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Human Subjects Research (HSR)

This series provides core training in human subjects research and includes the historical development of human subject protections, ethical issues, and current regulatory and guidance information.

About these Courses

Human Subjects Research (HSR) content is organized into two tracks: Biomedical (Biomed) and Social-Behavioral-Educational (SBE) . They are intended for anyone involved in research studies with human subjects, or who have responsibilities for setting policies and procedures with respect to such research, including Institutional Review Boards (IRBs). HSR Biomed and SBE courses are offered as Comprehensive and Foundation versions.

Comprehensive courses provide an expanded training covering not only major topical areas but also many concepts that are specific to types of research, roles in the protection of human subjects, and advanced modules on informed consent topics, vulnerable populations, stem cell research, phase I research, data and safety monitoring, big data research, mobile apps research, and disaster and conflict research.

Foundations courses provide foundational training covering major topic areas in human subjects protections.

This series also include refresher course options for both the Biomed and SBE tracks. Refresher courses provide retraining for individuals who have already completed a basic course. CITI Program offers a variety of refresher courses so learners can meet retraining requirements with fresh content.

Additional modules of interest within HSR allow for exploration of several important topics and may be selected to meet organizational needs.

HSR includes additional standalone courses for different specific roles including institutional/signatory officials, IRB chairs, public health researchers, and Certified IRB Professionals (CIPs) seeking recertification credit. Topic-focused mini-courses such as Single IRB (sIRB) Use and Administration , Clinical Trial Agreements , Phase I Research , and Community-Engaged and Community-Based Participatory Research , as well as a standalone Revised Common Rule course that covers the regulatory updates to the Common Rule (45 CFR 46, Subpart A) are also available.

All HSR modules reflect the revised Common Rule (2018 Requirements). Upon request, a selection of HSR modules are available as legacy versions (reflecting the pre-2018 requirements).

These courses were written and peer-reviewed by experts.

Note: Organizations subscribing to HSR have access to all of the modules included in the courses below.

Demo of Informed Consent Case Videos:

Language Availability: English, Korean, Spanish, French

Suggested Audiences: Human Subject Protection Staff, Institutional Review Boards (IRBs), Institutional/Signatory Officials, IRB Administrators and Staff, IRB Chairs, Research Team Members, Researchers, Students

Basic Courses

Biomedical (biomed) comprehensive.

This course provides an expansive review of human subjects research topics for biomedical researchers.

Biomedical (Biomed) Foundations

This foundational course provides a focused introduction to the essential human subjects research topics for biomedical researc...

Social-Behavioral-Educational (SBE) Comprehensive

This course provides an expansive review of human subjects research topics for social-behavioral-educational researchers.

Social-Behavioral-Educational (SBE) Foundations

This foundational course provides a focused introduction to the essential human subjects research topics for social-behavioral-...

Refresher Courses

Biomedical (biomed) refresher 1.

This course provides retraining on the HSR Biomed Basic course and discusses core human subjects research topics for biomedical...

Biomedical (Biomed) Refresher 2

Biomedical (Biomed) Refresher 3

Social-Behavioral-Educational (SBE) Refresher 1

This course provides retraining on the HSR SBE Basic course and discusses core human subjects research topics for social-behavi...

Social-Behavioral-Educational (SBE) Refresher 2

Additional Courses

This course provides detailed training for current and future Institutional Review Board (IRB) chairs.

Institutional/Signatory Official: Human Subjects Research

Provides a foundational training for institutional/signatory officials on their roles and responsibilities as part of an HRPP.

Essentials of Public Health Research

Provides an overview of the structure and function of public health systems, differentiates research and practice, and reviews consent and ethical issues for public health researchers.

Revised Common Rule

Comprehensive training covering the Final Rule updates to the Common Rule.

Single IRB (sIRB) Use and Administration

This course covers relying on a sIRB, serving as a sIRB of record, and authorization agreements.

Clinical Trial Agreements (CTAs)

Provides sites and investigators an overview of CTA development, negotiation, and execution.

Phase I Research

Provides an introduction to phase I research and the protection of phase I research subjects.

Community-Engaged and Community-Based Participatory Research

Delivers introductory information to help researchers and community partners participate in research partnerships.

Additional Courses for Independent Learners

Irb member – biomedical focus.

Provides foundational training for IRB members involved in the review of biomedical human subjects research.

IRB Member – Social-Behavioral-Educational Focus

Provides foundational training for IRB members involved in review of social-behavioral-educational human subjects research.

IRB Member – Biomedical and Social-Behavioral-Educational Combined

Provides foundational training for IRB members involved in the review of both biomedical and social-behavioral-educational huma...

CIP Certified Courses

Comprehensive cip course for advanced learners.

This course provides advanced learners all the CIP approved modules on topics such as informed consent, U.S. Food and Drug Admi...

CIP Course for Advanced Learners – IRB Administration Topics

This course provides advanced learners a topic-focused course on IRB administration and 4 CE hours for CIP recertification.

CIP Course for Advanced Learners – Biomedical and FDA Research Topics

This course provides advanced learners a topic-focused course on biomedical and U.S. Food and Drug Administration (FDA) researc...

CIP Course for Advanced Learners – Vulnerable Subjects and Consent

This course provides advanced learners a topic-focused course on subject population and informed consent topics as well as 9 CE...

Who should take human subjects research training?

Basic HSR courses are suitable for all persons involved in research studies involving human subjects (for example, researchers and staff), or who have responsibilities for setting policies and procedures with respect to such research, including Institutional Review Boards (IRBs) and other members of organizational communities where research with human subjects occurs.

There are additional standalone courses that are intended for specific audiences such as institutional/signatory officials, IRB chairs, public health researchers, and Certified IRB Professionals (CIPs) seeking recertification credits. Additional standalone courses on  IRB Administration  and the  Revised Common Rule are available. The Revised Common Rule course covers the regulatory updates to the Common Rule (45 CFR 46, Subpart A). Legacy versions of select basic and refresher modules are available for learners who need training on the pre-2018 requirements of the Common Rule. Legacy content must be requested by contacting CITI Program Support .

How long does it take to complete an HSR course?

HSR courses are comprised of modules that include detailed content, images, supplemental materials (such as, case studies), and a quiz. Learners may complete the modules at their own pace. Each module varies in length, and learners may require different amounts of time to complete the module based on their familiarity and knowledge of the topic. In general, modules can take about 30 to 45 minutes to complete.

What different courses are offered in HSR?

This series contains Basic and Refresher courses that are structured into two tracks: Biomedical (Biomed) and Social-Behavioral-Educational (SBE). These tracks contain different levels of review-- Compressive and Foundations.  The Foundations level provides a review of the core concepts of human subjects protections, while the Comprehensive level contains additional modules of interest that allow for exploration of several important topics and may be selected to meet organizational needs. Organizations may group these modules to form courses.

Additional courses that are intended for specific audiences such as institutional/signatory officials, IRB chairs, public health researchers, and Certified IRB Professionals (CIPs) seeking recertification credits are also available. HSR also includes a standalone  Revised Common Rule  course covering the regulatory updates to the Common Rule (2018 Requirements).

The Basic Biomed modules have three corresponding sets of refresher modules and the Basic SBE modules have two corresponding sets of refresher modules. These refresher modules are intended to provide learners with a review of core concepts. It is generally recommended that organizations select refresher module requirements that reflect their selections for the basic course(s). Refresher courses should be taken in a cycle specified by the organization (for example, Refresher Stage 1: 3 years after completion; Refresher Stage 2: 6 years after completion).

The CIP courses should be taken by independent learners who are seeking CIP continuing education (CE) credits for recertification.

How frequently should learners take HSR training?

There is no uniform standard regarding how frequently HSR training should occur. However, most organizations select a three-year cycle of retraining. HSR Refresher courses allow organizations an endless number of options when it comes to presenting content to meet their retraining needs, including different timings between basic and refresher course stages depending on the learner group.

Does HSR fulfill the human subjects training requirement?

Yes, CITI Program’s HSR training fulfills the human subjects research training requirements if the learner completes the basic modules for either the Biomed or SBE Comprehensive or Foundations courses.

As an administrator setting up my organization, how should I select HSR modules for my learner groups?

CITI Program allows organizations to customize their learner groups, which means they can choose the content modules their learners need to complete. We will work with your CITI Program designated admin to determine the learner groups that best fit your organizational needs. You can also choose to use our recommended learner groups.

What topics does HSR cover?

HSR covers the historical development of human subject protections, as well as current regulatory information and ethical issues. It also has additional modules on various topics related to human subject research protections, including cultural competence, advanced issues in informed consent, external IRBs, phase I research, stem cell research, and population-specific content.

What are the advantages of CITI Program’s HSR training?

HSR was developed and reviewed by human subject research experts to help organizations and individuals understand human subjects research protections. Along with CITI Program's advantages, including our experience, customization options, cost effectiveness, and focus on organizational and learner needs, this makes it an excellent choice for HSR training.

Can learner groups include components from HSR and other subjects?

Yes, like all CITI Program educational materials, the modules that make up HSR can be customized to meet the specific needs of your organization. This includes selecting modules from other CITI Program subjects (for example, Good Clinical Practice , Responsible Conduct of Research , or Information Privacy and Security ) when creating a learner group for HSR. Additional subscription charges may apply. We can work with your CITI Program designated admin to determine learner groups and courses for your organization.

Are HSR courses eligible for CIP CE education credits?

Yes, advanced-level modules that meet the criteria in the Certified IRB Professional (CIP) recertification guidelines are eligible as accredited continuing education units for CIPs. These modules were approved by the Council for Certification of IRB Professionals (CCIP) as advanced-level and eligible for CIP CE credit. View  CITI Program Advanced-Level Modules/Courses Eligible for CIP® Recertification Credit.  for a list of approved modules.

What are the Other Courses for Independent Learners?

The “Other Courses for Independent Learners” are meant to provide additional course options that meet the unique needs of independent learners.

• The IRB Member – Biomedical Focus course is meant for IRB members who review biomedical research.
• The IRB Member – Social-Behavioral-Educational Focus course is meant for IRB members who review social-behavioral-educational research.
• The IRB Member – Biomedical and Social-Behavioral-Educational Combined course is meant for IRB members who review biomedical and social-behavioral-educational research.

These courses are intended for independent learners only. For more information on customizing learner groups as part of an organization subscription, see the “Can learner groups include components from HSR and other subjects?” FAQ.

Are HSR courses eligible for continuing medical education (CME) credits?

Yes, the following courses are eligible for CME credits:

• HSR – Biomedical (Biomed) Comprehensive Course
• HSR – Social-Behavioral-Educational (SBE) Comprehensive Course
• HSR – Biomedical Refresher 1 Course
• HSR – Biomedical Refresher 2 Course
• HSR – Biomedical Refresher 3 Course
• HSR – Social-Behavioral-Educational Refresher 1 Course
• HSR – Social-Behavioral-Educational Refresher 2 Course
• IRB Chair Course

Click on the course name above for details. For more information on how to ensure CME credit availability for learners at your organization, contact  Support .

Are HSR courses updated to the Revised Common Rule (2018 requirements)?

Yes. All CITI Program modules affected by revisions to the Common Rule were revised by the general compliance date (21 January 2019). These modules reflect the 2018 Requirements of the Common Rule (the Final Rule issued by the U.S. Department of Health and Human Services [HHS] at 45 CFR 46, Subpart A - "Federal Policy for the Protection of Human Subjects" [the Common Rule] on 19 January 2017).

Prior to the general compliance date (21 January 2019), CITI Program modules reflected the pre-2018 requirements version of the Common Rule. CITI Program offers legacy content (upon request) that reflects the pre-2018 requirements of the Common Rule. Contact CITI Program Support for more information.

For more information, refer to support center article  Current CITI Program Modules and the Final Revisions to the Common Rule .

Will I be notified if this course is significantly revised or updated?

Yes, CITI Program will notify administrators via email and post news articles on our website when courses are significantly revised or updated.

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What Is Human Subjects Research?

Department of Philosophy, Dalhousie University

• Published: 15 December 2020
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This chapter provides an overview of the nature, scope, and practice of human subjects research. It begins by tackling the general question, “What is research?” Attempts to answer this question typically define research by its methods and/or goals, and the chapter surveys the limits of these definitions through discussion of tough boundary cases. Along the way, the chapter describes various methods (quantitative, qualitative) and types of human subjects research (clinical, social scientific, etc.). The second section of the chapter investigates who is referred to by the language of “human subjects”: which humans tend to be selected as research participants, where human subjects are located globally, and how these locations are changing. The chapter also raises questions about which subjects are considered human in this context, for instance, whether definitions include embryos, cadavers, or stem cells. Throughout, the chapter highlights the ethical issues raised by the various types of activities and subjects described.

Which of the following is human subjects research?

A clinician conducts a placebo-controlled, double-blind, randomized trial of a new treatment for depression.

A sociologist conducts a series of in-depth interviews with paramedics and firefighters about their experiences of burnout, which are then transcribed and analyzed for common themes.

On the basis of published research indicating a reduction of adverse events, a hospital administrator implements mandatory surgical checklists in one of their operating rooms and tracks the outcomes compared to the hospital’s other operating rooms; the administrator hopes that the expected positive results will help to convince reluctant hospital staff to adopt surgical checklists.

A team of economists selects three cities, sends invitation letters to all low-income citizens in those selected cities, and then partners with local government to provide a basic income to selected individuals for three years, tracking a range of health and life outcomes.

A patient seeks care from a family physician for a rare heart condition; after several unsuccessful treatments, the physician tries an unusual combination of medications, and the patient reports feeling much better.

Same as example 5, but the physician then writes up the case for publication in a peer-reviewed medical journal.

A pediatric oncologist offers patients with an otherwise untreatable form of cancer the option to try promising new treatments that are in the earliest stages of development.

Medical students manipulate human embryos in order to learn how to extract cells for genetic tests.

A geneticist analyzes and sequences the DNA from blood samples collected decades ago from the members of a marginal population.

If you found yourself struggling to decide which of these counts as human subjects research, you are not alone: experts and newcomers to research ethics alike find this task difficult. In fact, even highly respected regulatory bodies and authors of codes of ethics struggle to articulate clear and consistent answers to this question (for examples, see the opening chapters in this handbook). And because an affirmative answer to the question is thought to determine which activities are in need of prospective ethics review, the stakes of this debate are thought to be quite high.

The difficulty of this task persists for many reasons but, in particular, because both key concepts in the question—“research” and “human subjects”—are hard to define and plagued by tough, and ever-evolving, boundary cases. In what follows, I will outline these controversies and investigate whether there might be a clear sorting mechanism for the kinds of cases just outlined. For both concepts (“research” and “human subjects”), I will show that a clear definition is hard, if not impossible, to find. But this may not be as big a problem as it seems. In order to explain why not, I will explore a common underlying assumption about the high stakes of this assessment: the presumed connection between ethics and a particular type of regulatory review in human subjects research. Clarifying this relationship will help to defuse the worry about demarcation criteria for these concepts.

What is research? This is a harder question to answer than one might expect: any answer is in danger of being either underinclusive (for instance, by focusing narrowly on medical research when similar activities are carried out by researchers in other disciplines or professions) or overinclusive (labeling everything vaguely experimental or involving human interaction as research). The Tri-Council Policy Statement (TCPS 2) in Canada begins with a reflection on the broad range of practices and activities that qualify as research, before proposing a definition:

The scope of research is vast. On the purely physical side, it ranges from seeking to understand the origins of the universe down to the fundamental nature of matter. At the analytic level, it covers mathematics, logic and metaphysics. Research involving humans ranges widely, including attempts to understand the broad sweep of history, the workings of the human body and the body politic, the nature of human interactions and the impact of nature on humans—the list is as boundless as the human imagination. For the purposes of this Policy, research is defined as an undertaking intended to extend knowledge through a disciplined inquiry and/or systematic investigation . (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada 2018 , 5, emphasis added)

The ethical guidelines provided by the Council for International Organizations of Medical Sciences (CIOMS) provide a similar (though health-focused) definition and some examples of common research methods:

The term “health-related research” in these Guidelines refers to activities designed to develop or contribute to generalizable health knowledge within the more classic realm of research with humans, such as observational research, clinical trials, biobanking and epidemiological studies. Generalizable health knowledge consists of theories, principles or relationships, or the accumulation of information on which they are based related to health, which can be corroborated by accepted scientific methods of observation and inference . (2016, xii, emphasis added)

Likewise, according to the original Belmont Report in the United States, “the term ‘research’ designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge ” (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978, emphasis added).

Note first that each of these definitions would lead to a slightly different assessment of the cases outlined at the beginning of this chapter, so we can’t simply point to regulations to answer our question for us without engaging in further discussion about which regulations are correct. More to the point here, though, we can see that the following concepts tend to arise in definitions of research: scientific methods (observation, hypothesis testing, and/or inference), systematic and/or disciplined inquiry, generalizability, and contributing to knowledge. Research, it seems, is implicitly scientific research . Research is something that scientists do (as contrasted with journalists or celebrities, for instance). This qualification is supported by landmark ethical guidelines such as the original Nuremberg Code, Article 8 of which states, “The experiment should be conducted only by scientifically qualified persons” (Nuremberg Code 1949 , 182). And scientific research involves certain systematic and disciplined methods , which when used properly provide some assurance about the generalizability of results.

Does a focus on the scientific method help to sort the test cases? This seems a promising route since the scientific method is thought to be what makes results more reliable than unsystematic observation and inference, which connects to the aim of producing knowledge. The difficulty is that there are many different methods used by researchers in a range of disciplines. Each research method aims to answer a different question—some are comparative, while others try to find out why someone holds a position or acts a certain way.

Qualitative research methods involving human subjects range from those involving close contact and communication between researchers and individual subjects, which are often open-ended and dynamic, such as ethnographic studies, oral histories, narrative inquiries, focus groups, and minimally structured interviews, to more structured and less dynamic methods such as large-scale surveys and structured interviews. Qualitative research is excellent at answering “why” and “how” questions and much less focused on reporting numerical results than quantitative research. As such, it plays an important and complementary role to quantitative research: a quantitative study may determine that some percentage of elementary school teachers report feeling burned out, for instance, while a qualitative study can investigate why this occurring and how it is experienced or understood by those who self-report.

Quantitative research methods involving human subjects include case studies, case series, and n -of-1 studies, all of which focus on the description and analysis of individual cases. They include observational methods such as case–control and cohort studies, which track and compare groups of people over time (either prospectively or retrospectively). In these types of studies, subjects are not assigned to different groups but rather self-select or are otherwise independently sorted into groups (for instance, a study might follow cyclists and non-cyclists). And then there are interventional methods such as randomized controlled trials (RCTs), in which participants are assigned to intervention and control groups randomly, and, when double-blind, neither they nor the researchers involved know which group they were assigned to until the study is completed. In many domains, including economics, public policy, and medicine, the RCT design is regarded as the gold standard of quantitative methods because of its rigorous comparative design and perceived objectivity.

Quantitative clinical research, in particular, proceeds on the basis of positive results in earlier animal studies and then is carried out in phases. Phase I clinical research typically enrolls a small number of healthy subjects (20–80) and aims to determine whether a proposed intervention is safe in humans and at what approximate dose or intensity. Phase II clinical research enrolls a somewhat greater number of subjects (100–300)—this time those with the health condition the intervention aims to treat—and aims to assess both safety and efficacy (the effect under near-ideal conditions). Phase III clinical research enrolls large numbers of subjects (1,000+) and aims to determine whether an intervention is effective. This phase of research is typically the basis for national regulatory approval, meaning that the treatment can be prescribed and sold to patients in some jurisdiction once it has the support of (typically at least two) well-designed phase III trials. Phase IV, or post-marketing trials, track outcomes in the general population once a treatment is widely available.

In both qualitative and quantitative domains, there are meta-level research methods designed to amalgamate the results of research. These include literature reviews, systematic reviews, and meta-analyses. In an effort to reach busy audiences, there are also summaries and syntheses which aim to bring together all research on a given topic and provide an overall assessment. Guidelines for practitioners in medicine often draw upon these meta-level studies, as well as expert opinion, in recommending standards of practice. And the range of methods is always expanding: some newer methods, such as cluster RCTs and umbrella trials, are discussed by Hey and Weijer in this handbook.

Generalizable Knowledge

What this wide range of scientific methods, from in-depth interviews to RCTs, have in common is that they involve a systematic or disciplined effort to produce results that contribute not just to knowledge but to generalizable knowledge —a standard interpretation of this term is “the use of information to draw conclusions that apply beyond the specific individuals or groups from whom the information was obtained” (Coleman 2019 , 248). This brings us to the aims of research, which were a common component of the definitions of research offered earlier. Each of the methods described might be thought of as contributing to generalizable knowledge, while something like trial and error in clinical practice might be aimed only at benefiting an individual patient. In order to figure out whether quality improvement efforts—such as instituting a surgical checklist in one operating room and comparing with others—count as generating generalizable knowledge, we would look to their aim. In the case as I described it at the outset, the administrator believed that they already knew the intervention would be successful at reducing rates of adverse events, based on the research evidence. The aim was to convince the healthcare team in the hospital that these results applied locally so that they would adopt the practice. This seems to be a case where the primary aim is changing local behavior rather than adding to general knowledge. This way of separating quality improvement activities from research proper has become quite popular in recent years. Scholars take different positions on whether this way of settling the matter is successful or not. This debate turns on, among other things, different ideas of what is meant by “generalizable knowledge.”

