Nanomedicine is yielding new and improved treatments and diagnostics for a range of diseases and disorders. Nanomedicine applications incorporate materials and components with nanoscale dimensions (often defined as 1-100 nm, but sometimes defined to include dimensions up to 1000 nm, as discussed further below) where novel physiochemical properties emerge as a result of size-dependent phenomena and high surface-to-mass ratio. Nanotherapeutics and in vivo nanodiagnostics are a subset of nanomedicine products that enter the human body. These include drugs, biological products (biologics), implantable medical devices, and combination products that are designed to function in the body in ways unachievable at larger scales. Nanotherapeutics and in vivo nanodiagnostics incorporate materials that are engineered at the nanoscale to express novel properties that are medicinally useful. These nanomedicine applications can also contain nanomaterials that are biologically active, producing interactions that depend on biological triggers. Examples include nanoscale formulations of insoluble drugs to improve bioavailability and pharmacokinetics, drugs encapsulated in hollow nanoparticles with the ability to target and cross cellular and tissue membranes (including the bloodbrain barrier) and to release their payload at a specific time or location, imaging agents that demonstrate novel optical properties to aid in locating micrometastases, and antimicrobial and drug-eluting components or coatings of implantable medical devices such as stents.

Nanotechnology not only offers the promise of new enhancements to existing materials but also allows for the development of new materials and devices. The potential applications of nanotechnology range from medicine to agriculture to health and environmental science and beyond. Nanotechnology is growing at such a rate that Lux Research in 2007 estimated that nanotechnology will be incorporated into 15% of global manufactured goods by 2014. The U.S. National Nanotechnology Initiative defines nanotechnology as the following: “(1) Research and technology development involving structures with at least one dimension in the range of 1-100 nanometers (nm), frequently with atomic/molecular precision; (2) Creating and using structures, devices, and systems that have unique properties and functions because of their nanoscale dimensions; (3) The ability to control or manipulate on the atomic scale.” Nanomedicine and its subcategories of nanotherapeutics and in vivo nanodiagnostics incorporate nanoscale materials with unique properties that can enable new or improved treatments and diagnostics for many diseases and disorders.

While the definitions employed by different governmental agencies and scientific societies differ somewhat, the term “nanotechnology” is generally understood to refer to the manufacturing, characterization, and use of man-made devices with dimensions on the order of 1-100 nanometers (1 nanometer [nm] = 1 billionth of a meter). Devices that comprise a fundamental functional element that is nanotechnological are also frequently comprised within nanotechnology, as are manufactured objects with dimensions less than one micrometer. The differences in definition lead to occasional paradoxes, such as the fact that the most widely used nanodrug (albumin nanoparticles of dimensions up to 300 nm, comprising the anticancer drug paclitaxel) is labeled a “nanopharmaceutical” by governments of European countries, Canada, and Australia, but it is not a nanotechnology for the U.S. Food and Drug Administration (FDA). It is also common in scientific domains to restrict the term “nanotechnology” to objects that possess special, “emerging” properties that only arise because of their nanoscale dimension.

In prominent funding and policy statements, a particle with at least one dimension in the 1-300 nm size range must have novel physicochemical properties to count as a “nanoparticle.” Size is thus only one factor. Novelty of a particle's properties is also essential to its “nano” classification. When particles in this size range are introduced into living systems, they often interact with their host in novel ways that require some modification of existing methods and models used by pharmaceutical scientists and toxicologists for assessing their efficacy and safety. It is not clear, however, whether the novelty of the intended physicochemical properties is in any way related to the novel behavior of those particles when their toxicity is evaluated. In fact, when considering toxicity, much of the concern about nanoparticles relates to the unanticipated or poorly understood interactions.

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.

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.

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.

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.

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.

Like all policies, contemporary human research policies are the product of their history. The scandals and traumas motivating their creation — the Nazi doctors trials, Tuskegee, the Milgram experiment on obedience — however different in their particulars, all share a common narrative: a scientist, pursuing valued social ends, runs roughshod over the personal interests of disadvantaged human subjects. From the Nuremberg code through the latest revisions of the Declaration of Helsinki, research ethics policies have sought to erect a sphere of protection around the latter.

As a consequence of this history, all major policies start with a well-rehearsed model of human investigations. Clinical research is viewed as an encounter between investigators and volunteers. The clinical investigator is given certain duties. The human volunteer has certain moral entitlements. What is ethically at stake in human investigations inheres in the nature and quality of the interactions between investigators and volunteers. These interactions involve an asymmetry because the investigator has privileged knowledge and influence.

The Common Rule (45 CFR 46, subpart A) is a set of regulations for protecting human participants in research funded by the Department of Health and Human Services (DHHS), which has been adopted in part by 17 federal agencies. It includes four different subparts: Subpart A (general protections for human research participants), Subpart B (additional protections for pregnant women, fetuses, and neonates), Subpart C (additional protections for prisoners), and Subpart D (additional protections for children). The Common Rule has not been significantly revised since 1981 although some significant changes may be forthcoming. The Food and Drug Administration (FDA) has adopted its own regulations for the protection of human participants, which are similar to the Common Rule in many key areas, such as the structure and function of the Institutional Review Board (IRB), and the criteria for approving research.

