health care costs, widespread, unjustifiable variation in practice patterns, concerns about medical errors and quality of care, and what some perceived to be perverse effects of the malpractice system. One solution put forward was practice guidelines, which the Institute of Medicine (IOM) defined as systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.

First-in-human (FIH) research has several characteristics that require special attention with respect to ethics and human subjects protections. At least some nanomedical technologies may also have characteristics that merit special attention in clinical research, as other papers in this symposium show. This paper considers how to address these characteristics in the consent form and process for FIH nanomedicine research, focusing principally on experimental nanotherapeutic interventions but also considering nanodiagnostic interventions.

It is essential, as a starting point, to recognize that the consent form and process are by no means the primary protectors of human subjects (although they are sometimes so regarded). Instead, consideration of the form and content of informed consent becomes relevant only after a clinical trial has been reviewed and deemed scientifically and ethically acceptable.

Two convergent types of challenges to informed consent are posed by nanomedicine FIH research. First, some issues appear generally applicable to FIH research, but have specific nanomedicine implications.

I sometimes wonder whether some proponents of physician-assisted suicide (PAS) or physician-assisted death (PAD) think they own the copyright to such catchy phrases as “death with dignity” and “a good death” so that if you are against PAS or PAD, then you must be against a dignified death or a good death. If one removes the quotation marks around phrases like “aid-in-dying” or “compassionate care for the dying,” I am not opposed to such end-of-life care either. Indeed, how could anybody be against this type of care?

I do not want to abandon dying patients anymore than Dr. Timothy Quill does. Although, unfortunately, it will not always be easy to achieve the desired result, I agree with him that it ought to be a goal of medicine “to help people die well, to help them receive a good death” — or at least “the best possible” death under the circumstances. I part company with Professor Quill, however, when he urges us to change the law in the majority of our states so that in some circumstances patients may achieve a “good death” or a “dignified” one by means of lethal drugs.

And yet:

It has long been recognized that an understanding of at least some core legal rules and concepts is an important piece of medical training. To address this, law is now typically part of the core medical school curriculum, often incorporated into bioethics and/or practice of medicine coursework — whether as part of a distinct course or series of courses or threaded through the curriculum (or both). While often this education focuses on rules, some have recommended that it also include fundamentals of legal reasoning, and go beyond knowledge to include skills, attitudes, and behaviors vis-à-vis the law.

In one of the televised debates among Republican primary candidates for the 2012 U.S. presidential election, moderator Wolf Blitzer presented this hypothetical case to candidate Ron Paul:

Paul, known for his libertarian views, initially responded that the patient “should assume responsibility for himself,” and that he should have purchased a major medical policy before he became ill.

Medical technologies, including nanomedicine products, are intended to improve health but in many cases may also create their own health risks. Medical products that create their own health risks differ from most other risk-creating technologies in that the very purpose of the medical technology is to prevent or treat health risks. This paradox of technologies intended to reduce existing risks that may have the effect of creating new risks has two conflicting implications. On one hand, we may be more tolerant of health risks from medical technologies because these products are intended to, and often (but not always) do, reduce overall health risks and improve our health. The health benefits of a medical technology may outweigh the unavoidable adverse effects of that same technology in an individual patient or in the overall treated population.

For over 100 years, the field of contemporary public health has existed to improve the health of communities and populations. As public health practitioners conduct their work – be it focused on preventing transmission of infectious diseases, or prevention of injury, or prevention of and cures for chronic conditions – ethical dimensions arise. Borrowing heavily from the ethical tools developed for research ethics and bioethics, the nascent field of public health ethics soon began to feel the limits of the clinical model and began creating different frameworks to guide its ethical challenges. Several public health ethics frameworks have been introduced since the late 1990s, ranging from extensions of principle-based models to human rights and social justice perspectives to those based on political philosophy. None has coalesced as the framework of choice in the discipline of public health. This paper examines several of the most-known frameworks of public health ethics for their common theoretical underpinnings and values, and suggests next steps toward the formulation of a single framework.