Most interpretations of “generalizable” focus on the applicability of results to people who were not in a study. But this can be tricky. An RCT with strict criteria for who is included, that tests an intervention against placebo, and that strictly controls the context in which treatment is administered (for instance, only by specialists in a highly resourced urban hospital) may produce results indicating that a particular medical treatment is effective. This sort of clean explanatory RCT is thought by many scholars to be the exemplar of a study design yielding generalizable results. But a rural physician in a low-resource area dealing primarily with elderly patients who have multiple health conditions might not regard the results of the study just described as generalizable to their patients. (And they would probably be right about this—the gap between research evidence and individual patient care is a real one, and closing or narrowing that gap is something researchers have been working on for decades. The advance of pragmatic trials is one attempt to solve this problem, for instance.) Through this example, we see some of the challenges inherent in claims made about generalizability, particularly when interpretations focus on applicability. Not all areas of scientific investigation lend themselves to the production of law-like generalizations of the sort (ostensibly) found in physics or chemistry. And very few medical interventions work for all patients, without qualification. To return to the quality improvement case, there is a sense in which knowledge is gained through the investigation—something new is learned about whether surgical checklists work in this specific location—and the knowledge is intended to generalize—for instance, across other operating rooms in that facility. Is this not (at least locally) generalizable knowledge, then? Many people seem to want to say “no” here but struggle to find a clear rationale for their position.

The challenges encountered thus far in our efforts to define research indicate that a new strategy is in order; accordingly, let’s turn back to our original question—“What is human subjects research?”—and ask why we are seeking an answer to this question. Perhaps the question is ill-conceived, or perhaps our aims will help guide us toward one of these imperfect options or even something better. What are the stakes here? Why does it matter what counts as human subjects research? Why would anyone resist having their actions labeled “research”?

The common answer to this question—the one potential researchers themselves would likely be quick to offer—is that it matters because activities that are considered research involving human subjects must undergo review by a research ethics committee (REC) and secure approval before recruiting any participants. 1 In other words, there are regulations in most jurisdictions requiring that certain types of activities are subject to independent oversight. According to the TCPS 2 in Canada, for instance, “A determination that research is the intended purpose of the undertaking is key for differentiating activities that require ethics review by an REB and those that do not” (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada 2018 , 14). 2 A common rationale for this is that the primary aim of research is to gather knowledge to benefit people other than those in the study itself. By contrast, clinical practice, which also involves human subjects, is regulated differently (and with much less direct oversight)—by expectations that professionals will adhere to professional norms and guidelines. Because the aim of practice is benefit for the particular patient, it is thought that fewer or at least different ethical concerns arise. Similarly, other professions, like journalism, have their own sets of norms and rules guiding their activities, tied to their specific aims. The special ethical oversight of research activities is relatively new, in historical terms, since national regulations on human subjects research were enacted in most jurisdictions, in response to the public outcry over publicized cases of abuse of research subjects (for more on this, see the opening chapters of this handbook). When these regulations were proposed, those who drafted the regulations were acutely aware of the need to avoid encroaching on other domains of professional activity—particularly clinical practice (Beauchamp and Saghai 2012 ).

From the earliest attempts to offer a research–practice distinction it was clear that there would be troublesome boundary cases. 3 Phase I (or “first in human”) clinical trials—famously, those in pediatric oncology—tend to enroll patients who have cancer (not healthy subjects), and when there is no other treatment option available for that form of cancer, the research looks pretty much identical to practice (Kass et al. 2013 ). These sorts of activities might be thought of as “therapeutic research,” “innovative therapy,” or “unvalidated practice” depending on one’s orientation to the research–practice distinction. Other boundary cases recognized by early scholarship in this area included what would now be considered a type of comparative effectiveness research, in which two widely available treatments are compared to see which performs better, and quality improvement activities, in which healthcare systems experiment with new rules or guidelines in order to see how well they work in local settings (Beauchamp and Saghai 2012 , 49). Note that it is a necessary, not merely accidental, feature of such activities that they are in some sense both research and practice simultaneously. Phase IV studies are also often ambiguous—depending on how rigorously they are designed, they may also look simply like tracking adverse events in clinical practice. So while research has been defined in terms of its distinctive aim, the distinction is fuzzy and contested; and it continues to be plagued by borderline cases. 4

Note also that the way research was defined for regulatory purposes—against medical practice in particular—meant that the resulting distinction tracked the activities of greatest ethical concern in the medical context specifically. But human subjects research is a much broader category than simply medical research: there are a range of ways in which human subjects may be subjects of studies, including, for instance, in social scientific research. Because this type of research is helpful for understanding the stakes of getting the answer to the title question right, I will outline briefly the social scientific backlash to research ethics oversight, which typically involves delays associated with the prospective review of proposed research and some of the ways that ethics regulation has adjusted to accommodate the range of different types of investigations involving human subjects.

Cases from the social sciences are among the more prominent examples of controversial research in the twentieth century: the Milgram experiment on obedience to authority and Zimbardo’s prison experiment with students assigned to the role of prisoner or guard might come to mind (Haggerty 2004 ). Given that the outcry about the abuse of human subjects in medical research happened around the same time in many jurisdictions (roughly the 1970s), it is no surprise that ethics regulations were developed and applied across all domains of research with human subjects, including social science research. Resistance to these regulations is common, particularly (though not uniformly) in the social sciences, where being lumped in with medical researchers strikes many as bizarre overreach: “What began years ago as a sort of safeguard against doctors injecting cancer cells into research patients without first asking them if that was OK has turned into a serious, ambitious bureaucracy with interests to protect, a mission to promote, and a self-righteous and self-protective ideology to explain why it’s all necessary” (Becker 2004 , 415). Becker is referring here to what he calls “ethics creep,” which involves “a dual process whereby the regulatory system is expanding outward to incorporate a host of new activities and institutions, while at the same time intensifying the regulation of activities deemed to fall within its ambit” (Haggerty 2004 , 391).

A common critique raised by social scientists hinges on the inconsistency between the way different professionals, for instance, journalists and academic social scientists, are treated under current regulatory schemes. The very same activity—interviewing people, for instance—seems to trigger extensive and burdensome oversight when conducted by social scientists even though journalists proceed much more freely. In locating the problem with this arrangement, Haggerty draws attention to precisely the problem identified in this chapter, namely that central concepts like research are poorly defined in documents regarding the ethical regulation of research; they are “empty signifiers, capable of being interpreted in a multitude of ways, and occasionally serving as sites of contestation” (2004, 411). Interpretation is required, and because members of RECs feel responsible for protecting people, they tend to take what he calls a “just in case” approach, in which research is interpreted inclusively (and over-broadly) (2004, 411). This means that social scientists may be subject to extensive oversight.

In 2004, Haggerty articulated his concern as follows: “Over time, I fear that the [REC] structure will follow the pattern of most bureaucracies and continue to expand, formalizing procedures in ways that increasingly complicate, hamper, or censor certain forms of non-traditional, qualitative, or critical social scientific research” (pp. 392–393). This has also been referred to as part of the expansion of neoliberal audit culture and identified as part of the increasing bureaucratization of academia (Taylor and Patterson 2010 ). In response to this perceived ethics creep, some social scientists have called for “creative compliance” or even outright resistance to ethics regulations. One option—reclassifying one’s research as performance art (or some other unregulated activity) is offered with a wink, but behind closed doors researchers will sometimes admit using such tactics (Haggerty 2004 , 408). These efforts have in some cases been met with further regulation: “As some of us have tried new dodges to skirt the requirements, the [RECs] have wised up and closed loopholes” (Becker 2004 , 415).

Yet against these dire predictions and in response to the outcry and backlash generated by social scientists in the wake of early, more heavy-handed and medically oriented regulatory approaches, regulations (and their interpretation) have shifted in the opposite direction in many jurisdictions (for an overview of international regulations, see the chapter by Nelson and Forster in this handbook). In Canada, for instance, the most recent version of the TCPS 2 takes a proportionate approach to the review of research:

Given that research involving humans spans the full spectrum of risk, from minimal to significant, a crucial element of REB review is to ensure that the level of scrutiny of a research project is determined by the level of risk it poses to participants. … A reduced level of scrutiny applied to a research project assessed as minimal risk does not imply a lower level of adherence to the core principles. Rather, the intention is to ensure adequate protection of participants is maintained while reducing unnecessary impediments to, and facilitating the progress of, ethical research. (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada 2018 , 9)

As this statement indicates, while all research is held to the same high ethical standard, research of minimal risk is thought to require a lower degree of oversight. Ethics review in Canada begins with a determination that the activity is in fact research with human subjects; activities described as falling outside of the definition of research include the sorts of quality improvement activities outlined in the hospital administrator case and “creative practice activities” such as those undertaken by artists (p. 19). 5 Next, some activities that meet the definition of human subjects research are automatically exempt from review, including 1) research that relies entirely on legally accessible, publicly available information where the individuals have no reasonable expectation of privacy and 2) exclusively observational qualitative research conducted in public places where there is no reasonable expectation of privacy and individuals are not identified in the written report (pp. 15–18). This will cover much of the research conducted by historians and some observational studies conducted by social scientists, educators, etc.

At this point, if an activity is considered research and not exempt, it may still be afforded an expedited (“delegated”) review if it is low-risk: according to Article 6.12, “In keeping with a proportionate approach to research ethics review, the selection of the level of REB review shall be determined by the level of foreseeable risks to participants: the lower the level of risk, the lower the level of scrutiny (delegated review); the higher the level of risk, the higher the level of scrutiny (full board review)” (p. 79). In delegated review, the committee assigns one member (or some equivalently qualified person) to assess the proposal rather than assessing it all together. A negative assessment at this stage refers the study back to the full committee for review. Because social scientific research is more likely to be minimal-risk than medical research, it is well positioned to benefit from delegated review. Canada is not unique here: similar exclusions and exemptions typically exist in other national regulatory systems. And in some jurisdictions they are even broader: in the United States, for instance, public health surveillance, criminal justice, and intelligence activities are all excluded from the domain of “research” and exemptions (activities requiring only “limited review”) are offered for most interview- and survey-based research, secondary research even when it uses identifiable private information or biospecimens, and “benign behavioral interventions” (Coleman 2019 , 248). This is a more permissive approach, overall, than the one found in Canada, and the trajectory seems to be generally in the more permissive direction over time.

At this point, we have enough background about the relationship between research and regulation to return to our question about the stakes of this discussion: why would someone wish to avoid having their activity labeled research? The answer given by some investigators is that they might resist if they think there are immediate, and burdensome, regulatory implications. A few things can now be said about this. First, it may be the case that there were times and places where the burdens of regulatory oversight were heavy even in the face of minimally risky activities or where the interpretation of regulations was overzealous. But it is unlikely to be true today—most systems have built-in exemptions and expedited processes for these sorts of cases, as the Canadian example makes clear, and discrepancies in interpretation between RECs have had time to resolve. In the face of complaints from researchers, it is good to look closely at the current local regulations and the way they are implemented. Second, in some jurisdictions today there are known inefficiencies in the regulatory oversight system—this occurs for a wide range of reasons but particularly because the process typically relies on volunteer labor and can involve reading hundreds of pages of detailed, technical proposals at a time. As a result, there are sometimes long delays, and researchers are entirely within their rights to complain about this, though they should be careful about selecting an appropriate target of criticism, whether that’s the local REC or the system within which RECs operate. Further, instantaneous processing of files would be unreasonable on the part of researchers, so negotiation will be needed to find a reasonable timeline, given shared goals. 6 Finally, some of the resistance likely arises from a misunderstanding about what ethics is and how it operates in the world. This requires some attention.

For many researchers, regulatory oversight has become synonymous with ethical assessment. You might hear a hint of this when researchers talk about “getting through ethics,” “waiting for ethics,” or claiming to have “completed ethics” once they have received approval from an ethics board for their study. A similar sort of reduction of ethics to a formal process sometimes occurs in contexts where healthcare providers seek informed consent: they may talk about “consenting the patient” in advance of a procedure, for instance, which is typically reduced to having the patient sign a legal document. It is important to appreciate why this position is indefensible—why legal paperwork or regulatory approval isn’t in any meaningful way a substitute for ethics, understood properly.

To begin, consider a study that has received ethics approval and yet which, when it is actually carried out, has risks that are unreasonably high (perhaps most subjects enrolled will die) a flawed design (perhaps it is not possible to achieve statistically significant or otherwise meaningful results), subjects are told they can’t leave the study once enrolled (violating the voluntariness of their ongoing consent), or the particular individuals in the study are easily identifiable in the published final report (violating their privacy). That study is unethical, in spite of having received approval from an ethics committee. Any number of things may have gone wrong here. First, like all human activities, review is fallible, and sometimes committee members will make mistakes. Sometimes the mistake will be in applying the rules, but at other times the mistake might be in the rules themselves. The particular rules applied by any ethics committee are open to debate, discussion, and revisions in light of new developments in scientific or ethical domains. The regular updates to codes of ethics such as the “Declaration of Helsinki,” currently in its seventh revision since 1975, provide some indication of the rate of change in these domains. Second, the researchers may have provided only a general description of certain activities (such as the trial design or informed consent process) in their application to the ethics committee and then, in specifying these matters later on, made poor choices. Third, researchers may simply have deviated from what they promised to do in their application to the ethics board. The research process relies on a certain amount of trust and good will between reviewers and researchers, and this can be violated by unethical or incompetent researchers. Approval by an ethics committee, then, is not all there is to an assessment of whether some activity is actually ethical .

Awareness of this simple fact helps us to see the dangers of thinking that classifying something as research means a particular set of ethical rules applies that wouldn’t otherwise. Codes of ethics aim to identify and articulate ethical principles or rules, and ethics committees do their best to interpret and apply these general principles to particular cases. But whether those committees existed in the middle ground between principles and action or not (and until recently, they didn’t), ethical principles would still apply to certain activities whenever those activities had certain features. Research with human subjects, as noted, aims at generalizable knowledge, and it typically “uses” those subjects to get knowledge. Along the way, the subjects may be made better or worse off, and any interaction where people make others worse off raises ethical concerns about harms such as exploitation and disrespect. Think about the contrast between paradigmatic cases of medical practice and medical research here—in practice, a healthcare provider aims primarily to benefit the patient, while in research, they aim primarily to generate new knowledge. When getting new knowledge requires the use of another person’s body, it seems clear that we’re in risky ethical territory.

Another way of appreciating the scope of ethics as something far bigger than ethics regulations is to think about the fact that regulations won’t specifically state things like “don’t murder your subjects” or “don’t steal the personal belongings of your subjects” because these ethical prohibitions are thought to be covered by existing criminal laws and not in need of restating. There are many ways to be unethical beyond those listed in codes of ethics because those codes are only part of a larger social system.

Further, some of the ethical rules present in codes and guidelines arise because of the place of research within society and not merely because it is a transaction between individuals. Research proceeds only with the cooperation and support of the societies in which it is conducted, which provide funding, regulation, legal protections, social and physical infrastructure, potential subjects, and more. The requirement that research is socially valuable—that it contribute to knowledge on the topic and directly or indirectly benefits society—is one such rule imposed on research with human subjects (you can read more about this requirement elsewhere in this handbook). The requirement that research is scientifically valid—including the expectation that methods are rigorous and results are meaningful—draws on norms of science developed independently by scientists, which prioritize epistemic values such as fruitfulness, scope, and accuracy in theory construction. Scientists are also held to ethical restrictions around activities considered research misconduct, such as plagiarism, fabrication, and falsification, even though these activities aren’t listed explicitly in codes of ethics for research with human subjects.

Professional Ethics

We’ve been discussing, and trying to articulate the problems with, a particular resistance to being labeled research that results from a misunderstanding about how ethics operates in the world. Hopefully the responses to this argument have been convincing thus far. There is, however, a more nuanced version of the position remaining: some investigators might resist the research label because they believe they are governed by codes of ethics developed prior to current codes and articulated within their professions and see the bureaucracy associated with contemporary ethics review as a less nuanced and perhaps even misleading way to go about thinking through the ethical dimensions of their work. They see a perfectly functional self-regulating profession taken over by people with little or no understanding of the nature of their work or the subtle and precise responses to ethical dilemmas they’ve developed over time.

For example, journalists have ethical norms prioritizing the protection of sources—these norms evolved because of social-historical cases where harm arose (in the extreme, people who were killed when they were identified after a story was published) and a recognition of the need to avoid those harms going forward. This ethical rule for journalists is tied to what is valuable about the activity (here: truth) and a recognition of particular harms that could arise in telling the truth (here: people who assisted in exposing the truth could be killed). If you want to proceed with an activity that involves interaction with other people (maybe even in some sense “uses” them to gain knowledge) but in that interaction, or afterward, those people might be harmed, you should probably ask how that harm can be minimized. Responsible professionals in a range of domains have engaged in this thoughtful work for decades and even centuries. Anthropologists, for instance, have been reflecting about the particular ethical duties arising from ethnography since the method was developed, such as the shifting loyalties that result from the close relationships formed during fieldwork, and the desire of state entities to access and direct their research to secure information from enemies during wartime (Fluehr-Lobban 2002 ).

A decisive response to these concerns is unnecessary here: it is sufficient for the purpose of this chapter that we are aware of them. It is a matter of ongoing discussion in a range of human domains whether certain activities should be regulated or not or whether they should be regulated using one set of rules or another. In general, the position taken by liberal democratic states is that professions and industries with a history of serious harm to citizens have forfeited their right to self-regulation. Research on human subjects has a sufficiently sordid history to qualify here. Whether this inappropriately covers social scientists or others will likely be a matter for further debate. For our purposes, what is important is that we recognize that ethical rules apply regardless of which set of regulations is in force (state-imposed external ethics review, professional codes of ethics, or novel alternative oversight mechanisms). So while the stakes of the discussion are high in the sense that they determine this regulatory path, they are not as high as people tend to think because the ethical rules will apply regardless. Being labeled performance art rather than research might mean you avoid filling out some forms, but it won’t on its own change the nature of your ethical obligations since those arise out of the type of activity planned and its aims and consequences.

In sum, the best response we have to the question “What is research?” is probably that research aims to produce generalizable knowledge, but it is important to recognize that this is an imperfect definition and leaves open a range of debates, including those related to the correct interpretation of “generalizability.” It is also important to recognize that answering this question may not be the best way to decide what systems of accountability ought to track the ethical issues that arise in knowledge-gathering activities; it is worth always keeping in mind that a range of regulatory mechanisms are possible. We have also defused some of the anxiety around responses to this question by tracing and responding to some of the reasons for resistance to the label. The ethical principles arising from an activity aren’t invented and dictated by RECs—they apply whether an activity is labeled research or not and whether it is regulated as such or not. There is room for critical engagement here, but at the end of the day there’s just no escaping ethics.

Human Subjects

I have indicated that there is debate over not only what counts as research, as we’ve just seen, but also who is included in our discussions of human subjects. There are two versions of the question “Who are human subjects?,” each of which raises distinct ethical issues. First, we might wonder which humans end up being research subjects. Is there a paradigm or “model human” researchers have in mind? Are there some humans on whom research is forbidden or significantly restricted? Where are human subjects located globally, and how is this changing? Is there a shortage or surplus of human subjects available for research? How many people are research subjects annually? Depending on the answers to these questions, how might we assess the fairness of the burdens and benefits of research participation? This version of the question raises issues about representation in research as well as more general concerns of distributive and social justice.

Second, we might wonder which subjects are included in discussions of human subjects research. Are any of the following included, for instance: fetuses, embryos, brain-dead humans, cadavers, human organs or tissues, reproductive tissues, or stem cells? And, particularly if some of these items are included, why stop at the boundary of the human species? What lies behind the strict demarcation between human and nonhuman animals as subjects of research? Thinking more broadly, what are the implications of various positions on this matter for research on (hypothetical) conscious, sentient robots or aliens? This version of the question raises issues of moral status. I’ll outline both of these sets of issues.

Which Humans?

The human subjects of research have not always been representative of the diversity of humanity or even of the local populations within which research was conducted. The tendency of Western researchers (white men, for the most part), prior to ethics regulations, to seek out vulnerable populations such as prisoners, children at boarding schools, hospital patients, sex workers, citizens of other countries, racial minorities, and impoverished persons (and especially people at the intersection of these categories) for inclusion in research is well documented. The attraction of these groups was precisely their vulnerability—the fact that it was difficult or impossible for them to refuse involvement, for instance. Early responses to this situation focused on protections for variously identified vulnerable populations. While these concerns persist, and took on new life when multinational research became more common in the 1990s, another concern about representation has arisen more recently: the underrepresentation of certain groups in research. While the first set of concerns track disproportionate burdens of research participation, the second set tracks the lost benefits of research participation. The ethical assessment of the former actions—essentially, preying on the vulnerable—is more easily appreciated, so I’ll say a bit about the latter problem. Failing to ensure that subjects are representative of particular groups can lead not only to missed opportunities to benefit those populations but also to direct harm when research is falsely generalized across that group, as when a drug with positive results in one group is dangerous or toxic to another.