Nanomedicine is a rapidly growing field in the academic as well as commercial arena. While some had predicted nanomedicine sales to reach $20.1 billion in 2011, the actual growth was much more rapid, with the global nanomedicine market being valued at $53 billion in 2009, and forecast to increase at an annual growth rate of 13.5% to reach more than $100 billion in 2014. In 2006, more than 130 nanotechnology-based drugs and delivery systems had entered preclinical, clinical, or commercial development. The European Medicines Agency (EMA) reviewed 18 marketing authorization applications for nanomedicines in 2010. In 2011, 22 drugs that had been approved by the FDA, and 87 Phase I and Phase II clinical trials were listed in the U.S. National Institutes of Health (NIH) data base, www.clinicaltrials.gov. Although the fastest growing areas of nanomedicine are applications in medical imaging and diagnosis using contrast-enhancing agents, most nanomedicine research and commercialization is in the area of cancer drug therapy, including nano gold shells.

Historian James H. Jones published the first edition of Bad Blood, the definitive history of the Tuskegee Syphilis Experiment, in 1981. Its clear-eyed examination of that research and its implications remains a bioethics classic, and the 30-year anniversary of its publication served as the impetus for the reexamination of research ethics that this symposium presents. Recent revelations about the United States Public Health Service study that infected mental patients and prisoners in Guatemala with syphilis in the late 1940s in order to determine the efficacy of treatment represent only one of the many attestations to the persistence of ongoing, critical, and underaddressed issues in research ethics that Bad Blood first explored. Those issues include, but are not limited to: the complex and contested matters of the value of a given research question, the validity of the clinical trial designed to address it, and the priorities of science.

In 1878, Friedrich Engels famously wrote that on the road to realizing the communist utopia, “the state is not abolished, it withers away.” In a similar manner, biomedical researchers telling us that come the promised land of individualized genomic medicine, the need for using race will also “wither away” in the face of scientific progress. Such millennial hopes are, no doubt, sincere, but they enable the continued casual proliferation of racial categories throughout biomedical research, product development, marketing, and clinical practice. My contrasting quotation to frame this article is drawn from the 20th century pioneer of rock and roll, Buddy Holly (né Charles Hardin Holley) whose 1957 hit “Not Fade Away” begins with the line, “I’m gonna tell you how it's gonna be” — the point being that far from withering away, race is persisting even as genomic milestones are being reached and passed.

Personalized medicine with its promise of developing interventions tailored to an individual's health need and genetically related response to treatment might seem a promising antidote to the documented underutilization of standard depression treatments by African Americans. In addition, understanding depression not merely in biochemical terms but also in genetic terms might seem to counter cultural beliefs and stigma that attach to depression when conceived as a mood or behavioral problem under an individual's control. After all, if there is one thing for which a person is not responsible and cannot be blamed, it is her genes. Nevertheless, for multiple reasons, a personalized medical approach to depression treatment, and its attendant conceptualization of depression and treatment response as genetically influenced, present the risk of exacerbating well-documented disparities in access to, and utilization of, treatment for depression among African-American and Caucasian elderly adults.

For decades, the dominant research paradigm has included trials conducted in clinical settings with little involvement from communities. However, concerns about the relevance and applicability of the processes or outcomes of such research have led to calls for greater community engagement in the research process. As such, there has been a shift in emphasis from simply recruiting research participants from community settings to engaging community members more broadly in all aspects of the research process. The move toward community engaged research (CEnR) is in part driven by the recognition that inclusion of diverse perspectives in multidisciplinary teams is essential to addressing complex problems. Investigators have come to recognize the inherent value of engaging community members as collaborators in multidisciplinary teams that are conducting research on issues of concern to communities. The insider perspective from community members is now recognized as essential in designing effective and well-received recruitment strategies, culturally appropriate measures, and identifying meaningful and broad-reaching venues for dissemination.

The government-sponsored Tuskegee syphilis study had a huge impact on U.S. research ethics and policy. Study investigators regarded subjects as “mere means” to their research ends, which led to a variety of ethical violations. Investigators used deception so that subjects would see participation as therapeutic — researchers promoted the therapeutic misconception because this advanced study objectives. The research would produce important information, and this justified lying to research subjects.

Today we see this sort of intentional deception as unjustified no matter how important a study might be. But what do we make of the claim that the syphilis study had value? As James Jones reported, its objectives were to test the prevailing views that syphilis affected blacks and whites differently, and that the disease was less harmful to blacks than whites. U.S. Public Health Service researchers and officials assumed the study had sufficient value to justify not only deceiving subjects, but also depriving them of safe and effective treatment.

Over the past 40 years, a complex review and oversight system has grown within the United States and internationally to regulate the conduct of human subjects research. This system developed in response to revelations of abuses of human subjects in experiments such as those conducted in the Nazi concentration camps, the Tuskegee Study of Untreated Syphilis in the Negro Male, the Willowbrook Hepatitis Studies, and the studies described by Beecher in his 1966 article in the New England Journal of Medicine. The oversight system is based on a foundation, first implemented by the U.S. Public Health Service (PHS) in 1966 and by the U.S. Food and Drug Administration in 1971, of prior review and approval of a written experimental protocol by an independent committee. The World Medical Association articulated the ethical centrality of independent review in its 1975 revision of the Declaration of Helsinki, and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research endorsed the requirement in its flagship Belmont Report.