Women were underrepresented in clinical research in the United States (and elsewhere) until at least the 1990s. As a result of improved regulations, the United States has shifted toward more equitable inclusion of women in publicly funded clinical trials, though most studies still fail to analyze results by sex/gender in spite of the recognized benefits of doing so (cf. Geller et al. 2018 ). This is a development worth noting, but it is important to keep in mind that this tracks only clinical research, funded publicly, in one country. We shouldn’t assume the underrepresentation of women in human subjects research has been resolved or even that sensible extension to related domains has been made—the selection of exclusively male mice for animal research continued for many years after these changes were made to human subjects regulation and is still the status quo in many countries and contexts (Shansky 2019 ). The attempted justification for these exclusions has been decisively refuted in the literature dozens of times. Addressing one common mistake clearly driven by outdated gender norms, Shansky reminds us, “Women, but not men, are still pejoratively described as hormonal or emotional, which curiously neglects the well-documented fact that men also possess both hormones and emotions” (2019, 825). The resulting imbalance has affected research in many fields that continue to rely on animal studies such as neuroscience, endocrinology, physiology, and pharmacology. As a result of the exclusion of female mice from neuroscience research, and because research in animals provides the foundation for clinical trials, “the current understanding of how to most effectively treat disease in humans is similarly unbalanced” (Shansky 2019 , 825).

Over the past five years, Canadian and American funding bodies have introduced new requirements for researchers to consider sex as a biological variable in animal studies, and similar efforts have been made by the European Commission (Shansky 2019 ). Of course, sex/gender is not the only characteristic that has been unequally distributed in research studies. The same arguments offered in support of ending the exclusion of female animals from animal research and women from clinical research have been marshaled in favor of improving the inclusion of children, pregnant women, and specific ethnic minority groups (for instance, particular indigenous groups in Canada) with limited success. As mentioned, these exclusions have the potential to lead to significant harm to these populations, particularly in clinical practice since interventions never tested on a population may turn out to have more harms than benefits, and the lack of information about effects of treatments in that population might leave clinicians and others uncertain about how best to act even when acting quickly is critical. It may also simply be unjust in its own right to exclude people from research that might benefit them.

In addition to the explicit long-standing exclusion of particular identifiable groups, such as women, researchers have excluded populations indirectly by, for instance, preferring subjects who are healthier, are younger, and have fewer comorbid conditions. One result of these exclusions has been an underrepresentation of elderly people in clinical research. Because underrepresentation in research means the bench-to-bedside knowledge translation gap is bigger, this likely means elderly people are missing out on certain health benefits. And they aren’t the only ones losing out on benefits: clinical research subjects are not generally representative of a large percentage of the patient population for whom the interventions are intended. For instance, Humphreys and colleagues found that “highly cited trials do not enroll an average of 40.1% of identified patients with the disorder being studied, primarily owing to eligibility criteria” (2013, 1030). Other identifiable groups who may be affected by exclusions indirectly are people whose immigration status is uncertain, people who don’t speak the local language, and people who live far from the urban centers where much research occurs. Who is overrepresented in studies, then? People from “Western, Educated, Industrialized, Rich, and Democratic . . . societies” (Henrich, Heine, and Norenzayan 2010 , 61). The 2019 World Health Organization’s World RePORT , drawing on data from 2016, indicates that the recipients of research funding from the top 10 funders globally continue to be mostly institutions and investigators in North America and Europe working on non-communicable diseases (World Health Organization 2019 ).

While this is true today, some things are changing. Though most clinical research (approximately 70 percent) is still conducted in North America and Europe, “significant West-to-East and North-to-South shifts appear to be underway” with researchers looking increasingly to Asia, Africa, South America, and eastern Europe (Sismondo 2018 , 55). One reason this is thought to be happening is that researchers are keen to find countries where the medical system is advanced enough to locate their trials, with access to a large population, but at the lowest cost possible. According to Sismondo, costs per subject in clinical trials are estimated to be 30–50 percent lower in India than in North America or western Europe (2018, 55). Researchers are also interested in finding populations where individuals are not already taking other medications, and countries like India may have a greater proportion of subjects like this (Sismondo 2018 , 54). There are also more altruistic motives: low- and middle-income countries (LMICs) have particular health problems, and some researchers in high-income countries (HICs) may have an interest in helping to alleviate those problems, such as high rates of HIV transmission, epidemics such as the recent Ebola outbreaks, neonatal disorders, and neglected tropical diseases. Research in developmental economics suggests that these motives and effects can also be mixed in quite complicated ways: for instance, aid organizations may seek to alleviate global poverty and design studies to inform this effort but, in doing so, also reinforce the continued existence of their organization, create cycles of dependency, or perpetuate assumptions about the lack of knowledge or expertise in targeted populations.

Another reason for this global shift is that researchers often report difficulty recruiting subjects in HICs. For example, according to McDonald and colleagues ( 2006 , np), for multi-center RCTs funded by two UK funding agencies, “Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials.” In general, “Recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged” (McDonald et al. 2006 , np). This shortage of (appropriate) research subjects is of interest to research ethics because it can drive the demographic shifts just described, which raises concerns about potential exploitation of subjects in multinational studies. It also arguably lends further support to the social value requirement of research since a resource shared by all researchers (including industry researchers) is in limited supply: human research subjects. Perhaps this means lower-value research ought not to be conducted, or the bar for what counts as a sufficiently socially valuable study should be raised (Borgerson 2016 ).

The relationship between funders, researchers, and subjects is also of interest to bioethicists. One of the reasons ethical concerns arise in LMICs is that the research is often funded and designed in HICs, and this raises worries about potential exploitation. Another concern arises when the results of the research conducted in LMICs won’t benefit other people in those same populations. One of the reasons given for the increased interest in conducting research in LMICs is that populations are “treatment-naive”—this means in general they don’t have access to healthcare, and they are likely to be unable to afford whatever treatment emerges from the research if it is successful. This feature of multinational research has generated extensive discussion among bioethicists, many of whom now agree that research should be responsive to the health needs of local populations if it is to avoid charges of exploitation. Yet this worrisome overview of the global situation was provided in 2013:

Total global investments in health R&D (both public and private sector) in 2009 reached US$240 billion. Of the US$214 billion invested in high-income countries, 60% of health R&D investments came from the business sector, 30% from the public sector, and about 10% from other sources (including private non-profit organisations). Only about 1% of all health R&D investments were allocated to neglected diseases in 2010. Diseases of relevance to high-income countries were investigated in clinical trials seven-to-eight-times more often than were diseases whose burden lies mainly in low-income and middle-income countries. (Røttingen et al. 2013 , 1286)

Dandona et al. also found that research priorities were misaligned with the health needs of the local population in India specifically: “funding for some of the leading causes of disease burden, including neonatal disorders, cardiovascular disease, chronic respiratory disease, mental health, musculoskeletal disorders and injuries was substantially lower than their contribution to the disease burden” (2017, 309). The gap between funding priorities and disease burden has been of interest to economists, political scientists, and bioethicists alike for many years.

A roughly 70/30 split between industry funding and other sources is common in clinical research. Of the US$1.42 billion spent on health research in India in 2011–2012, “95% of this funding was from Indian sources, including 79% by the Indian pharmaceutical industry” (Dandona et al. 2017 , 309). In the United States, “Principal research sponsors in 2003 were industry (57%) and the National Institutes of Health (28%)” (Moses et al. 2005 , 1333). Even though there seem to be shifts underway toward more industry-sponsored research in the clinical context, practicing physicians are still a vital part of research, often supplying the subjects for research:

Currently, about three-quarters of studies in the United States are conducted in the private sector by non-academic physicians who recruit their own patients or local community members into drug studies. Over 60,000 of these studies take place in the United States each year, accounting for 75 percent of the 80,000 clinical trials conducted worldwide; to execute these studies, more than 50,000 U.S. physicians registered with the Food and Drug Administration (FDA) as principal investigators on one or more clinical trials in 2001. As for the human subjects, 3.62 million Americans participated in pharmaceutical clinical trials in 2003 alone. (Fisher 2009 , 2)

The particular ethical obligations arising from the dual role of physician-investigators, such as the need to balance a commitment to doing what’s best for the patient with an interest in seeking knowledge, have received attention from bioethicists, as have the financial conflicts of interest arising when physicians play not only these two roles but a third role in their relationship to industry sponsors.

Another matter of interest to bioethicists is that there are some people who make a career out of being research subjects. Some of them self-identify as “guinea pigs for hire” and seek participation in phase I studies (on healthy subjects) (Lemmens and Elliott 2001 ). The inclusion of these people in studies raises ethical issues about appropriate compensation (whether wages and benefits or payment), undue inducement (if the payment is thought to be too high), scientific validity (whether people strongly oriented to please researchers so that they may be hired again will be more inclined to deceive researchers, for instance), upper limits of risk for studies under conditions of informed consent, and social justice and fair subject selection (since career research subjects tend to be from particular demographic groups, such as homeless people and students). For more on this issue, see the chapter by Fisher in this handbook.

Finally, a note about the number of research subjects: the research enterprise is massive and enrolls millions of human subjects every year. It is surprisingly difficult to get a clear picture of the enterprise globally (for more on why, see Young et al. 2015 ). Our best estimates come from clinical research: drawing on the 2009 CenterWatch Sourcebook, Sismondo suggests that, while estimates vary widely, there are approximately three to six million subjects involved each year (2018). And these numbers seem to be increasing. If we were able to add in figures from research in the social sciences, these numbers would skyrocket. In fact , you might be a research subject right now : there is ongoing debate over whether the tactics used by social media sites to track and manipulate their users qualify as human subjects research. If they do—and this turns partly on how we settle the issues raised in the first part of this chapter—we might find out that many of us are unwitting research subjects.

Which Subjects?

Who counts as a human subject of research? Codes of research ethics are often inclusive in their definition, for instance: “The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects , including research on identifiable human material and data ” (World Medical Association, 2013 , 2191, emphasis added). Codes that initially had a narrow focus on medical research have expanded over time to cover new areas, for instance, increasing interest in the storage and use of biospecimens in research (biobanking) led CIOMS to merge its ethical guidelines for epidemiological research and biomedical research in 2016 (CIOMS, xi). Guidelines for research on human subjects are likely to be inclusive about who or what counts as a subject because many of the same ethical issues—privacy and informed consent, for instance—arise whether the subject’s body, tissues, or data are manipulated. In jurisdictions like Canada “human subjects” includes embryos and cadavers, though in the United States (ex vivo) embryos and cadavers are excluded from the definition. This doesn’t necessarily mean the use of cadavers, for instance, is unregulated but rather that it may be regulated differently. In all cases, the potential for harm to an identifiable person raises ethical concern.

If a central focus of research ethics is the prevention or minimization of harm, what then are we to make of the differences between the way humans and nonhuman animals are treated by researchers? The latter are not regarded as human subjects, even on inclusive definitions. And yet the “vast majority of biomedical research activity is conducted on animals or their tissues, cells, or even parts of cells” (Levine 2008 , 214). While research on human subjects is guided by ethical principles such as respect for persons, informed consent, fair subject selection, and a favorable risk–benefit ratio, research on nonhuman animals is typically governed by different approaches, such as the 3R framework: reduction (in numbers of animals used), refinement (improving the conditions for the animals), and replacement (using animals with lower capacity for pain or computer models when possible). Clear demarcation criteria, separating humans from other animals, have been very hard to come by, particularly as researchers discover more about the intellectual, emotional, and social capacities of a wide range of animals from crows to chimpanzees to elephants. The issue of which beings “count” morally, then, is unsettled, and as a result these divisions between the ethical principles applied in each domain rest on unsettled foundations.

It is good to keep this in mind because for many areas of research from neuroscience to immunology animal research is the basis for human research. You can’t typically propose a clinical trial on humans without convincing evidence from animal studies that the intervention might be successful. This expectation persists even though animals are never going to be ideal models for human behaviors, diseases, or functions—the ideal model for humans is humans. The reason why research doesn’t just skip over animals and start with humans, then, is ethical: it is thought to be acceptable to subject animals to risks that we find unacceptable for humans. There are deep and important issues here regarding the relative value of different lives. These issues surface in research ethics when trade-offs are proposed between human and animal studies. For instance, if “higher-level” animals like chimpanzees are no longer used in animal research (for ethical reasons), this may mean that the results from studies on the replacement animals (e.g., mice) lead to more uncertainty in the leap from animal to human studies. But this is at odds with a commitment to reduce harms to human research subjects. It will not be straightforward to find the right ethical path through these trade-offs (for one recent attempt, see Johnson and Barnard 2014 ). But if it is concern about harm to the interests of sentient beings that drives us toward research ethics oversight, we can’t proceed without attending to these difficult decisions. In the discussion of human subjects of research in section 2.1, I reviewed concerns about exploitation that arise when one group is harmed for the benefit of another. If the moral status of animals is even somewhat higher than that of inanimate objects, similar issues will arise when humans extract knowledge for our benefit from the bodies of animals.

In the future, we may have to decide how and whether to proceed with research on advanced forms of artificial intelligence or other nonhuman intelligent beings. So these gaps and unsettled foundations might matter to whether our current divisions between humans and other species are defensible in the long run.

In sum, neither “research” nor “human subjects” is easily defined, and efforts to use these concepts to draw black-and-white ethical lines around activities will struggle with a continuous and growing body of boundary cases. This is a productive realization since it helps us to see the gaps in current regulations (ethical concerns extend far beyond those captured in such regulations) and envision and work toward more efficient and nuanced systems of ethical accountability, such as those aspired to in systems aiming for the deep integration of research and practice (for more on these alternatives, see the chapter by Kim in this handbook). But it is also helpful for those of us working within current systems since it reminds us of the need to keep our focus on what we’re worried about, whether that’s exploitation, disrespect, scientific misconduct, power imbalances within relationships, conflicts of interest, violations of privacy, injustice in the selection of research participants, or opportunity costs when healthcare resources are used inefficiently. And our worries need to be responsive to an ever-changing reality: the internationalization of research, in particular, may well create new incentives (or reinforce existing incentives) that push researchers toward activities that breach different ethical principles or breach well-established principles in new ways. We will always need to be ready to provide timely, creative, and well-grounded responses to new ethical violations.

This chapter aimed to accomplish two things: 1) provide an overview of the scope and practice of research with human subjects and 2) highlight some of the philosophical issues raised by any attempt to provide such an overview. Let us return to our opening cases to see if we can apply what we’ve learned. Using the aim of generalizable knowledge as an initial sorting mechanism, it seems all cases except the family physician who “experiments” with different treatments will qualify as research. This is consistent with most regulatory assessments (keeping in mind they will then exclude and exempt some research from review). And all interventions involve human subjects directly or—in the case of blood samples—indirectly and so would likely be included because identifiable individuals raise ethical concerns about consent and privacy. Embryo research is a tough case, and different jurisdictions and different scholars handle it differently; we didn’t attempt to settle the issue here. Note that while most of the cases turn out to be human subjects research on the most common definitions, we are left with lingering worries—for instance, why does the clinical practice case change from practice to research when it is written up for publication—forget about the regulations, what changes here ethically ? Hopefully it is clear that while some things are settled in this domain, there is still much to work out. As is so often the case in philosophy, even the simplest question—"What is human subjects research?”—is harder to answer than it seems.

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I use the generic term “research ethics committee” in this chapter to refer to the committee providing prospective ethical review of research. In some jurisdictions these have other names, such as “research ethics boards” or “institutional review boards.”

The document goes on to say, “In some cases it can be difficult to make this distinction, underscoring the need to have reviewers or ad hoc advisors . . . who can assist with this determination” (p. 14). This highlights a lesson articulated in this section of the chapter: it is not easy to determine which activities are “research.”

I use the term “boundary cases” here to refer to any study designs that can’t be easily classified as “research” or “practice.” As the examples indicate, this includes “hybrid” or “overlap” activities which intentionally blend research and practice, such as those found in proposed models for learning health care systems.

This is one of the (many) reasons why scholars are so interested in the design and pursuit of learning health care systems in which the research–practice distinction is downplayed or eliminated and new mechanisms of accountability are explored. This and related issues are discussed by Kim elsewhere in this handbook.

The TCPS 2 has a very specific scope: it only covers research funded by the three federal funding agencies in Canada. Other parties, such as independent or private researchers and funders in Canada, typically agree to abide by these rules; but only researchers funded through these agencies are strictly bound by them.

A recent court decision in Newfoundland and Labrador, Canada, for instance, sets this “reasonable” window at 30 days (CBC News 2019 ).

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• v.20(1); Spring 2020

Why Human Subjects Research Protection Is Important

Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study. The road leading to the current regulations and ethical considerations has been long and checkered.

Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations.

Results: Key documents—from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011—that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research.

Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research. The examples also reinforce the importance of individual responsibility. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities.

INTRODUCTION

Participation of human subjects in research presents a challenging ethical dilemma. A research subject may be asked to participate in a study of no benefit and no substantial risk or in a study with the potential for significant benefit but also significant risk. In placebo-controlled studies, subjects may be exposed to significant risk for no benefit to the individual. These variants are confounded by treatment protocols—most commonly encountered in oncology trials—that compare the effect of an investigational arm to the standard of care, further blurring the distinction between research and medical treatment.

Institutional review boards (IRBs) have the federally mandated responsibility to review research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in the study. The road leading to the current regulations and ethical considerations has been long and checkered. The system that has evolved minimizes the risks for unethical behavior and serious adverse events but is not infallible. Understanding how we have arrived at the current approach and analyzing some of the ethical lapses that directed this course support efforts to continually reevaluate the regulations in order to improve the safety of subjects who are willing to participate in research activities.

EVOLUTION OF HUMAN SUBJECTS PROTECTION

Our current approach to human subjects protection has evolved with efforts to understand questionable ethical behavior in research over the course of several hundred years. One might suggest that the jester conscripted to sample the king's food to ensure that it was safe to eat presaged the use of vulnerable populations as subjects for research, but the evolution of the management of smallpox is perhaps a more applicable early perspective on research in humans. Three centuries ago, reports of good outcomes following variolation—inhalation of the scabs from persons infected with smallpox—were circulating in Asia. In 1717, Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey, became an advocate of variolation after learning about it in Constantinople. In 1721, after she returned to England, Lady Montagu and the Princess of Wales urged variolation of “several prisoners and abandoned children” by having smallpox scabs inserted under their skin. Several months later, the children and prisoners were deliberately exposed to smallpox. When none contracted the disease, the procedure was deemed safe, and members of the royal family were treated according to this new protocol. 1

Later that same century, Edward Jenner developed inoculation with a vaccine. Many of his contemporaries had noted that milkmaids who had contracted cowpox seemed immune to the much more lethal smallpox. In May 1796, Jenner isolated material from the cowpox lesions on the milkmaid Sarah Nelms and inoculated 8-year-old James Phipps who developed fever and malaise about 9 days after the inoculation. Some accounts report that Phipps was the son of Jenner's gardener. A few months later, Jenner deliberately inoculated Phipps with material from fresh smallpox lesions, and the child remained healthy. The adoption of this process was not immediate but slowly spread and is widely cited as the first scientific approach proving vaccination. 2

This early use of children and prisoners portends a long history of selecting what are now considered vulnerable populations to be the subjects of research. Participation was commonly without consent, with no knowledge of their participation, and with no explanation of the research. Information was withheld from those selected to participate in research activities perceived as dangerous to more acceptable members of society, and the therapies developed were generalized only if they were proven relatively safe and effective in what are now recognized as vulnerable populations.

Numerous instances of research experiments in subsequent years exposed vulnerable subjects to risk, including a pivotal research disaster in Germany just before World War II that led to regulations for human subjects participation in research projects.

The Reich Circular of 1931

As reported by Sir Graham Wilson in the book The Hazards of Immunization , “Between 10 December 1929 and 30 April 1930, 251 of 412 infants born in the old Hanseatic town of Lubeck received three doses of BCG [bacillus Calmette-Guerin] vaccine by the mouth during the first ten days of life. Of these 251, 72 died of tuberculosis, most of them in two to five months and all but one before the end of the first year. In addition, 135 suffered from clinical tuberculosis but eventually recovered; and 44 became tuberculin-positive but remained well.” 3

Bonah and Menut describe how Albert Calmette was able to establish the BCG vaccine as a nonexperimental “prophylactic treatment” against tuberculosis. 4 By definition, a medical experiment, as opposed to any other medical action, has definite ethical implications and consequences. Even though the BCG vaccine was in experimental stages, Calmette convinced a court that the vaccine was a “post-experimental, routine medical treatment.” By avoiding the definition of an experiment, Calmette did not have to inform the children's parents about the risks of the vaccine. As a result of this tragedy, Dr Julius Moses, a critic of unethical human experimentation who referred to “experimental mania,” drafted guidelines for human experimentation. After debate in parliament and the press, the guidelines were published and became official in 1931. The guidelines applied to everyone in Germany. 5 , 6

These rules for research in human subjects were issued as the Reich Circular of 1931 ( Figure 1 ). The document is quite informative for its contrast with later events in Germany and worth reviewing for correlation with ethical concepts now well accepted in ethical thinking. It is worth noting that these guidelines emphasize special responsibilities for utilization of “innovative therapy,” suggesting a similar level of responsibility for these procedures as for research.

The Reich Circular, 1931 6

World War II and the Nuremberg Code

Despite the ethical ideals espoused in the Reich Circular, the travesty of the Holocaust followed shortly afterward, leading to war criminal trials after the surrender of Germany ended World War II in Europe.

The Nuremberg trials that began in 1945 and concluded in 1947 were held in response to the atrocities Germany committed during the war. The so-called Doctors’ Trial represents a major turning point in human research protection. Twenty-three physicians were indicted, accused of crimes against humanity by conducting criminal scientific and medical experiments on concentration camp prisoners. Sixteen defendants were found guilty. 7

Several German doctors had argued that no international law or informal statement differentiated between legal and illegal human experimentation, despite the aforementioned Reich Circular. Two US doctors who worked with the prosecution during the trial, Andrew Ivy and Leo Alexander, objected to this argument. On April 17, 1947, Dr Alexander submitted a memorandum to the United States Counsel for War Crimes outlining 6 points defining legitimate medical research. The trial verdict reiterated almost all of these points in a section entitled Permissible Medical Experiments and expanded the original 6 points into 10. These 10 points became known as the Nuremberg Code ( Figure 2 ). 8

The Nuremberg Code, 1947 10

Similar atrocities were carried out on Chinese citizens in Japanese camps; of particular note are the biological warfare experiments at Unit 731 in the Pacific theater that were obscured by agreements made during the surrender of Japan and with the complicity of the United States. 9 The details of these atrocities remained classified until they were acknowledged by Congress in the Japanese Imperial Government Disclosure Act of 2000 (Pub L No. 106-567, Title VIII of the Intelligence Authorization Act of 2000) that called for declassification and release of records related to Japanese war crimes during World War II. 10

Declaration of Helsinki

The tenets of the Nuremberg Code, while guiding the future for human research protection, represent a military code of conduct with no standing in civil international or US law. By absolutely requiring the voluntary consent of the individual, the Nuremberg Code notably does not address the needs of children or other special populations unable to provide consent. The Nuremberg Code inspired the World Medical Association (WMA)—an international association currently comprised of 114 national medical associations, including the American Medical Association—to propose a similar code of conduct for participating members by publishing the Declaration of Helsinki in 1964. This document reiterates the provisions of the Nuremberg Code and expands the provisions to allow for the participation of children and other potentially compromised subjects in research. The Declaration of Helsinki serves as a guideline for ethical research and has been amended 7 times, most recently at the WMA General Assembly in October 2013, to reflect contemporary ethical issues as they have evolved since the initial statement in 1964. 11

Ethics Violations in the United States

Meanwhile, research continued in the United States with particular concerns attached to research involving vulnerable populations, exemplified by numerous studies involving institutionalized children and studies that breached ethically sound research practices. Henry Beecher, a well-recognized physician at Massachusetts General Hospital, surveyed the contemporary literature to identify ethical concerns and organized lectures around his observations. These lectures eventually culminated in a special article published in the New England Journal of Medicine in 1966. 12

In “Ethics and Clinical Research,” Beecher reported that he had reviewed 100 consecutive articles published in 1964 “in an excellent journal,” and after culling his list to address the editor's request, selected 12 articles that demonstrated serious ethical concerns. The purpose of Beecher's article was to demonstrate the widespread lapse in ethical issues in medical research and to encourage reform in the ethical approach to human subjects research that inspired Congress to reconsider legislative reforms for human subjects protection.

An article by Jean Heller that appeared in the Washington Star on July 25, 1972 placed an exclamation point in the history of human research ethics. 13 Heller reported on a long-term study sponsored by the US Public Health Service on the effect of syphilis if left untreated in poor rural African American subjects. Officially known as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” the study enrolled 399 subjects with syphilis and 201 uninfected controls from the African American community surrounding Tuskegee, AL for “treatment of bad blood.” In exchange for taking part in the study, the men received free medical examinations, free meals, and burial insurance but were not given the benefit of providing informed consent. No treatment was provided; the research plan was to follow the subjects to establish a natural history for the disease if left untreated. Although originally projected to last 6 months, the study continued for 40 years. 14

Treatments available at the onset of the trial in 1932, even if provided, were not very effective and would have been heavy metals, involving at least 30 months of treatment, a 30% cure rate, and significant toxicity. By 1945, penicillin had been proven to be an effective therapy for syphilis with few side effects. Once penicillin was established as effective, the US Public Health Service set up centers for treatment but determined that the data from the Tuskegee experiments were too important to abandon and decided that the study should be continued with no treatment provided to the participants. Similar determinations were made in subsequent years, with the last review occurring as recently as 1969. 14

While medical research such as the Tuskegee study garnered most of the attention for ethical lapses, other areas of research involving human subjects also raised concerns. The Milgram experiments carried out in the early 1960s at Yale University are a lightning rod for discussion of ethical issues in human subjects research in social sciences. 15 Intrigued by the Nuremberg trials defendants’ argument that they were simply following orders, Stanley Milgram set out to determine if the German defendants were particularly obedient to authority figures compared to other members of society. Milgram recruited subjects for an experiment in learning via newspaper ads. The male research subjects were assigned to act as a teacher asking questions of a learner (a confederate of Milgram) who was attached to electrodes. The teachers were instructed to increase the severity of electrical shocks if the learner answered the questions incorrectly. Shocks were labeled from 15v to 450v, with 15v indicated as mild, 300v as severe, and 450v as XXX. Many of the teacher subjects eventually shocked the learner at 450v and exhibited increasing signs of distress as the shocks they delivered increased in perceived severity. 15 These experiments evoked significant concern among those in social sciences in regard to the questionable ethics of the deception used, as well as the potential for long-term psychological harm that might be incurred by unwitting participants.

Federal Policy for Protection of Human Subjects and the National Research Act

The public outcry over the Tuskegee study, other reports of ethical lapses in both medical and social research, and the alarm in the medical community raised by Dr Beecher's article in the New England Journal of Medicine led Congress to action. On May 30, 1974, the US Department of Health, Education, and Welfare (DHEW), responsible for oversight of the National Institutes of Health, replaced previous policies with comprehensive regulations governing the protection of human subjects (45 CFR §46). 16 One month later in July 1974, Congress passed the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 Title II of the act, Protection of Human Subjects of Biomedical and Behavioral Research, created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. Along with being assigned several other tasks, the National Commission was directed to make recommendations to the DHEW secretary about the ethical principles that should underlie human subjects research. 18

The Belmont Report

The National Commission issued several reports in response to the directives. The most notable among a collection of important documents is the Belmont Report, named after the Smithsonian conference center where the group convened, that was issued in 1978. 19 This document, widely regarded as the landmark analysis of ethics in human subjects research, serves as the foundation for discussion of ethical concerns in research ethics involving human subjects, as well as the source of federal regulations for research established by the Office for Human Research Protections (OHRP).

The Belmont Report is divided into three sections. The first section briefly states the National Commission's recognition that even as the report was being written, the distinction between medical practice and research was blurred. The report defines medical practice as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation for success. Research, on the other hand, is defined as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).” This section further expounds on the conflation between the use of the terms experimental and research. When used in reference to a procedure or treatment that significantly deviates from typical (ie, a treatment that is “new, different or untested”), the report notes that an “experimental” treatment is not necessarily research. Although they excluded “experimental” treatment from research and the applicable anticipated regulations, the National Commission strongly recommended that such treatments should eventually be incorporated into formal research protocols “to determine if they are safe and effective.” The first section of the Belmont Report concludes with the recognition that practice and research may go hand in hand: “the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.” 19 This language is reminiscent of the Reich Circular recommendation regarding “innovative therapy.”

The second section is the heart of the report and defines three principles that should guide the discourse surrounding any ethical concerns related to research in human subjects: respect for persons, beneficence, and justice. The principle of nonmaleficence, now commonly accepted as one of the four principles of biomedical ethics, was notably absent.

• Respect for persons : The principle of respect for persons requires that “individuals should be treated as autonomous agents,” and those with “diminished autonomy are entitled to protection.” These concepts inform “two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.” The National Commission defines the elements that would be necessary to qualify as an autonomous individual and explores circumstances that would define those who should be considered to be of diminished autonomy and thus deserving of protection.
• Beneficence : The principle of beneficence as defined by the National Commission encompasses the concept of do no harm included in the Hippocratic Oath and notes that the term is commonly thought “to cover acts of kindness or charity that go beyond strict obligation.” The National Commission proposes two general rules that inform beneficence as an obligation: “(1) do not harm and (2) maximize possible benefits and minimize possible harms.” The implications of these duties within the context of both individual investigators and society at large are examined.
• Justice : The principle of justice is posed as the following question: “Who ought to receive the benefits of research and bear its burdens?” This principle is broad in potential implications and can be summarized as evaluating the appropriate distribution of the risks and burdens of research among individuals, groups, or even situations in which inherent inequalities may need to be considered to reach an ethically informed decision. The National Commission proposes the following framework for beginning these discussions: “(1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.” The discussion of justice continues with the historic context for including the principle of justice and how lapses in justice (ie, the Tuskegee study) were the primary impetus for the formation of the National Commission.

The final section of the Belmont Report addresses the application of these principles and the implications of their requirements when considering three important elements of research involving human subjects: informed consent, assessment of risks and benefits, and selection of subjects for research.

Informed consent. The consent process has three components: information, comprehension, and voluntariness. Reaching agreement on an appropriate standard for evaluating the quality of information that should be provided to potential participants about a proposed research project is difficult and eventually ends with the suggestion that the standard of “the reasonable volunteer” might best fulfill the requirements of respect for persons, beneficence, and justice. A caveat is provided, citing the problem posed by research where “informing subjects of some pertinent aspect of the research is likely to impair the validity of the research,” a key area of ethical concern (lack of disclosure) raised by the Milgram study discussed previously. The National Commission proposes that such studies may only be appropriate if “(1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them,” further noting that “Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.” 19

Regarding the component of comprehension, the Belmont Report states, “The manner and context in which information is conveyed is as important as the information itself.” The level of comprehension is also important within the context of the individual's ability to understand the information, with emphasis that the obligation for ensuring subject understanding increases in importance relative to the level of risk posed by participation in the study. The National Commission suggests that some level of questioning the subject to ensure comprehension is appropriate and even suggests that written responses to questions may be appropriate if risks are exceptionally high. 19 If participation of subjects with compromised abilities is anticipated, researchers must be particularly diligent in evaluating the level of comprehension by the subject's proxy and ensure that the proxy is indeed capable of representing the best interests of the subject. The report even suggests that the proxy might need to be present or available during the research interventions to withdraw the subject from the study if the proxy perceives that withdrawal may be in the subject's best interest.

Voluntariness is a concept consistently emphasized in the Reich Circular, the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. Although voluntariness may appear to be self-evident, it may be the most difficult concept to address. The Belmont Report emphasizes that the subject must be “free of coercion and undue influence.” Coercion is specifically defined as “an overt threat of harm” and in most circumstances is relatively easy to evaluate. However, arguments can be made about what defines “undue influence.” Discussions about appropriate levels of compensation for participation are common, particularly when studies involve financial or other considerations made to possibly financially compromised subjects. The Belmont Report specifically notes, “inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.” Other concerns related to undue influence involve social standing, employment, or other circumstances that may be difficult to assess but are worthy of consideration for individual subjects.

Assessment of risks and benefits. The National Commission notes that a favorable risk/benefit assessment is associated with the principle of beneficence. This definition is particularly appropriate in that the National Commission's interpretation of beneficence includes the duty of nonmaleficence. The Belmont Report examines the meaning of risk and benefit in the setting of potential types of harm that may be experienced by individual subjects, the families of the individual subjects, society at large, or special groups of subjects in society. Benefits are also discussed in relation to the individual and society at large. In summarizing the risks and benefits of research, the Belmont Report states

…assessment of the justifiability of research should reflect at least the following considerations:

Brutal or inhumane treatment of human subjects is never morally justified.

Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures.

When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject—or, in some rare cases, to the manifest voluntariness of the participation).

When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits.

Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. 19

Selection of subjects for research. The third element, selection of subjects for research, finds its primary guidance in the principle of justice where the moral requirements demand that the procedures and outcomes for the selection of subjects are fair to the individual and within the social context. Participation in potentially beneficial research should be fairly distributed to all who wish to participate, and risky research should not be offered only to less desirable subjects. In the context of society, risks should be distributed after careful consideration of the burdens and the ability of individuals in identifiable groups to bear those burdens. As a generalization, adults should be considered before children, and participation by institutionalized individuals should invoke very careful consideration. Even with these safeguards, the National Commission believed that the selection of subjects may continue to reflect injustice arising from social, racial, sexual, and cultural biases institutionalized in society. Harking back to the ethical concerns that prompted the National Commission, the Belmont Report concludes with the following: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.” 19

Although not included in the body of the report, a footnote specifically addresses the difficulty in extrapolating these tenets to human subjects research in the social sciences: “Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.” 19 An appropriate ethical approach for some areas of social and psychological studies remains elusive. Matthew Salganik, professor of sociology at Princeton University, discusses the issues surrounding the difficulty in applying the Belmont Report recommendations at his blog. 20

The Belmont Report was submitted to Congress on April 18, 1979.

Other Reports by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research

Although the Belmont Report is the centerpiece for the analysis of research in human subjects, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research provided significant additional guidance for Congress to consider as the legislators moved forward to formulate regulations for the governance of human subjects in research. During the 4 years of the National Commission's appointment, other publications provided analysis of concerns related to specific questions (Table), and many of the recommendations were incorporated into the subsequent regulations for human subjects protection. 21

Table .

Human Subjects Protection in Research Reports From the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1974-1978 21

FOIA, Freedom of Information Act.

Principles of Biomedical Ethics

Another landmark publication from 1979 deserves attention for its sustained influence on the field of biomedical ethics and its deviation from the three ethical principles put forth by the Belmont Report. In Principles of Biomedical Ethics , Tom Beauchamp and James Childress argue for inclusion of nonmaleficence as an independent principle to formulate the now-familiar four principles that inform contemporary bioethical discourse. 22 As previously noted, nonmaleficence is considered a duty under the umbrella of the principle of beneficence in the Belmont Report. Beauchamp and Childress maintained that the tradition to do no harm central to the tenets of the Hippocratic Oath incorporates the concept of nonmaleficence at its core and is essential to any discussion of the ethics of medical practice. As such, they argued, this concept should be considered as separate from and not subsidiary to beneficence: “First, to confuse them is to obscure distinctions that we make in ordinary moral discourse. Second, ordinary moral discourse expresses the defensible conviction that we have certain duties not to injure others that are not only distinct from but also more stringent than our duties to benefit others.” 22 The authors make the distinction that the negative duty to cause no harm should be encompassed by nonmaleficence, and the positive but not so strongly established moral duty to benefit others should constitute the core of beneficence. The authors acknowledged that other eminent scholars disagreed with the separation of nonmaleficence and beneficence, but they constructed an argument that has been upheld by the historic inclusion of nonmaleficence in most bioethics discussions following their book's original publication (the book is now its seventh edition). The book has had a significant influence on the still-evolving field of bioethics contemporary to its publication and the Belmont Report. Both authors regularly served as staff members for the Kennedy Institute Intensive Bioethics Course, and Beauchamp served as staff philosopher for the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research that produced the Belmont Report. The authors acknowledged the influence of several other members of the commission and other colleagues who contributed significantly to their deliberations as their work progressed.

US Legislative Updates, 1981

DHEW officially became the Department of Health and Human Services (HHS) in 1980, and in response to the Belmont Report, the HHS and the US Food and Drug Administration (FDA) significantly revised their protection of human subjects regulations in 1981 (45 CFR §46 and 21 CFR §50). 16 , 18 , 23

These regulations specifically address concerns related to vulnerable populations in Subparts B, C, and D, incorporating the recommendations from the National Commission. The Research on the Fetus report 24 informed Subpart B (additional protections for pregnant women, human fetuses, and neonates), Subpart C (additional protections for prisoners) reflected the recommendations in Research Involving Prisoners , 25 and Subpart D (additional protections for children) was informed by the Research Involving Children report. 26

HUMAN SUBJECTS PROTECTION OVERSIGHT

Oversight in the united states.

To this point, this review has focused on some of the historic events and documents precipitating evaluation of the ethical requirements for human subjects research in the United States and a review of the regulations that evolved from that history. The question not yet addressed is how these regulations should be enforced. As with the discussion of research ethics, the approach to enforcement of regulations also lies within the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 In addition to establishing the National Commission responsible for the Belmont Report, the National Research Act elected to perpetuate the regulatory mechanism for research extant within many departments of DHEW that evolved from the US Public Health Service requirements initiated by the Surgeon General in 1966. The background of this development is described in William Curran's article, “Government Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies.” 27

This system for review of human subjects research within DHEW as described in The Institutional Guide to DHEW Policy on Protection of Human Subjects 28 became the model for institutional review boards (IRBs) that the National Research Act would require of grantees and contractees for review of research involving human subjects. The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was specifically charged with reviewing the function of IRBs and making recommendations for integrating the role of the IRB into the regulatory process to provide oversight of the application of ethical principles and of the regulations. 18

On September 1, 1978, the National Commission completed the less spectacular but equally important report, Institutional Review Boards , 29 before submitting the Belmont Report on September 30 that same year. Institutional Review Boards outlines the National Commission's concept of the ideal environment for the application of the federal regulations.

In the introduction to the report, the National Commission provides this understated assessment of the role of the IRB: “This review of proposed research by IRBs is the primary mechanism for assuring that the rights of human subjects are protected.” 29 The document outlines the ideal responsibilities of the IRB in the oversight of research to ensure that human subjects receive appropriate protections and ethical treatment for their willingness to participate in research, sometimes at no benefit to themselves. The National Commission summarized their objective as follows:

In the recommendations that follow, the Commission expresses its judgment about the ways in which those elements [that must be considered in balancing society's interests in protecting the rights of the subjects and in developing knowledge that can benefit the subjects or society as a whole] ought to be brought to bear on research practices, so that a reasonable and ethical balance of society's interests may be attained.

The Commission's deliberations begin with the premise that investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others, who are independent of the research, must share this responsibility, because investigators are always in positions of potential conflict by virtue of their concern with the pursuit of knowledge as well as the welfare of the human subjects of their research.

The Commission believes that the rights of subjects should be protected by local review committees operating pursuant to federal regulations and located in institutions where research involving human subjects is conducted. 29

The document continues this proposal and is seemingly all-inclusive in its conception of the IRB. Highlights include a list of the requirements that must be met to approve research and details for reviewing and approving the consent process, including the essential elements to be included and the safeguards that should be in place to ensure that the process is respected. Specific recommendations also address the constitution of the IRB; how it should be funded; and legal protections for the board, the process, and its members.

Most of the recommendations from the Institutional Review Boards report were incorporated into the HHS regulations—HHS being the responsible federal agency—as part of the rules revision in 1981 in response to the Belmont Report and several other publications of the National Commission. Acting independently from HHS, the FDA also adopted IRBs as a regulatory mechanism, with regulations first issued in 1981 as part of the agency's response to provisions of the National Research Act. 18 , 30

One particularly relevant recommendation of the National Commission from Institutional Review Boards remained outstanding after the changes in 1981: “Recommendation (1) (A) Federal law should be enacted or amended to authorize the Secretary of Health, Education, and Welfare to promulgate regulations governing ethical review of all research involving human subjects that is subject to federal regulation.” 29

The report notes significant “variations arising out of differences in wording, imposition of additional requirements, introduction of minor changes, etc.” among the different agencies apart from DHEW involved in research involving human subjects and expresses concern that this variability places an unnecessary burden on the individual IRBs for interpreting and properly enforcing the regulations. The National Commission's recommendation was to establish “DHEW as the sole authority” for regulations, expressing the belief that such a rule “would reduce the burden on IRBs to interpret and apply the regulations to which they are subject. Moreover, uniformity would assure a minimum level of protection to human subjects of research, no matter which federal agency is supporting the research or which entity is conducting it.” 29 Having inherited the mantle of responsibility from the now-extinct DHEW and recognizing the reality of this assessment, the newly designated HHS explored implementation of this recommendation, particularly as it related to the function of IRBs. As with most changes affecting multiple branches of government, the process became complex. In December 1981, the President's Commission for the Study of Ethical Problems in Medicine and in Biomedical and Behavioral Research, a new commission appointed by Congress in 1978, entered the fray and recommended that all federal departments and agencies adopt the HHS regulations (45 CFR §46). In addition, an ad hoc Committee for the Protection of Human Subjects—composed of representatives and ex officio members from departments and agencies that conducted, supported, or regulated research involving human subjects—was appointed in May 1982 by the president's science advisor to respond to the recommendations of this new commission. After much consideration and negotiation, these efforts were finally addressed by adoption of the Federal Policy for the Protection of Human Subjects, known as the Common Rule, in 1991 and codified in the individual regulations by 15 federal departments and agencies. Each of these agencies includes in its chapter of the Code of Federal Regulations (CFR) section numbers and language that are identical to those of the HHS codification at 45 CFR §46, Subpart A for the regulation of human subjects participation in research. The HHS regulations also include Subparts B, C, and D as additional regulations pertaining to vulnerable subjects. 16 , 31

In addition to harmonizing the regulations across agencies of the federal government, the Common Rule requires institutions that receive funds for research involving human subjects from federal agencies that are signatories to the Common Rule to certify that the research has been reviewed and approved by an IRB that meets the specific requirements for composition, for functioning, and for the criteria followed to approve research. By mandate of the Common Rule, IRBs are empowered to approve, require modifications of, or disapprove research activities and are required to conduct continuing review of ongoing research at least annually.

The FDA concurs with the Common Rule but claims special privilege in not signing on to it. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR §50 and §56 so that they conformed to the Federal Policy for the Protection of Human Subjects to the extent permitted but noted that the FDA is a regulatory agency that rarely supports or conducts research under its regulations. 32

International Oversight

With the adoption of the Common Rule, regulations for human subjects research conducted within the United States became well established, but research has never been confined by the borders of the United States. Even though a project funded by federal monetary support may have some leverage to require adherence to US regulations, significant numbers of human research subjects participate in studies well beyond the influence of the US regulations. The international norms for participation of human subjects in research evolved along a course that frequently cross-pollinated with the concepts culminating in the Common Rule. The Declaration of Helsinki was an early statement of basic tenets that should apply to all research involving human subjects, and it has continued to evolve, with updates reflecting new issues as they become relevant. While addressing the ethical concepts, the Declaration of Helsinki does not provide an organizational or regulatory framework for human subjects protection. Providing this framework on an international basis presented a challenge well beyond the challenge of harmonizing regulations across different federal agencies as was accomplished by the Common Rule. The difficulties encountered in implementing the Common Rule represent only a microcosm of the enormous task of harmonizing regulatory and organizational concepts across the borders of different cultures and political systems. However, this task was particularly relevant because of the evolution of research into an international enterprise with multicenter drug trials and the expansion of vaccine trials in children. Many of these studies are conducted by multinational contract research organizations that have access to populations of subjects with exposure to diseases that may not be widely encountered in the United States.

An argument can be made that the process for oversight of human subjects in research at the international level started in 1948 before the Declaration of Helsinki when the United Nations Educational, Scientific and Cultural Organization (UNESCO) joined with the World Health Organization (WHO) to establish a permanent Council for Coordination of International Medical Congresses, formally constituted in Brussels in 1949 as a nongovernmental organization with the purpose of facilitating “the exchange of views and scientific information in the medical sciences by securing continuity and coordination between international organizations of medical sciences, by making their work known, and by providing them with material aid where necessary.” 33 The scope of activities gradually expanded to include collaborative efforts among international medical activities in addition to the coordination of participating congresses. In 1992, the name of the council was changed to the Council for International Organizations of Medical Sciences (CIOMS), and its statutes were revised to reflect the expanded role. 33

The original council ventured into medical research by organizing a 1959 meeting in Vienna under the auspices of UNESCO and the WHO “to discuss the principles, organization and scope of ‘controlled clinical trials,’ which must be carried out if new methods or preparations used for the treatment of disease are to be accurately assessed clinically.” The executive secretary summarized the meeting: “The conference was in itself an experiment.” 34

Following this meeting, the council became much more involved in considerations regarding research and particularly the participation of human subjects in research trials, eventually publishing Proposed International Guidelines for Biomedical Research Involving Human Subjects in 1982. The purpose of the guidelines was “to indicate how the ethical principles that should guide the conduct of biomedical research involving human subjects, as set forth in the Declaration of Helsinki, could be applied, particularly in developing countries, given their socioeconomic circumstances, laws and regulations, and executive and administrative arrangements.” 35 This quote is from the background notes for International Ethical Guidelines for Biomedical Research Involving Human Subjects published in 1993 after discussion and reconsideration of the comments received in response to the proposed guidelines. 35

The publication of the guidelines in 1993, soon after the name change to CIOMS, represented a landmark for international research ethics. The steering committee included an international staff of 24 members and an even larger list of advisors and consultants. The committee was co-chaired by Robert Levine from Yale University, who was listed as a “Special Consultant” on the Belmont Report and authored the first four articles for discussion in the appendix to the Belmont Report, and John H. Bryant, an American physician with a distinguished career in international medical practice. In addition to the Declaration of Helsinki, the International Ethical Guidelines for Biomedical Research Involving Human Subjects was strongly influenced by the Belmont Report as demonstrated by the inclusion of the following text under the heading General Ethical Principles:

All research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for persons, beneficence and justice. It is generally agreed that these principles, which in the abstract have equal moral force, guide the conscientious preparation of proposals for scientific studies. 35

The guidelines acknowledge the evolution of the principles following the publication of the Belmont Report with the statement, “Beneficence further proscribes the deliberate infliction of harm on persons; this aspect of beneficence is sometimes expressed as a separate principle, non-maleficence (do no harm).” 35

The table of contents of the 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects , provided in Figure 3 , outlines the subjects the steering committee felt to be the most pertinent issues for research conducted in an international setting. In addition to the obvious influence of the Declaration of Helsinki, this document reinterprets many of the issues presented in the Belmont Report, in reports from the presidential commissions, and in 45 CFR §46, Subparts A, B, C, and D to provide an adaptable set of guidelines suitable for application across a broad spectrum of cultural and political environments. The notable exception to the similarities with the US regulations is the inclusion of a guideline titled “Compensation of Research Subjects for Accidental Injury” that provides for the following: “Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependents are entitled to material compensation. The right to compensation may not be waived.” 35 To date, no uniform program for compensation of human subjects injured in research is addressed in the US regulations.

Table of Contents, International Ethical Guidelines for Biomedical Research Involving Human Subjects, 1993 35

The International Ethical Guidelines for Biomedical Research Involving Human Subjects was updated in 2002, and CIOMS continues its efforts to revise the guidelines as dictated by changes in research requiring human subjects.

THE GUATEMALA SEXUALLY TRANSMITTED DISEASES STUDY

All the efforts described to this point promoted regulations and procedures based on an ethically sound approach to protecting human subjects who, by consent or proxy, will be participating in research. The ethics of the research environment seems to have improved as a result of these efforts both in the United States and internationally. Notable instances of particularly egregious studies have come to light since the publication of the Belmont Report, but most of these studies originated before that document was issued. One study in particular raised eyebrows for its similarity to the transgressions committed in the Tuskegee study and, after investigation, was found to have ties to the Tuskegee study.

In October 2010, the United States disclosed that the US Public Health Service sponsored studies of sexually transmitted diseases in Guatemala beginning in 1946. This exposé began with the discovery of documents among papers donated by Dr John Cutler to the library at the University of Pittsburgh. Before retiring, Cutler was on the faculty at the university's School of Public Health following a long career in the US Public Health Service where he had been one of the staff members involved with the Tuskegee study. Hoping to gain insight into the Tuskegee study, Dr Susan Reverby from Wellesley was reviewing Cutler's papers when she came across previously unknown information about experiments investigating sexually transmitted diseases in Guatemala that Cutler and his associates conducted. 36 An account in the American Journal of Public Health reports that “… more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases” and many were never treated. 37

When the details of these experiments came to light, they precipitated an apology from President Barack Obama and specific directives to the Presidential Commission for the Study of Bioethical Issues, a commission appointed by Obama, to “convene a panel to conduct, beginning in January 2011, a thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government. I also request that the Commission oversee a thorough fact-finding investigation into the specifics of the U.S. Public Health Service Sexually Transmitted Diseases Inoculation Study” ( Figure 4 ). 38

Directive from President Barack Obama to investigate the Guatemalan studies, 2010 38

The Presidential Commission's first report, “ Ethically Impossible” STD Research in Guatemala from 1946 to 1948 , provides a detailed account of the history surrounding the Guatemala studies and all of the supporting evidence. In the preface, the Presidential Commission reports, “With dual responsibilities to give a full and fair accounting of events largely hidden from history for nearly 65 years and also provide an assessment of the current system, the Commission decided to publish two reports. This is the first report, a historical account and ethical assessment of the Guatemala experiments.” 38

The specific political circumstances in which the experiments were conceived and carried out is critical to gaining some understanding of how ethically questionable research, however ill-conceived, was carried out by people who most probably had good intentions. The significance of the deleterious effects of sexually transmitted diseases among troops in World War II and how those effects precipitated the experiments are difficult to understand in today's world of effective antibiotics. In the 1940s wartime environment, however, understanding all aspects of sexually transmitted diseases was perceived as a crucial aspect of the military's ability to field an effective fighting force for the war in Europe. The experiments must be viewed in this historic context to understand the powerful motivation behind the studies.

The “ Ethically Impossible ” report includes an excerpt from a 1943 letter from Dr Joseph Earle Moore, Chair of the Subcommittee on Venereal Diseases under the National Research Council, to A. N. Richards, Chair of the Medical Research Committee of the Office of Scientific Research and Development, in which Moore wrote that he expected “approximately 350,000 fresh infections with gonorrhea [in the Armed Forces], [which] will account for 7,000,000 lost man days per year, the equivalent of putting out of action for a full year the entire strength of two full armored divisions or of ten aircraft carriers.” 38 Moore estimated that the cost of treating the anticipated infections would be $34 million, equivalent to approximately $440 million today, adjusted for inflation.

Within this context, serious planning to meet the challenge of understanding and treating sexually transmitted diseases appears to have coalesced at the national level in 1942. Planning for these studies continued through the following year, with one of the principals suggesting “the possibility of using federal prisoners, Army prisoners, or conscientious objectors as an alternative” for research subjects. 38 In 1943, experiments began at the US Penitentiary in Terre Haute, IN, that continued for 2 years. The focus of the experiments was on efforts to infect prisoners with Neisseria gonorrhoeae to test various methods for prophylaxis and treatment. Isolates of bacteria were applied directly to the penises of subjects in an effort to reliably infect the “volunteers.” However, the failure to reliably infect subjects in this fashion clearly indicated that studies of prophylactic techniques would not be possible with this approach, leading to consideration of other options.

The studies were performed under the direction of Dr John F. Mahoney, then head of the US Public Health Service/Venereal Disease Research Laboratory (VDRL) set up within the US Marine Hospital in Staten Island, NY. Mahoney directed the Terra Haute prison studies from his Staten Island laboratory, while 28-year-old Dr Cutler ran the studies at the prison. Following the end of World War II in 1945, the military support for the studies was less enthusiastic, but the Public Health Service remained committed to supporting the research with plans to move the research to Guatemala. A 1947 article Mahoney published in the Journal of Venereal Disease Information provides some insight into why the studies were moved: “It has been considered impractical to work out, under postwar conditions in the United States, the solution of certain phases concerned with the prevention and treatment of syphilis. These problems are largely concerned with the development of an effective prophylactic agent for both gonorrhea and syphilis and the prolonged observation of patients treated with penicillin for early syphilis. Because of the relatively fixed character of the population and because of the highly cooperative attitude of the officials, both civil and military, an experimental laboratory in Guatemala City has been established….” 39

As fate would have it, a Guatemalan physician named Funes, who had served a fellowship at the VDRL and returned to Guatemala, was essential to the transition of the studies to his country. In August 1946, Cutler transitioned from Terra Haute to Guatemala at Funes's urging. Cutler staffed a clinic that provided the regular health inspections required for registered sex workers and suggested that the facility provide an environment of “normal exposure” through which sexually transmitted diseases could be more predictably transmitted. The studies in Guatemala evaluated possible prophylactic intervention “in cooperation with the Guatemalan Venereal Disease Control Department” that Funes directed and the local penitentiary “where exposure of volunteers to infected prostitutes would provide the testing opportunities.” 38 Enrolling prisoners, a contained and restricted population, after they had had sexual intercourse with commercial sex workers known to be infected with sexually transmitted diseases, promised to establish, according to Cutler, a “rapid and unequivocal answer as to the value of various prophylactic techniques” through the preferred technique of “normal exposure.” 38

After beginning with studies of “normal exposure” in prisoners, Cutler expanded the population of research subjects to include patients in a psychiatric hospital and again tried artificial means of infection, including scarification—mechanically damaging the skin and mucous membranes of the penis—to enhance the likelihood of infecting the subject. An even more aggressive study included at least 7 women in a psychiatric institution who were infected by the injection of syphilis specimens directly into the subarachnoid space surrounding the brain. Only 5 of them later received medical therapy. 38 In addition, studies to follow the serology of children in a large orphanage were undertaken to better understand the specificity of tests for sexually transmitted diseases, an additional goal of the Guatemalan studies.

Studies in which subjects were intentionally infected were completed in the later months of 1948, and Cutler left Guatemala in December 1948 to join a WHO Disease Demonstration Team in India. From April 1949 to July 1950, this team worked to establish a venereal disease control demonstration in various parts of India and teach advanced methods of control for sexually transmitted diseases. Meanwhile, the US Public Health Service hired Funes and another Guatemalan physician, Dr Salvado, to continue “the observation of certain of the patient groups” after Cutler left Guatemala. Funes's staff collected data on residents of the orphanage, inmates of the penitentiary, individuals from the psychiatric hospital, schoolchildren, and the members of “various Indian tribes in the vicinity of Guatemala” who had participated in the experiments. Funes was hired to “advise concerning the clinical examinations of treated patients, their re-treatment as may be required, the collection of blood specimens for serologic examinations at periodic intervals, the preparation and shipment of all blood specimens collected for serologic examination” to the United States, and “the submission of such reports as may be necessary for the completion of the study of this patient group.” 38 Based on the one report available in the Cutler Documents, Funes and his staff followed approximately 248 people from the mental institution, completing 243 blood draws and 170 lumbar punctures. Several of those subjects tested positive for syphilis during the follow-up experiments. The subjects from the psychiatric hospital were followed until at least 1953. The published work resulting from the Guatemala experiments also indicates that Funes continued to do serological testing on the children at the orphanage until at least 1949.

The experiments in Terra Haute were conducted and supported by many of the same people involved in the Guatemala experiments with the same goal of finding suitable prophylaxes for sexually transmitted diseases. However, throughout their discussion of the background leading to the experiments in the United States and the subsequent Guatemalan experiments, the Presidential Commission provides details of concerns voiced among those planning the studies. These details construct a compelling argument that all along the way there was an undercurrent of concern that the studies proposed were at the least controversial, most probably unethical, and in some instances arguably illegal. The Presidential Commission reached the conclusion that “Conducting the experiments in Guatemala provided an opportunity to work with reduced concern for some of the key obstacles associated with the Terre Haute experiments: fear of adverse legal consequences and bad publicity.” In a footnote to the report, the authors point out that “These concerns followed the researchers to Guatemala, however, as evidenced by some of their efforts to limit and restrict access to information about the work.” 38

The Presidential Commission summarized their findings as follows: “In the Commission's view, the Guatemala experiments involved unconscionable violations of ethics, even as judged against the researchers’ own understanding of the practices and requirements of medical ethics of the day.” The report concludes

Although some individuals are more blameworthy than others, the blame for this episode cannot be said to fall solely on the shoulders of one or two individuals. The unconscionable events that unfolded in Guatemala in the years 1946 to 1948 also represented an institutional failure of the sort that modern requirements of transparency and accountability are designed to prevent. In the final analysis, institutions are comprised of individuals who, however flawed, are expected to exercise sound judgment in the pursuit of their institutional mission. This is all the more true and important when those individuals hold privileged and powerful roles as professionals and public officials. One lesson of the Guatemala experiments, never to take ethics for granted, let alone confuse ethical principles with burdensome obstacles to be overcome or evaded, is a sobering one for our own and all subsequent generations. We should be ever vigilant to ensure that such reprehensible exploitation of our fellow human beings is never repeated. 38

The second charge from President Obama to the Presidential Commission was to provide a “thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.” The Presidential Commission addressed this directive in their report Moral Science: Protecting Participants in Human Subjects Research that was completed in December 2011. 40

Regarding whether the regulations would prevent abuses similar to the studies in Guatemala, the Commission noted, “Existing evidence suggests both that the rules governing federal research today adequately guard against abuses analogous to those perpetrated in Guatemala in the 1940s and that current regulations generally appear to protect people from avoidable harm or unethical treatment, insofar as is feasible given limited resources, no matter where U.S.-supported research occurs.” 40 The report summary continued as follows:

The current U.S. system provides substantial protections for the health, rights, and welfare of research subjects and, in general, serves to “protect people from harm or unethical treatment” when they volunteer to participate as subjects in scientific studies supported by the federal government. However, because of the currently limited ability of some governmental agencies to identify basic information about all of their human subjects research, the Commission cannot say that all federally funded research provides optimal protections against avoidable harms and unethical treatment. The Commission finds significant room for improvement in several areas where, for example, immediate changes can be made to increase accountability and thereby reduce the likelihood of harm or unethical treatment. 40

The report outlines the Presidential Commission's observations and recommendations based on a thorough review of federally funded research, including studies that may involve human subjects in other countries. One issue the Commission raised was the general lack of accessibility to data: “there is no ready source that comprehensively describes its [the federally funded human research enterprise] basic characteristics, such as level of funding, or number of studies, subjects, or geographic locations. Instead, what exists are isolated pockets of information and some descriptive summaries.” 40 This difficulty in acquiring information prompted the Presidential Commission's first recommendation to improve accountability through public access: “accountability can and should be refined through improving access to basic information about the scope and volume of human subjects research funded by the government.” The commission cites precedent for this recommendation from the Institute of Medicine–issued Responsible Research: A Systems Approach to Protecting Research Participants , with its recommendation to extend the oversight system to all research, regardless of funding source or research setting. 41

Treatment and compensation for research-related injuries were also identified as an issue of concern, a subject that has been scrutinized regularly in past discussions as human research protection has evolved. Obama's Commission noted that this issue still required attention at the time of their review, pointing out that most other developed countries require sponsors, investigators, or others engaged in research to provide treatment or reimbursement free of charge to the subject for research-related injury or illness. As discussed earlier, one of the deviations from the general agreement between CIOMS and US regulations is the recommendation for subject compensation in the CIOMS guidelines. The Presidential Commission “draws a bright line affirming the view of most bioethicists and others, including the majority of nations supporting human subjects research around the globe, that human subjects should not individually bear the costs of care required to treat harms resulting directly from that research.” 40 Recognizing that previous bioethics commissions and other advisory bodies had opined in favor of compensation or treatment for research-related injuries with relative silence by the government, the Commission advocated a response as to reasons for changing or maintaining the status quo. This issue remains open with no progress as this article is being written.

The Commission also asked that the OHRP examine, recognize, and define when protections delineated in foreign laws and regulations are accepted as equivalent to US regulations and exercise its longstanding authority to recognize these protections when available. Protections offered by international partners have been a source of confusion, as the federal regulations state that equivalent protections from international studies should be accommodated but do not provide guidance for how they should be defined. This directive has been reevaluated several times since its inception, including a specific request from the United Kingdom in 2007 to provide a determination of equivalence for human research protections afforded by UK regulations. As of the Commission's report in 2011, the OHRP had not formally recognized any country's protections as equivalent.

The Commission also noted that the FDA, while not signatory to the Common Rule, does adhere to the regulations at 45 CFR §46, Subpart A whenever possible and accepts data from foreign studies that comply with certain international standards for human subjects protection, such as studies that abide by good clinical practice, the Declaration of Helsinki, or certain host country regulations. This practice should provide a model to develop a system for recognizing equivalent protections as currently regulated by provisions in the Common Rule.

In its final recommendation, Promoting Current Federal Reform Efforts, the Presidential Commission called for broad reform of federal research rules and procedures beyond simply addressing equivalent protections.

The Commission supports the federal government's proposed reforms to:

a) Restructure research oversight to appropriately calibrate the level and intensity of the review activities with the level of risk to human subjects;

b) Eliminate continuing review for certain lower-risk studies and regularly update the list of research categories that may undergo expedited review;

c) Reduce unnecessary, duplicative, or redundant institutional review board review in multi-site studies. Regardless of the process used to review and approve studies, institutions should retain responsibility for ensuring that human subjects are protected at their location as protection of human subjects includes much more than institutional review board review. The use of a single institutional review board of record should be made the regulatory default unless institutions or investigators have sufficient justification to act otherwise;

d) Make available standardized consent form templates with clear language understandable to subjects;

e) Harmonize the Common Rule and existing regulations of the Food and Drug Administration, and require that all federal agencies conducting human subjects research adopt human subjects regulations that are consistent with the ethical requirements of the Common Rule; and

f) Work toward developing an interoperable or compatible data collection system for adverse event reporting across the federal government. 40

Most of these provisions were included in the revisions to the Common Rule that updated the original provisions from 1991 and were effective January 21, 2019, with the exception of staged implementation of single IRB review for multisite studies. Twenty federal agencies follow the Common Rule, with the notable exception of the FDA. So far, no official indication of the FDA's intent has been provided, although the expectation is that some effort will be made to harmonize the regulations—at least in a similar fashion as previous agreements.

OTHER HUMAN SUBJECTS PROTECTION FAILURES

This exposition of how we have arrived at the current rules and regulations for protecting human subjects who participate in research is lengthy but is at best an outline. Even this abbreviated history should elicit an appreciation of the complexity of the ethics surrounding protection of human subjects in research. A fair question is whether these provisions have significantly altered the landscape since Dr Beecher published his concerns in the New England Journal of Medicine in 1966. A cursory review turns up a few exceptions to the relative safety afforded by the current protections, with three that are particularly instructive.

Jesse Gelsinger

Jesse Gelsinger had just turned 18, the legal age for consent, when he volunteered in 1999 for a phase 1 gene therapy study designed for treatment of ornithine transcarbamylase (OTC) deficiency. Phase 1 studies are designed primarily to determine the appropriate dose of a drug. Gelsinger was born with a mild form of OTC that was well controlled by diet and drug therapy; he had minimal risk of serious complications from the disease as long as he followed his treatment protocol. He did not stand to benefit significantly from his participation in the phase 1 study but felt that he should volunteer because of the knowledge that might benefit others.

Gelsinger died 4 days after receiving an experimental therapy consisting of a gene attached to an adenovirus that would theoretically serve as a delivery system to insert the new gene into the DNA of his liver cells. The death was unexpected in a relatively healthy 18-year-old, and the outcome precipitated a long and contentious investigation into how the protections that should have prevented Gelsinger from participating in the study were circumvented or ignored. The investigation uncovered questions regarding (1) information that should have been included in the consent form, (2) the actual risk posed by the study based on complications from similar studies that were not disclosed in reports to regulatory bodies, (3) why Gelsinger was enrolled in the study in violation of the protocol's inclusion/exclusion criteria, (4) the potential risk/benefit analysis based on the mild nature of his disease that would argue against his participation, and (5) an undisclosed conflict of interest for the director of the gene studies program that may have clouded decisions at critical points during conduct of the study. 42 - 45

Examination of this study demonstrates that the protections afforded to subjects are well established but still depend on the assumption that the individuals responsible for every step of the evaluation and approval of studies and those who actually conduct the research all perform reliably in their roles.

Johns Hopkins Lead Abatement Study

Another notable case revolves around the issues of appropriate consent, appropriate risks for children (or any vulnerable population), and disclosure of results obtained in research studies. The Kennedy Krieger Institute (KKI), an affiliate of Johns Hopkins Children's Center, conducted a study evaluating the effectiveness of lead abatement programs in low-income housing in Baltimore, MD during the 1990s. The study recruited families to live in houses either untouched or treated with different abatement techniques to determine which processes were most effective in protecting children from the significant neurologic effects of elevated lead levels that were endemic among children living in low-income housing in Baltimore. The goal was “to find a relatively inexpensive and effective method for reducing—though not eliminating—the amount of lead in children's homes and thereby reducing the devastating effect of lead exposure on children's brains.” 46 A total of 108 families with young children were recruited to live in houses with lead levels ranging from none to levels just below the existing legal limit, and the children's serum lead levels were monitored. In two homes, the lead levels in the children crossed into toxic levels, but the families were not informed or advised to move out of the toxic environment. Eventually, a lawsuit was filed on behalf of the two children, and it raised significant ethical questions surrounding informed consent, appropriate risks, and disclosure of results that are reviewed at length in the article “With the Best Intentions: Lead Research and the Challenge to Public Health.” 46 The Maryland Court of Appeals opinion equated the multiyear lead study with the Tuskegee study in its egregious disregard for research ethics in a vulnerable population.

Ellen Roche

Ellen Roche was a healthy 24-year-old laboratory technician at the Johns Hopkins Asthma and Allergy Center. She volunteered to take part in a 2001 lung function physiology experiment in which normal pulmonary function in healthy volunteers would be manipulated by inhalation of hexamethonium, a compound that interferes with normal nervous system interaction with the lungs to mimic a mild asthma attack. Although it had been used in the 1950s to treat hypertension, hexamethonium fell into disuse as more effective drugs became available, and the FDA withdrew approval in 1972. Of note, hexamethonium was never approved as an inhaled medication. Roche was the fourth patient to receive hexamethonium in the trial. At least one previous subject had had mild persistent respiratory symptoms that the investigator dismissed as a cold. Roche became very ill, with significant pulmonary abnormalities presenting within 24 hours. The symptoms progressed to multisystem organ failure, and she died within a month. 47 , 48

The ensuing investigation turned up several concerns:

• The literature search relied on PubMed and one contemporary textbook of pulmonary medicine to explore the potential use of hexamethonium for the purpose proposed in the research plan. Neither source revealed any indication of concerns, although other databases and older textbooks warned of significant pulmonary complications associated with hexamethonium.
• No request was made to determine if the FDA required an investigational new drug application, even though the medication was no longer approved and had never been approved as an inhalational drug.
• The consent form referred to hexamethonium as a medication but failed to mention that FDA approval had been withdrawn.
• A few subjects included in previous studies used inhaled hexamethonium with no mention of problems in the subsequent publications, but two subjects did have significant difficulties that were not reported as the investigator did not consider them related to the drug.
• The hexamethonium used in the study was of chemical grade and was not prepared as a pharmaceutical agent. 47 , 48

This list is not complete and raises many concerns, but the focus of the investigation became the lack of adequate research to confirm that the compound used to induce asthma symptoms was safe. The responsibility for this failure primarily attached to the investigator, with additional concern focusing on a review process that failed to follow proper procedures for approval of the protocol. During the follow-up, several articles from the 1950s reporting that hexamethonium could cause fatal lung inflammation similar to the pulmonary complications leading to the demise of Ellen Roche were identified. PubMed's coverage of the literature starts in the mid-1960s. In addition, review of the FDA records related to the withdrawal of hexamethonium in 1972 cited the drug's “substantial potential toxicity” as one element leading to the decision. 48

The examples of ethical issues from history and the scarcity of contemporary examples demonstrate that regulations for the protection of humans participating in research have evolved in a way that minimizes the probability of harm to subjects choosing to participate in research. These examples also reinforce the importance of individual responsibility to faithfully execute the requirements of their assigned roles. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Furthermore, these examples support the argument that no amount of regulation or oversight can completely remove the variable of individual failures to adhere to the rules or accept the responsibility associated with their role in research that may precipitate serious unexpected consequences. The rules and expectations for those charged with the review, administration, and performance of research requiring human subjects can only minimize the probability that these instances will occur. The point at which the primary responsibility of protecting human subjects from preventable harm deviates to focus on some other aspect of the research that leads to harm is rarely predictable. Simplified to the world of Monty Python, “Nobody expects the Spanish Inquisition!”

ACKNOWLEDGMENTS

The author has no financial or proprietary interest in the subject matter of this article.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Systems-Based Practice.

Defining Research with Human Subjects

A study is considered research with human subjects if it meets the definitions of both research AND human subjects, as defined in the federal regulations for protecting research subjects.

Research.  A systematic inquiry designed to answer a research question or contribute to a field of knowledge, including pilot studies and research development.

Human subject:  A living individual about whom an investigator (whether professional or student) conducting research:

• Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
• Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

The following sections will explain some of the words in the previous definitions.

The regulatory language:

A systematic inquiry designed to answer a research question or contribute to a field of knowledge, including pilot studies and research development.

The explanation:

Understanding what constitutes a systematic inquiry varies among disciplines and depends on the procedures and steps used to answer research questions and how the search for knowledge is organize and structured.

Pilot Studies and Research Development

Pilot studies are designed to conduct preliminary analyses before committing to a full-blown study or experiment.

Research development includes activities such as convening a focus group consisting of members of the proposed research population to help develop a culturally appropriate questionnaire.

Practical applications:

• You are conducting a pilot study or other activities preliminary to research; or
• You have designed a study to collect information or biospecimens in a systematic way to answer a research question; or
• You intend to study, analyze, or otherwise use existing information or biospecimens to answer a research question.

Human Subjects

Human subjects are living individuals about whom researchers obtain information or biospecimens through interaction, intervention, or observation of private behavior, to also include the use, study, and analysis of said information or biospecimens.

Obtaining, using, analyzing, and generating identifiable private information or identifiable biospecimens that are provided to a researcher is also considered to be human subjects.

To meet the definition of human subjects, the data being collected or used are about people. Asking participants questions about their attitudes, opinions, preferences, behavior, experiences, background/history, and characteristics, or analyzing demographic, academic or medical records, are just some examples of human subjects data.

• Interacting with people to gather data about them using methods such as interviews, focus groups, questionnaires, and participant observation; or
• Conducting interventions with people such as experiments or manipulations of subjects or subjects' environments; or
• Observing or recording behavior, whether in-person and captured in real time or in virtual spaces, like social media sites (e.g., Twitter) or online forums (e.g., Reddit); or
• Obtaining existing information about individuals, such as students’ school records or patients’ health records, or data sets provided by another researcher or organization.

Interactions and Interventions

Interventions are manipulations of the subject or the subject's environment, for example is a behavioral change study using text messages about healthy foods.

Interactions include communication or interpersonal contact between investigator and participant.

A study may include both interventions and interactions.

Interactions and interventions do not require in-person contact, but may be conducted on-line.

Private Information

Private information  includes information or biospecimens: 1) about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place; 2) that has been provided for specific purposes by an individual; and 3) that the individual can reasonably expect will not be made public (for example, a medical record).

Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for the information to constitute research involving human subjects.

The regulations are clear that it is the subjects’ expectations that determine what behaviors, biospecimens, and identifiable information must be considered private. Subjects’ understanding of what privacy means are not universal, but are very specific and based on multiple interrelated factors, such as the research setting, cultural norms, the age of the subjects, and life experiences. For example, in the United States, health records are considered private and protected by law, but in some countries, health information is not considered private but are of communal concern. 

Identifiable Information

The identity of the subject is associated with the data gathered from the subject(s) existing data about the subjects. Even if the data (including biospecimens) do not include direct identifiers, such as names or email addresses, the data are considered identifiable if names of individuals can easily be deduced from the data.

If there are keys linking individuals to their data, the data are considered identifiable.

Levels of Review

Not all projects that meet the definition of research with human subjects need review by the actual committee. For example, projects that pose  negligible risk to participants may be reviewed and recommended for approval by IRB staff ; other projects may need to undergo review and approval by at least one member of the IRB committee or a quorum of the full board. Determination as to the need for review should always be made by the IRB staff.

Examples of Studies That MAY Meet the Definition of Research with Human Subjects

The following examples will likely require further consultation with an IRB staff member.

Analysis of existing information with no identifiers

If researchers have no interaction with human subjects, but will be conducting a secondary analysis of existing data without individual identifiers, the analysis of those data may not be research with human subjects. 

Expert consultation

Key words in the definition of a human subject are "a living individual about whom" a researcher obtains, uses, studies, analyzes, or generates information. People can provide you information that is not about them but is important for the research. For example, a researcher may contact non-governmental organizations to ask about sources of funding.

Program evaluations and quality improvement studies

Program evaluations are generally intended to query whether a particular program or curriculum meets its goals. They often involve pre- and post-surveys or evaluations.

Some program evaluations include a research component. If data are collected about the characteristics of the participants to analyze the relationship between demographic variable and success of the program, the study may become research with human subjects.  Research question:  Are there different learning outcomes associated with different levels of participant confidence?

Classroom research

Classes designed to teach research methods such as fieldwork, statistical analysis, or interview techniques, may assign students to conduct interviews, distribute questionnaires, or engage in participant observation. If the purpose of these activities is solely pedagogical and are not designed to contribute to a body of knowledge, the activities do not meet the definition of research with human subjects. 

Vignettes: Applying the Definitions

Art in Cambodia

An art history student wants to study art created by Cambodians in response to the massacres committed by the Khmer Rouge. The art she will study includes paintings, sculpture, video, and the performing arts.

Much of the research will be archival, using library and online resources. In addition, she will visit Cambodia. While there, she will speak with several museum curators for assistance locating and viewing art collections related to the massacres.

Is this research with human subjects?

No. Although the student will speak with curators, they are not the subjects of her research and she is not interested in learning anything about them. They will, in effect, serve as local guides.

What would make the study research with human subjects?

The student interviews people as they interact with art to understand the role of the arts in evoking and/or coming to terms with traumatic past events. She interviews people who view the art, such as visitors to museums, and discusses what the art means to them. She may collect information about their experiences during the genocide and compare those experiences with their reactions to the art. 

Bank-Supported Micro-Finance in Chile

A researcher is interested in the practice of microfinance in the Chilean Mapuche community. She meets with bankers and asks about the criteria for granting loans, the demographics of the people who receive loans, the types of businesses to which the bank prefers to grant loans, how many loans they give, the payback rates, and other data about the bank’s loan practices.

No. Although the researcher is interviewing bankers, the bankers are only providing information about their banking practices and are not providing any information about themselves. The questions are about “what” rather than “about whom.” The bankers are not human subjects. This type of interview is sometimes referred to as expert consultation.

The researcher explores the impact of small loans, both intended and unintended, on the recipients of the loans. The researcher interviews the recipients of the loans and gathers information from them about their lives before and after they received funding, how the loans affected their relationships with family members and other community members, the impact of the loans on their aspirations, and so on. He asks “about whom” questions designed to understand the impact of micro-loans.

Developing Teaching Materials

A researcher goes to a country in which the infrastructure has been severely damaged to help rebuild schools. The student interviews community members about what curricular materials they need, develops some materials, and teaches a math class.

No. Although interviews are conducted, the intent of interviewing is to assist in resource development rather than answer a research question designed to contribute to a field of knowledge.

If the researcher does pre- and post-testing to assess student learning in his class, is this research with human subjects?

No. The intent is to find out if the materials are effective. This is sometimes referred to as program assessment.

What would make this research with human subjects?

The researcher studies the impact of nutrition and personal variables on learning. He assesses the nutritional composition of the local diet, assesses students’ general health, and compares those data with test scores. He also measures motivation, family composition, and other characteristics of the students using written questionnaires.

Water Conservation

A researcher wants to find out if the campus water conservation program is effective. She will gather some information about water volume usage from the University engineering department. She will also survey residential students about their water usage habits over the last six months, their perceptions of the campus drought education program, and their reactions to the incentives offered by the program (water-saving competitions, free water-saving devices, etc.) She will report her findings to the program’s steering committee and administrators.

No. Although the researcher will systematically survey other students and will be collecting information about them, her intention is to assess the effectiveness of the conservation program.

The researcher designs an online survey to collect information that may help understand factors that influence the residential students’ responses to the conservation program. She asks questions about green attitudes and behaviors, positions on social and political issues, as well as motivation and narcissism.

Campus IRB Guides

Research: Human Subjects

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This paper describes the development of global research ethics guidelines and emphasizes the importance of the conceptual distinction between research and other activities in the health field. It also presents the main principles of human subject research and provides some examples of the ethics challenges in global research.

• Human research
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Carlson, R. V., Boyd, K. M., & Webb, D. J. (2004). The revision of the Declaration of Helsinki: Past, present and future. British Journal of Clinical Pharmacology, 57 (6), 695–713.

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Presidential Commission for the Study of Bioethical Issues. (2011). Ensuring ethical study design. In Moral science: Protecting participants in human subjects research (pp. 88–96). Washington, DC: Presidential Commission for the Study of Bioethical Issues. http://www.bioethics.gov . Accessed 24 Sept 2015.

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WMA Declaration of Helsinki. (2013). Ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/ . Accessed 24 Sept 2015.

Further Readings

Emanuel, E. J., Grady, C., Crouch, R. A., Lie, R. K., Miller, F. G., & Wendler, D. (Eds.). (2008). The Oxford textbook of clinical research ethics . New York: Oxford University Press.

European Textbook on Ethics in Research. (2009). Luxembourg: European Commission Directorate-General for Research. https://ec.europa.eu/research/science-society/document_library/pdf_06/textbook-on-ethics-report_en.pdf . Accessed 24 Sept 2015.

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The Changing Landscape of Human Subjects Research

Amy Waltz, JD, CIP Associate Director – Regulatory Affairs, Reliance, Outreach Indiana University

Abstract : Understanding context is key to understanding the regulations and complying with regulatory requirements. This article explores the historical context and events that shaped the current human subjects protection regulations and how changes in human subjects research and public perception have impacted the proposed revisions to the human subjects protection regulations. The 2017 revisions to the Common Rule (45CFR46) and the impact of these revisions on government funded research are also addressed.

Introduction

Research compliance is one of the few areas within the United States regulatory system that demonstrates a direct correlation between real-life events, public opinion, and changes in regulatory policy. In 2017, the Common Rule, the set of regulations that defines human subject protection in the United States, was revised for the first time in more than twenty-five years, beginning a new regulatory era in research compliance.

It is extremely important for the research community to understand the context behind those regulations and the recent changes. Understanding the historical context helps researchers and institutional review board (IRB) administrators appropriately balance potential administrative burden with ensuring the highest ethical conduct of research. While the Common Rule, and IRBs, are often seen by researchers as simple administrative burden, they are based in a historical context rife with ethical violations, even when the violators meant well.

The research community is in an excellent position right now, being given the revised Common Rule and the regulatory flexibility that it provides, to use the past to define the future of research.

Early examples of human subjects research

Research in the early years of medical experimentation looked very different than it does today. Those who participated in research, unwittingly or not, were not categorized as “human subjects” and specifically protected. Today, the lines between research and clinical care are carefully drawn. Research and clinical care are explained differently to subjects, and logistics, such as billing, is handled separately in many cases. In the early days of medical experimentation, no formal distinction between research and clinical care was made, and human subjects research was not considered a separate scientific discipline as it is today. Instead, research was simply conducted alongside clinical treatment. 

For example, the great Sidney Farber created chemotherapy at Boston Children’s Hospital. At that time, there were no treatment options for pediatric cancer patients, who almost always succumbed to their disease. As those who work in rare and difficult diseases today can understand, serving as a treating provider for pediatric cancer patients, knowing there was little to be done, was exceedingly difficult. Dr. Farber and his colleagues developed chemical compounds to try to help children with leukemia. Dr. Farber’s work was methodical, ground breaking, and ultimately defined the treatment of cancer; however, the informed consent document as we know it today did not exist for Dr. Farber’s experiments.

Another example of early human subjects research has captured the interest of Americans in recent years. In 1951, George Gey created the first immortal cell line from cells removed from an African-American woman named Henrietta Lacks, who had been diagnosed with a violent form of cervical cancer. The cancer spread extremely rapidly and she passed away within a few months of diagnosis. Dr. Gey was a researcher at Johns Hopkins University who had been searching for an immortal cell line, or a group of cells that would grow for prolonged periods, which he hoped would allow bench scientists to conduct better research. He had asked colleagues at the University and affiliated hospitals to take an extra swab of cells from cancer patients for testing by Dr. Gey. The cells taken from Henrietta Lacks were collected with that request in mind, and no one thought to obtain consent. At that time, the concept of informed consent for research as we know it simply did not exist yet.  

Henrietta Lacks’ immortal cells have changed the face of medical research. Her cells are used throughout the medical and research world; however, neither Henrietta Lacks nor her family consented to the original or ongoing use of her cells. The story became widely known in 2010 when Rebecca Skloot published The Immortal Life of Henrietta Lacks, which became a New York Times bestseller. The book resulted in the first public acknowledgment of the contribution of the Lacks’ family to medical science and sparked a national public discussion about the ethical use of biospecimens for research, including how biospecimens are collected, and the information people should have when their biospecimens are used for medical research. Today, the Lacks family is involved in discussions of how some of Henrietta Lacks’ cells are used. The book changed the way the research world treated the Lacks family.  The discussion in the research community about biospecimens has changed the regulatory perspective on research requirements.

The worst-case scenario

These examples took place well before research regulations existed. The first consideration of human subjects as we know it today did not occur until after the global public learned of Nazi experimentation during World War II. Before and during World War II, the Nazis committed terrible atrocities in the name of medical science using prisoners of war, Jews, and children. Nazi doctors conducted systematic investigations designed to test very specific hypotheses. Many of the experiments were focused on the war effort and attempted to create a better soldier or lessen the effects of the body’s reaction to cold, hunger, altitude, and pain. The infamous Nazi doctor, Josef Mengele, conducted genetic research on more than 700 pairs of twins.

The world did not hear about these atrocities until the Allied forces entered Nazi Germany toward the end of the war and found evidence of carefully-documented medical experimentation in concentration camps and Nazi strongholds around Europe. After the war, hundreds of Nazis were tried for war crimes and crimes against humanity, including medical experimentation, at the Nuremburg Trials.

Like most legal trials, the judgments rendered at the Nuremberg Trials, and the rationale for those judgments, were documented in the judges’ opinions about the cases. The Nuremberg judges who oversaw the medical experimentation cases thought carefully about the ethics of medical research and how medical research should be conducted. They discussed it extensively in their opinions. The judges eventually wrote the first ethical doctrine for conducting medical research, which became known as the Nuremburg Code. The document is often considered the basis for other ethical doctrines world-wide.

The worst-case scenario here at home

After the Nuremberg Code, unethical research practices were a topic of global debate. Unfortunately, there were examples of ethical violations in medical research here in the United States as well. The Tuskegee syphilis studies brought ethical issues in research with human subjects to the forefront of the public eye. These studies were conducted from the 1930sthrough the 1970s, and they were funded by the United States Public Health Service. The Tuskegee syphilis studies were designed to study the natural progression of untreated syphilis over time. When the research began, syphilis was prevalent in African-American men, especially those in poverty, so study doctors focused on that population, offering recruitment incentives which would be especially attractive to the target participants: free medical care, meals, and burial insurance. Given the participants’ need for these things, many now consider those incentives to be unduly influential.

Undue influence was not the only ethical issue in the Tuskegee syphilis studies. Conduct of the study led to a lack of informed consent and failure to mitigate further risk to participants. For example, when the researchers began having trouble recruiting participants, they simply stopped telling potential subjects that they were studying syphilis. Many of the participants never knew that they had syphilis and were never told, despite participating in the syphilis studies for years. Furthermore, study doctors never offered participants a treatment for their disease, despite the fact that a viable treatment became available in the 1940s, while the studies were ongoing.

It is difficult to imagine research being conducted in this way under the current regulatory environment. Subsequent regulatory oversight of human subjects research in the United States focused on avoiding and mitigating the types of issues demonstrated by the Tuskegee syphilis studies.

Development of the regulations

This historical context drove the development of the regulations in the United States (Table 1). The major ethical violations that occurred in the Tuskegee syphilis studies – coercion, lack of informed consent or understanding, failure to treat, and harming research participants, led regulators to directly address such issues in the Belmont Report and the subsequent regulations.

In the mid-1970s, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research set out to develop a set of regulations to ensure that unethical conduct of research no longer happened. After years of work, the Commission developed an ethical guideline, the Belmont Report, which describes the guiding principles for ethical conduct of research in the United States. The Belmont Report outlined three main tenants: respect for persons, beneficence, and justice.

• Respect for persons is the concept of autonomy of research participants, and it requires informed consent to participate in research, as well as a clear understanding that participation in research is voluntary. This tenet also requires protection of persons with diminished autonomy, who may not be able to consent for themselves.
• Beneficence embodies the medical tenet to “do no harm,” and it requires that research be conducted in a way that maximizes benefits and minimizes harm to research participants.
• Justice requires equitable recruitment practices in research so that the benefits and burdens of research are distributed fairly, and those who will benefit from research are those who participate on the research.

The Common Rule

The three tenets of the Belmont Report became the basis of today’s Common Rule. The Common Rule is the set of regulations that requires independent review of research by an IRB to ensure that the research has a sound design and requires additional safeguards for vulnerable populations. The Common Rule has been accepted by the US Department of Health and Human Services and fifteen other Federal departments and agencies that apply to government-funded research. The IRB, under the Common Rule, must determine that:

• Risks are minimized.
• Risks to subjects are reasonable in relation to the anticipated benefits.
• Selection of subjects is equitable.
• Informed consent will be obtained from participants, and that potential participants understand the research and that their participation is voluntary, unless informed consent is waived when specific criteria are met.
• Informed consent will be documented (unless waived).
• The research plan includes adequate provision to protect the privacy and confidentiality of participants.
• If subjects are vulnerable to coercion or undue influence, additional safeguards have been included.

The ethical violations in the early years of medical research led to the Belmont Report, which led to today’s Common Rule – a direct correlation from real-life events and public opinion to changes in regulatory policy that continues today.

Today’s research environment

Since publication of the Common Rule in 1991, the research environment has changed dramatically. New technologies such as digital records, electronic medical records, the human genome project, mobile technology, and big data, among others, have changed the way that research is conducted. Research design has changed. Today, researchers encourage keeping data for possible use in future research. Research repositories, precision medicine programs based in research, and translational research are important initiatives. Comparative effectiveness research has changed thinking about informed consent. Today’s research environment includes concerns about privacy and public engagement in research. For example, when the Common Rule was first published, the Health Insurance and Portability and Accountability Act did not exist. Greater visibility of research in general means research participants are actively engaged in the research process, patients seek out research participation, and research participants help researchers design research in ways that were unheard of in the early 1990s.  

The new Common Rule

In 2017, the first revision to Common Rule in over twenty-five years was published, taking steps to provide a better balance between protection of human subjects and facilitation of new research advances. (Table 3). The revisions strive to reduce some of the administrative burden on researchers and to reduce delay and ambiguity in the current IRB process.

Under the new Common Rule, more research will be considered minimal risk, and even more research will have the opportunity to be exempted from the regulations. In addition, the renewal requirements for minimal risk research have been removed from the Common Rule, reducing administrative burden on IRBs and researchers. New requirements for informed consent will require new informed consent templates and revisions to the informed consent process. The requirement for single IRB review for multi-center studies by 2020 will result in more collaboration with external IRBs.

The effective date of the revised common rule was January 19, 2019.

As a national research community, we now find ourselves in a new era of research. The revision to the Common Rule is just one more example of how the research world is changing. Navigating change can be difficult and complicated; however, the changes provided by the revised Common Rule will offer advantages to researchers and IRBs while providing better protection for human subjects. For the first time since 1991, the research community has an opportunity to build a more desirable research environment, necessitating flexibility and better communication between IRBs and researchers alike. Taking advantage of this new era will require strong collaboration between IRB administrators, research coordinators, and researchers to find and utilize those areas of flexibility within the regulations.

How Context Drove the Regulations

• Lack of understanding
• Failure to treat
• Unverified results
• Respect for persons
• Beneficence
• Minimization of risk
• Risk/benefit ratio
• Informed consent
• Protection of vulnerable populations

The Revised Common Rule

• Balance protection of human subjects with facilitation of research
• Reduce administrative burden, delay, and ambiguity
• Address protections across a broader variety of research
• Harmonize human subjects policies across federal departments and agencies
• New exempt categories based on risk profile
• New requirements for the informed consent process
• “Broad consent” as a new form of informed consent
• Use of a single IRB for multi-site projects
• No continuing review of minimal risk research

4 thoughts on “The Changing Landscape of Human Subjects Research”

Thank you for posting this very interesting summary. These changes are still new to many of us and we should all work to adapt them into our common practice while getting site up and running.

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Are there any changes in the definition of the “Human Subjects” in the last ten years? Does anyone know that?

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Human Subjects Research

Summary of requirements.

Researchers submitting studies involving human participants must meet the following requirements:

• Obtain prior approval for human subjects research by an institutional review board (IRB) or equivalent ethics committee(s)
• Submit documentation from the review board or ethics committee confirming approval of the research. Identifying information about study participants must be redacted from the approval document before it is submitted to the journal 
• Declare compliance with ethical practices upon submission of a manuscript
• Report details on how informed consent for the research was obtained (or explain why consent was not obtained)
• For clinical trials, provide trial registration details, the study protocol, and CONSORT documentation (more information below)
• Confirm that an identified individual has provided written consent for the use of that information

Policy Enforcement

All submissions describing clinical research and/or research on human subjects will be checked to ensure that the requirements above are met. Failure to meet requirements may be grounds for rejection. If issues are discovered after publication, we may issue a correction or retraction as appropriate. We also reserve the right to contact the author’s institution. 

Clinical Studies

Clinical investigations must be conducted according to the principles expressed in the Declaration of Helsinki .

Clinical Trials

PLOS follows the World Health Organization’s (WHO) definition of a clinical trial:

Our policies for clinical trial submissions are designed to promote transparency and reproducibility and to ensure the integrity of the reporting of patient-centered trials. Compliance with our policies is required at submission in order for a manuscript to proceed.

Editors and reviewers should carefully review trial protocols and registration details and assess manuscripts according to CONSORT or other relevant guidelines. Most clinical trial submissions will also be reviewed by a statistician.

Concerns about clinical trial submissions should be brought to the attention of the editorial office as quickly as possible.

Registering clinical trials

All trials submitted to PLOS must be entered in a publicly accessible registry approved by the WHO or ICMJE. See the list of approved registries .

PLOS journals consider prospective trial registration (that is, registration before participant enrollment has begun) to be best publication practice, as recommended by the ICMJE. Clinical trials that began to enroll participants before ICMJE recommendations took effect on July 1, 2005 may be retrospectively registered.

Authors wishing to submit a clinical trial that was not publicly registered before participant enrollment began must register the trial retrospectively in a publicly accessible registry. They must also:

• Register all related clinical trials and confirm they have done so in the Methods section
• Explain in the Methods the specific reasons for failing to register before participant enrollment
• Confirm that future trials will be registered prospectively

PLOS journal editors may decline to further consider any clinical trial for which, in the editor’s judgment, absence of prospective registration raises concerns of selective publication or selective reporting of research outcomes. 

PLOS supports the public disclosure of all clinical trial results, as mandated, for example, by the 2007 FDA Amendments Act. Prior disclosure of results on a clinical trial registry site will not affect consideration.

Required documentation

Clinical trial reports must adhere to the relevant reporting guidelines for their study design, such as CONSORT for randomized controlled trials, TREND for non-randomized trials, and other specialized guidelines as appropriate.

For all clinical trial submissions, authors must include the following:

• Registration details (reported in the Abstract)
• CONSORT checklist or relevant reporting guideline (uploaded as supporting information)
• CONSORT flow diagram (uploaded as Fig 1)
• Trial protocol (uploaded as supporting information)
• Details of prior approval for human subjects research by an institutional review board (IRB) or equivalent ethics committee(s)

The submission will not be considered if documentation is not provided. The checklist, flow diagram, and protocol will be published with the article if the manuscript is accepted.

The manuscript file must include the following information:

• An explanation of any deviation from the trial protocol
• Description of informed consent obtained from participants
• Any information on statistical methods or participants not indicated in the CONSORT documentation

PLOS reserves the right to ask for a blank sample copy of any forms used in the trial.

Patient Privacy and Informed Consent for Publication

We uphold the right to anonymity and take all necessary steps to protect the privacy of those who participate in research.

Authors must avoid providing identifying information unless strictly necessary for the submission. For submissions that include identifying information, or potentially identifying information of patients or other participants, authors must confirm that the individual has provided written consent for the use of that information as per the Consent Form for Publication in a PLOS Journal.

All submissions are checked for documentation of patient consent for publication and for any potentially identifying information. Submissions that include identifying patient information without appropriate patient consent will not be considered for publication.

If identifying information is discovered after publication, the article will be temporarily withdrawn while any content compromising participant privacy is removed.

Additional guidance on preparing clinical data for publication can be found in our Data Policy .

At submission, authors must declare what cell lines were used. Describing sources of cell lines indicates their origin and allows for the research to be reproduced.

For de novo cell lines derived from human tissue, authors must confirm that they obtained approval from an institutional review board or equivalent ethics committee and consent from the donor or next of kin.

Manuscripts using cell lines are checked at initial submission. Those that do not meet the requirements for cell line research will be rejected. Issues with cell lines’ identity, ethical oversight, or potential contamination discovered after publication may lead to a correction or retraction.

Editors and reviewers should evaluate cell line information during peer review and notify the journal if any concerns arise.

Human Subjects Research FAQs

Getting started and completing the forms.

For an activity to be considered human subjects research requiring the University of Texas at Austin IRB’s oversight, the activity must:

• be research
• involve human subjects or information about living individuals, and
• engage the institution in the activity (e.g. through agents/employees/affiliates conducting research, agreements, funding etc.)

Department of Health and Human Services (DHHS)

Research, as defined by DHHS means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge (45 CFR 46.102(d)).

• Systematic Investigation is a planned activity involving qualitative or quantitative data collection and data analysis that sets forth an objective(s) and a set of procedures intended to reach the objective(s), i.e., to acquire knowledge, develop a theory, or answer a question.
• Generalizable Knowledge means information from which one may infer a general conclusion; knowledge brought into general use or that can be applied to a wider or different range of circumstances. For example, publication and presentation are typical methods used to disseminate research findings, thereby contributing to “generalizable knowledge.” However, not all information that is published or presented represents generalizable knowledge. Generalizable knowledge is also interpreted to include data intended for general use, regardless of its eventual distribution or acceptance.

Food and Drug Administration (FDA)

Research as defined by the FDA means any experiment that involves a test article and one or more human participants, and that either must meet the requirements for prior submission to the FDA under section 505 (i) or 520 (g) of the Federal Food, Drug, and Cosmetic Act, or need not meet the requirements for prior submission to the FDA under these sections of the Federal Food, Drug and Cosmetic Act, but the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit.

The terms research, clinical research, clinical study, study, and clinical investigation are synonymous for purposes of FDA regulations (21 CFR 50.3(c), 21 CFR 56.102(c)).

Human Subjects has reference to two definitions defined by federal agencies:

• Obtains information or biospecimens through intervention or interaction with the individual and uses, studies, or analyzes the information or biospecimens; or
• Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.
• FDA defines human subject as an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. When medical device research involves in vitro diagnostics and unidentified tissue specimens, the FDA defines the unidentified tissue specimens as human subjects.

According to HHS regulations, the University becomes engaged in human subjects research when its employees or agents (i) intervene or interact with living individuals for research purposes, or (ii) obtain individually identifiable private information about those individuals for research purposes.

• Under FDA regulations, the institution becomes engaged in human subjects research when it undertakes a clinical investigation on individuals who are or become subjects in the investigation, either as recipients of a test article or as controls and may be either patients or healthy non-patients.
• Principle Investigators are automatically considered to be “engaged” in human subjects research whenever they apply for or receive a direct award to support research that includes human subjects, even if all the activities involving human subjects will be carried out by a subcontractor or collaborator. In all cases the institution to which the grant has been awarded bears the responsibility for protecting human subjects under the award.

If you have any questions about the above and how it applies to your proposed research activity prior to submission, please contact the UT Austin IRB at [email protected] . If your research activity has already been submitted, please reach out to your assigned IRB Analyst directly via comment within UTRMS, or by email.

References/Resources:

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 2: Definitions.
• The Code of Federal Regulations - 21 CFR 50.3(c) , 21 CFR 56.102(c) , 45 CFR 46.102(d)

Yes and no. There are types of Quality Improvement (QI)/Program Evaluations that may qualify as human subjects research and would require UT Austin IRB Review, and types that would not be considered human subjects research.

To be considered human subjects research the activity still needs to meet the definition of research and involve human subjects (See FAQ: What qualifies as Human Subjects Research requiring IRB Review? ).

• Research: Develop or contribute to generalizable knowledge (e.g., testing hypotheses)
• Quality Improvement: Improve a practice or process within a particular institution or ensure it confirms with expected norms
• Program Evaluation: Improve a specific program
• Research: Systematic; follows a rigid protocol that remains unchanged throughout the research; may involve randomization; May involve significant deviation from standard practice
• Quality Improvement: Adaptive, iterative design; may or may not be systematic; generally does not involve randomization; Unlikely to involve significant deviation from standard practice
• Program Evaluation: Adaptive, iterative design; may or may not be systematic; generally individuals not randomized; may involve comparison of variations
• Research: Activities not mandated by institution or program (e.g., activity would not occur separately from research activity)
• Quality Improvement: Activity mandated by the institution or clinic as part of its operations (e.g., activity would still occur regardless of proposed research component)
• Program Evaluation: Activity mandated by the program, usually its funder, as part of its operations (e.g., activity would still occur regardless of proposed research component)

Effect on Program/Practice under Study

• Research: Findings are not expected to directly affect institutional or programmatic practice
• Quality Improvement: Findings are expected to directly affect institutional practice and identify corrective action(s) needed
• Program Evaluation: Findings are expected to directly affect the conduct of the program and identify improvements
• Research: Usually involves a subset of individuals; no obligation to participate; may involve statistical justification of sample size to achieve endpoints
• Quality Improvement: Responsibility to participate as a component of the practice or process; information on all or most involved in the practice or process is expected to be included; exclusion of information from some individuals significantly affect conclusions
• Program Evaluation: Responsibility to participate as a component of the program; information on all or most involved in the program or treatment; exclusion of information from some individuals significantly affect conclusions
• Research: Participants may or may not benefit directly; often a delayed benefit to future knowledge or individuals
• Quality Improvement: Directly benefits a practice, process, or system; may or may not benefit participants
• Program Evaluation: Evaluation concentrates on program improvements or whether the program continues; no expected benefit participants

Dissemination of Results*

• Research: Intent to disseminate results generally presumed at the outset of project as part of professional expectations, obligations; results expected to develop or contribute to generalizable knowledge by filling a gap in scientific knowledge or supporting, refining, or refuting results from other research studies
• Quality Improvement: Intent to disseminate results generally not presumed at the outset of the project; often does not occur beyond the institution evaluated; when published or presented to a wider audience, the intent is to suggest potentially effective models, strategies, assessment tools or provide benchmarks rather than to develop or contribute to generalizable knowledge
• Program Evaluation: Intent to disseminate results generally presumed at the outset of the project; dissemination of information to program stakeholders and participants; may be publicly posted (e.g., website) to ensure transparency of results; when published or presented to a wider audience, the intent is to suggest potentially effective models, strategies, assessment tools or provide benchmarks rather than to develop or contribute to generalizable knowledge

*Please Note: The intent to publish is an insufficient criterion for determining whether a quality improvement activity/Program Evaluation involves research. Some journals will require an official IRB determination letter regardless of the activity being human subjects research. In this case, an application will need to be submitted to the IRB in order to receive a “not human research” determination.

Examples of QI activities that are likely NOT research include:

• Implementing a practice to improve the quality of patient care
• Collecting patient or provider data regarding the implementation of the practice for clinical, practical, or administrative purposes
• Measuring and reporting provider performance data for clinical, practical, or administrative uses
• A group of affiliated hospitals implements an application to reduce prescription amount errors, and collects patient prescription information from medical charts to assess whether the application helped reduce error rates as expected.

Examples of Activities that are likely QI and Research:

• A project involves introducing an untested clinical intervention for purposes which include not only improving the quality of care but also collecting information about patient outcomes for the purpose of establishing scientific evidence to determine how well the intervention achieves its intended results.
• Collaborative (multi-site) – All the sites are trying to improve some aspect of clinical care (ex. implementing an application (app) to help improve making clinical decisions). The whole department decides this app will improve care, and implement the app. They collect data as the app is implemented, and in addition, analyze this data for generalizable knowledge.
• A teacher implements a practice to have all students reflect on their learning by keeping a journal, with the intention of improving teaching practice. However, the teacher also wants to prove that this method works, so they analyze student journals with grades to generalize the success of this method.

Additional resources to assist in determining if your activity is human subjects research requiring review:

U.S. Department of Health and Human Services, Office for Human Research Protections, Quality Improvement Activities FAQs: https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/quality-improvement-activities/index.html

UT Austin IRB, Quality Improvement Project Assessment Form: https://redcap.prc.utexas.edu/redcap/surveys/?s=WL8MXEYXRT

References:

The above is adapted in part from Virginia Commonwealth University IRB’s guidance, Quality Improvement vs. Research – Do I Need IRB Approval? , and The University of Wisconsin-Madison Health Sciences IRB’s Comparison of the Characteristics of Research, Quality Improvement, and Program Evaluation Activities .

All activities meeting any of the definitions of human subjects research conducted under the auspices of UT Austin must be reviewed by the Institutional Review Board (IRB) prior to the start of the activity. The Office of Research Support and Compliance (RSC) recognizes that some student classroom activities involve questionnaires, interviews, or other interactions with individuals that, in a different context, might meet the definition of human subjects research. It is RSC policy that classroom activities where the purpose is to teach students research techniques or methodology with no intention to develop or contribute to generalizable knowledge do not require IRB review. More information can be found within the Student Class Projects Guidance document.

Of note, the University requires all research to be conducted under the guidance of a qualified Principal Investigator (PI). As a teaching institution, students will be engaged in conducting research as an integral part of their educational experience. Faculty who assume PI responsibility for student-led research involving human subjects must be willing to provide oversight to the research activities and assume full responsibility for the conduct of the research. If you are unsure if you are eligible to serve as a Principal Investigator, please review the eligibility table here .

UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 3.12.2 Class Projects and Section 3.16.2 Faculty Principal Investigators for Student-Led Research.

To determine whether oral history or other activities solely consisting of open-ended qualitative type interviews are subject to the University’s human research protections policies, the activity must meet the following standards and general principles for evaluating oral history type activities:

• The activity involves a prospective research plan which incorporates data collection, including qualitative data, and data analysis to answer a research question; and
• The activity is designed to draw general conclusions (i.e., knowledge gained from a study may be applied to populations outside of the specific study population), inform policy, or generalize findings.
• Systematic investigations involving open-ended interviews that are designed to develop or contribute to generalizable knowledge (e.g., designed to draw conclusions, inform policy, or generalize findings) would constitute “research” as defined by 45 CFR 46. For example, an open-ended interview of surviving Gulf War veterans to document their experiences and to draw conclusions about their experiences, inform policy, or generalize findings would require IRB review and approval.
• Oral historians and qualitative investigators may want to create archives for the purpose of providing a resource for others to do research. Since the intent of the archive is to create a repository of information for other investigators to conduct research as define by 45 CFR 46, the creation of such an archive would constitute research under 45 CFR 46. For example, open ended interviews are conducted with surviving Negro League Baseball players in order to create an archive for future research. The creation of such an archive would constitute research under 45 CFR 46 since the intent is to collect data for future research.

Conversely, oral history activities, such as open-ended interviews, that only document a specific historical event or the experiences of individuals without intent to draw conclusions or generalize findings would not constitute “research” as defined by 45 CFR 46. For example, an oral history video recording of interviews with Holocaust survivors is created for viewing in the Holocaust Museum. The creation of the video does not intend to draw conclusions, inform policy, or generalize findings. The sole purpose is to create a historical record of specific personal events and experiences related to the Holocaust and provide a venue for Holocaust survivors to tell their story.

Please see for more information. Researchers are advised to consult with the IRB staff regarding whether their oral history project requires IRB review and approval at [email protected] .

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 3.12.3 Oral History Projects
• HRP-UT981-Guidance Student Class Projects
• The Code of Federal Regulations - 45 CFR 46

Pilot studies that meet the definition of research involving human subjects require IRB review. However, if the study does not meet the definition of research involving human subjects it would not require IRB review.

Definitions can be found in the response to the FAQ: What qualifies as Human Subjects Research requiring IRB Review?

If you have any questions about the above and how it applies to your proposed project, please contact the UT Austin IRB at [email protected] . If your research activity has already been submitted, please reach out to your assigned IRB Analyst directly via comment within UTRMS, or by email.

A complete application must be submitted to the UT Austin IRB through the electronic submission system, UT Research Management Suite – IRB Module (UTRMS-IRB). The Getting Started and Creating a New Study Submission (PDF) document provides step by step instructions on how to create and attach submission documents. Study proposal templates have been created by the UT Austin IRB and are available to download from the UTRMS-IRB Library, Templates tab (Figure 2).

The following materials should be submitted with an application for greater than minimal risk research or otherwise requiring review by the IRB Committee at a convened board meeting, as applicable:

• A research proposal using HRP-UT901 – Template IRB Proposal Standard Submission or HRP-UT903 Template IRB Proposal Secondary Use Submission form.*
• Informed consent documents, parental permission forms, minor assent forms, as appropriate.
• Recruitment materials; i.e., flyers, posters, web-pages, email messages, etc.
• Copies of all measures/instruments if the study involves the use of questionnaires, surveys, or similar instruments.
• Data and Safety Monitoring Plan/Board (DSM-P/B), as applicable
• Site letters for extramural research.
• Review/confirmation of Environmental Health and Safety (EHS), Institutional Animal Care and Use Committee (IACUC), and/or Institutional Biosafety Committee (IBC) approval.
• Sponsor protocol (and the Investigator’s Brochure, when one exists).
• A multicenter research protocol.
• DHHS-approved protocol and/or sample consent document (when one exists).
• Supplemental forms as applicable.**

The following materials should be submitted with an application for an expedited review, as applicable:

• EHS, IACUC, IBC approval documentation.
• Sponsor protocol.

The following materials should be submitted with an application for an exempt determination, as applicable:

• A research proposal using HRP-UT902 – Template IRB Proposal Exempt Submission or HRP-UT903 – Template IRB Proposal Secondary Use Submission form.*
• disclosure to participants that the activity involves research,
• a description of the research procedures,
• who to contact with questions, and
• notice that participation is voluntary.

The following materials should be submitted with an application for a Not Human Subjects Research determination (if required for publication or funding source), as applicable:

• A research proposal using HRP-UT902 – Template IRB Proposal Exempt Submission form or HRP-UT903 – Template IRB Proposal Secondary Use Submission form.*

* When to use HRP-UT903 – Template IRB Proposal Secondary Use Submission form: Use only when the research involves secondary use of data that was originally created for purposes unrelated to the proposed research activity.

** When Supplemental Forms Should be Included in Application/Submission: Available supplemental forms are applicable to research involving biospecimens, investigational devices, investigational drugs/biologics, protected health information, international research, prisoners, registry or repository data, and U.S. Department of Defense are available for download from the UTRMS Library.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 3: General Policies and Procedures.

No, an activity receiving Expedited Review does not mean that the review will occur faster or slower than other submissions. Expedited Review applies to research activities that have been determined to be minimal risk and fits one or more of the categories authorized by 45 CFR 46.110 for expedited review. Please see Section 5.3 Research Appropriate for Expedited Review of HRP-UT1000 IRB Policies and Procedures Manual for more information.

• The Code of Federal Regulations - 45 CFR 46.110 .

All faculty, staff, and students who are or will be involved in the conduct of human subjects research should be listed as Local Study Team Members within the UTRMS study record upon initial submission or through modifications (for non-exempt research).

This applies to all persons with a significant role in the research (e.g., Principal Investigators, Co-Investigators, Project Managers, or Research Assistants) and designated to:

• Recruit potential research participants,
• Obtain informed consent from prospective research participants,
• Interact or intervene with participants to collect research data, or
• Analyze identifiable research data.

All researchers affiliated with UT Austin should automatically be available to select from the personnel pick list. If you have any questions, and the activity is already under review with an assigned analyst, please post a comment to the UTRMS-IRB study workspace with your questions and select “IRB Coordinator” to be notified of its posting.

University policy requires training for all faculty, faculty mentors, researchers, and students, including researchers from other institutions who wish to conduct human subjects research at the University. All personnel, originally listed or later added to a study through an amendment/modification, must complete human subjects research training. In order to comply with the policy, researchers are required to complete the University’s training affiliated with Collaborative Institutional Training Initiative (CITI) . Completion of this training must be accomplished every three years.

Principal Investigators (PIs) and their research staff are required to disclose financial interests in UTRMS-COI according to the University Conflicts of Interest Policy found in the Handbook of Operating Procedures and Policy Memoranda (7-1210, 7-1220).

• Exempt research: PIs who have a potential financial conflict of interest* relating to the submitted study are required to submit Research Certifications in UTRMS-COI confirming financial disclosures are current.
• Non-exempt research (i.e., expedited and full board research) : PIs and research staff identified by the PI as Covered Individuals* are required to submit Research Certifications in UTRMS-COI confirming financial disclosures are current.

*Covered Individuals are defined as individuals who, regardless of title or position, have decision making authority related to the design, conduct, reporting, review, or oversight of research (HOP 7-1210).

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual ; Section 3.8.4 Principal Investigator and Research Staff, Section 3.15 Training Requirements.
• UT Austin’s Handbook of Operating Procedures and Policy Memoranda (HOP) 7-1210 and 7-1220 .
• IRB Training webpage.
• Conflict of Interest Program webpage.
• Who is a Covered Individual? document.

Disclaimer: This question and response applies only to research that is greater than minimal risk or otherwise requires review by the Committee at a convened Institutional Review Board Meeting.

Once a research activity has been reviewed and a determination made by the IRB Committee, correspondence will be sent via email notifying the Principal Investigator as well as the listed Primary Contact or PI Proxy (if applicable) of the determination.

One of the following determinations will be made:

• Approved: Made when all criteria for approval are met. Approved by the IRB as written with no explicit conditions.
• Approved with Explicit Conditions or Modifications Required to Secure Approval: Approved with requirements for minor changes or simple concurrence of the PI. These will be identified to the PI and must be completed and documented prior to beginning the research. Minor or prescriptive changes or requirements will be reviewed for approval by the IRB chair or a designated IRB member, typically the IRB staff person assigned to the study. Substantive changes or requirements, requests for more information for IRB consideration, and other issues related to the criteria for approval require review and approval by the convened IRB.
• Deferred or Tabled : Generally, the protocol or consent form has deficiencies that prevent accurate determination of risks and benefits or requires significant clarifications, modifications, or conditions that, when met or addressed, require full IRB review and approval of the PI’s responses and revisions. The deficiencies will be specified to the PI, and on occasion the PI is asked to attend the full board meeting in order to clarify the points in question. The PI must revise the protocol, consent forms, or other documents as specified by the IRB and re-submit the entire protocol for full review at a convened meeting. The PI may request reconsideration of determination by submitting a written response to the IRB. The IRB will invite the PI to the IRB meeting if the IRB has additional questions. The IRB will reconsider its original decision in light of new information presented by the PI.
• Disapproved: This determination may only be made at a convened IRB meeting. The protocol describes a research activity that is deemed to have risks which outweigh potential benefits or the protocol is significantly deficient in several major areas. The protocol and/or other documents will need to be completely re-written and re-submitted as a new submission. PIs may request reconsideration of disapproved studies by submitting a written response to the IRB. The IRB will invite the PI to the IRB meeting if the IRB has additional questions. The IRB will reconsider its original decision in light of new information presented by the PI. The second decision is final.

Activities that are approved without required modifications to secure approval will populate the study record with initial approval, effective and approval end dates within the top right corner of the main/parent study page in UTRMS (Figure 3).

If determinations other than approval have been made, the top left corner of the main/parent study page in UTRMS will reflect the current status (Figure 4).

If you have any questions, and the activity is already under review with an assigned analyst, please post a comment with your questions and select “IRB Coordinator” to be notified of its posting. For general inquiries, please contact the UT Austin IRB at [email protected] .

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 5.5 Possible IRB Protocol Determinations.

Please budget at least two to three weeks for Exempt Review and three to four weeks for Expedited Review. Greater than minimal risk research or activities otherwise requiring review by the IRB Committee at a convened board meeting must be submitted by the agenda deadline date to be added for review at a specific meeting date (approximately one month in advance). Please review the published agenda and meeting dates for the convened board.

Research that is physically conducted on private property (schools, hospitals, community agencies, NGOs, businesses) requires documented approval from that site (site letter). A site approval letter should:

• Be written on official letterhead by the person most responsible for activities being conducted at the site location.
• Provide attestation that the person most responsible is informed about the research and approves the conduct of the research at the site location.

For research occurring at or using Ascension Seton facilities/resources/data, confirmation of a Seton Site Approval Tool (SAT) submission is required as part of your IRB Submission/Application. Specifically, we require the confirmation email that states the request has been submitted as Seton will require the IRB determination letter prior to their own approval. This applies to all Ascension Seton clinics, Dell Children’s Medical Center, Dell Seton Medical Center at UT Austin and you can complete the SAT submission here .

When performing human subjects research physically in other countries, University researchers are expected to comply with U.S. regulations and guidelines and any applicable regulations of the country in which the research is performed. Researchers demonstrate whether the university or researcher has permission to conduct research in the country by local ethics committee review and approval or by certification (approval) by the local government when there is no local ethics committee. Researchers conducting transnational research are required to complete and upload a copy of HRP-UT908 Template IRB Supplemental Form International Research, located within the UTRMS-IRB Library . For assistance in determining applicable international research protections, please access the U.S. Department of Health and Human Services, Office for Human Research Protections, International Compilation of Human Research Standards .

This is a common issue encountered for student-led research projects that require oversight of the research by an eligible Principal Investigator (PI). If you do not see a submit option it is likely that you are not the listed PI of record or assigned PI Proxy status (a listed study team member who has been assigned by the PI to act on behalf of the PI). Only the PI and the PI Proxy have access to the “Submit” function on the left side of the study page underneath “Next Steps” (Figure 6). If this situation applies to you, please reach out to the listed PI to either submit the application or assign you as PI Proxy following the instructions here .

If the research activity is an industry sponsored clinical trial or multisite research where UT Austin IRB is the reviewing IRB or is deferring oversight, then there may fees involved.

• Fee Schedule for Industry Sponsored Clinical Trials
• Fee Schedule for Multi-Site Research Requiring Single IRB Review

Research involving deception and incomplete disclosure involves intentionally communicating information to research subjects in a way that produces false beliefs. Obfuscation or withholding information at the outset of a study is also considered deception. Any research in which information is withheld until subjects have participated to some degree should be considered as a deception study.

The following are general guidelines regarding the design, review and conduct of studies involving deception and incomplete disclosure:

• Use of deception and incomplete disclosure is usually only acceptable for studies that are minimal risk.
• The use of deception/incomplete disclosure should have no adverse effects on the well-being of subjects.
• The IRB must be supplied with sufficient information to determine that the value of the research outweighs the risk of waiving some aspects of the requirement for full disclosure in the informed consent process. (See Section 6.7 Waiver of Informed Consent and Waiver of Documentation of Consent)
• There is no reasonable alternative to scientifically and effectively address the research question without the use of deception/incomplete disclosure.
• Subjects are not deceived about any aspect of the study that would alter their willingness to participate.
• As soon as it is appropriate, debriefing should be accomplished and the deception/incomplete disclosure explained to subjects.
• When appropriate, subjects should be informed prospectively of the use of deception/incomplete disclosure and consent to its use.
• During debriefing inform subjects of their right to withdraw their data, if they wish, and how that will be accomplished.

To assist the IRB in its review and determination of the appropriateness of the research study, Principal Investigator(s) should address the following items in the relevant documents:

• Explain the reason(s) for use of deception/incomplete disclosure in the study design. Specifically, address why complete disclosure would compromise the scientific validity of the study.
• Describe the extent of the deception/incomplete disclosure in detail and how it relates to the study aims and design.
• Justify and discuss how the proposed research, involving deception/incomplete disclosure involves no more than minimal risk to subjects. Consider all levels of increased risk subjects could experience as a result of the deception/incomplete disclosure methodology.
• Justify and discuss why there are no feasible or scientifically valid alternative methods, which do not involve deception/incomplete disclosure, to conduct the research.
• Describe the methods for prompt disclosure to debrief subjects. This should be accomplished as soon as possible after subjects complete research related activities. Also describe how you will assure that subjects leave the study setting with a clear and accurate understanding of the deception/incomplete disclosure and the reasons for using this methodology. If debriefing is not planned, justify why.
• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 15: Research Using Deceptive or Incomplete Disclosure.

Typically, UT Austin researchers must receive UT Austin IRB approval to conduct research with human subjects, regardless of where the research takes place. When collaborative projects are expected to involve researchers from multiple institutions, contact the IRB Reliance Office to determine next steps ( [email protected] ).  While, in some cases, each investigator should work with their own institution’s IRB, in other cases it might be desirable (or required by sponsor or funding agency) to arrange a Reliance agreement to designate one IRB to review and approve the research as a whole.

• UT Austin IRB’s Reliance Guidance

Yes, UT Austin researchers must receive UT Austin IRB approval or exempt determination to conduct research with human subjects, regardless of where the research takes place. You should also be aware that your project may need local IRB approval (or the equivalent ethical review), in addition to UT Austin IRB’s determination. If the research will be conducted outside the United States, please be sure to fill out the HRP-UT908 - Template IRB Supplemental Form International Research form, located within the UTRMS-IRB Library .

Disclaimer: If you are or will be conducting research outside of the United States, please be aware that UT currently has an international travel policy that involves approval for student/faculty/staff travel to areas of high risk. Please refer to the official UT Travel Policy to Restricted Regions for more details, and to see whether your travel requires review.

The key question for researchers who want to use drawings as incentives for research participation is whether the subject’s participation requires a substantial amount of time and effort. Researchers should ensure that no conditions are imposed for enrollment. This means that everyone is eligible for the drawing upon providing consent to participate in the study. If the researcher wants to impose a condition (e.g., completion of the survey) before entry is granted to the subject, then the IRB (with legal counsel if needed) will need to make the determination as to whether the condition(s) involve a “substantial expenditure of time and effort” on behalf of the subject.

The determination of “substantial time and effort” is made on a case-by-case basis and considers various factors such as the time involvement of the subject, if return visits are required, what is asked of the subject (e.g., survey completion, blood draw), etc.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 4.8.2 Use of Lotteries.

Consent & Recruitment

Researchers should consider obtaining informed consent as a process, not just a consent form, by which the research study is thoroughly explained to the potential subject. The requirement to obtain informed consent should be seen as not only a legal obligation, but also as an ethical obligation. Documentation of informed consent is accomplished through the use of a consent form. Prior to enrolling subjects in a research activity, researchers are required to obtain legally effective informed consent from a potential subject or their Legally Authorized Representative (LAR) and, if the research involves children, a parent’s permission or child’s consent.

Exceptions to Informed Consent Requirements:

Exempt Research:

• There will be a consent process.
• The consent process will disclose that the activities involve research.
• The consent process will disclose the procedures to be performed.
• The consent process will disclose that participation is voluntary.
• The consent process will disclose the name and contact information for the investigator.
• There are adequate provisions to maintain the privacy interests of subjects.

Note: Documentation of consent is not a required element and signatures are not required to be collected. Researchers may create their own consent document/information implementing the above requirements or the HRP-UT926 - Template Exempt Information Sheet available within the UTRMS Library.

Expedited or Greater than Minimal Risk Research:

• Informed Consent is required unless a waiver or alteration of some or all of the elements is requested by the researcher and the waiver is approved by the IRB.
• Written documentation of informed consent (written signature of the subject) is required unless the research meets the criteria for waiver of documentation.

Note: Waiver/Alteration applications are included within sections the HRP-UT901 – Template IRB Proposal Standard Submission form.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 6: Informed Consent.
• See UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 6.7 Waiver of Informed Consent and Waiver of Documentation of Consent for more information about waivers and alterations.
• HRP-UT901 – Template IRB Proposal Standard Submission, HRP-UT920a - Template Informed Consent Form English, HRP-UT921a - Template Parental Permission Form English, HRP-UT922a - Template Assent Form English, HRP-UT926 - Template Exempt Information Sheet from the UTRMS Library .

The regulations are clear that written documentation of informed consent (or permission of the parents if the subject is a child) of the subject (or Legally Authorized Representative) is required for non-exempt research unless a waiver or alteration is approved by the IRB.

If potential subjects are deemed as decisionally impaired, informed consent must be obtained from a Legally Authorized Representative (LAR). They should be told that their obligation is to try to determine what the subject would do if they were competent, or if the subject’s wishes cannot be determined, what they think is in the best interest of the decisionally impaired subject. The IRB must approve the inclusion of decisionally impaired subjects. When a PI proposes to conduct a research project utilizing adult subjects who by virtue of age, physical impairment, mental impairment, or any other reason may not be able to personally execute legally effective informed consent, the IRB shall review the project on the basis of risk and benefit.

• The Code of Federal Regulations, 45 CFR 46 .
• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 6: Informed Consent, Section 12.4 Research Involving Children.

We prefer that you do not use students from your own class as subjects because of the inherent power relationship (e.g., through their responsibility for assigning grades) where it is likely that some students will feel pressure to comply with requests made by their instructors. In other words, the primary issue with gathering data from one’s own course is the potential for undue influence.

In the rare instances in which recruiting from one’s own class is permissible, researchers are expected to minimize the potential for students to feel pressured to participate. There are various strategies for minimizing the potential pressure to participate. One way that researchers have reduced the potential to cause undue influence is to design the study so that the instructor is blind to the identity of the participants (at least until after the final grades have been assigned). For example, a researcher can run the study and keep any identifying information from the instructor. If a researcher designs a study in this way these points are crucial:

Before being asked to participate, potential subjects should be informed that the instructor will not know who did and who did not participate (at least until after the final grades have been assigned).

The research should be designed so that the instructor cannot infer who participated through indirect means (e.g., by seeing who walks into the laboratory, by getting a list of who earned extra credit for participating in the study).

When recruiting from their own class is the only feasible way to do a study, researchers are expected to design the research in such a way that the potential for students to feel pressure is minimized. For example, if the research project concerns a teaching method that will be implemented in the course, then the only possible subject pool comes from the students enrolled in that course. If a research project has a reasonable chance of yielding benefits, and the only feasible way to complete the study is to recruit in the researcher’s course, the reach may be permissible if the researcher is able to sufficiently reduce the potential for students to feel pressure to participate.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 4.5 Researchers Recruiting from Their Own Courses.

Training-Related Topics

University policy requires training for all faculty, faculty mentors, researchers, and students, including researchers from other institutions who are engaged in human subjects research at the University. See FAQ: What qualifies as Human Subjects Research requiring IRB Review? for the definition of engagement in human subjects research at UT Austin.

All personnel, originally listed or later added to a study through an amendment/modification, must complete human subjects research training course required by UT Austin. In order to comply with the policy, researchers are required to complete the University’s training affiliated with Collaborative Institutional Training Initiative (CITI). Completion of this training must be accomplished every three years.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 3.15 Training Requirements.

On the study’s main page within UTRMS-IRB, there is a link above the review timeline called “Study Staff Training Report” (Figure 7). Here, all listed study team members will have all their human subjects research training displayed should it be affiliated within our system.

First, if you were added as the Primary Contact, make sure you were added as a study team member as well. Assigning Primary Contact does not automatically assign a researcher to the list of study team members.

Second, if you do not see your study staff training (for example, half of the boxes in the row are blank) or your updated training hasn’t showed up yet, please leave a Comment on the study with your name, UT EID, and CITI Member ID (not the CITI Record ID). The IRB Analyst assigned to your study will send in an affiliation request. The information should show up within 24 – 48 hours. If it does not, please contact the IRB at [email protected] .

After You Submit Your Proposal

Please contact your assigned IRB Analyst directly via comment within UTRMS, by email, or calling the number they provided, or contact the IRB Office at [email protected] .

Only studies with an approval end date/expiration date require a continuing review to be submitted to the IRB. Research determined to be minimal risk (receiving an exempt determination or expedited review) will not require annual continuing review unless specified by the IRB or additional federal regulations apply (e.g. FDA regulated).

To determine if a study has an approval end date or expiration date, visit the parent/main study page (Figure 8).

IRB approval for non-exempt research requiring a continuing review can be for no longer than a one-year period of time and there is no grace period beyond the expiration date of IRB approval. Extensions of approval beyond the expiration date cannot be granted. Failure to submit the required documents and receive IRB continuing approval for the protocol before the end of the approval period will result in a status of “Lapsed.” This will occur even if the PI has provided the required documents but IRB review and approval is not completed before the expiration date. If a protocol is placed in this status, the PI will be notified that they must cease all research activities (recruitment, advertisement, screening, enrollment, consent, interventions, interactions, and collection and analysis of private identifiable information) until the required documents are submitted, reviewed, and approved by the IRB.

• UT Austin IRB’s HRP-UT1000 IRB Policies and Procedures Manual , Section 7.7 Failure to Comply with Continuing Review Requirements – Lapsed Protocols.

This means that the assigned IRB Analyst has requested changes or clarification to your application or submitted documentation. The PI, PI Proxy and Primary Contact will receive an email notification advising them of the request. Details regarding the request can be found in the study workspace.

What If...?

No, appropriate authorization to obtain and use existing data for research purposes would still need to be obtained. For example, clinicians may have access to an individual’s HIPAA regulated protected health information (PHI) through the regular course of employment. When that PHI is accessed or used for research purposes, written HIPAA Authorization would need to be obtained (unless a waiver of HIPAA Authorization has been requested and granted) prior to its use for research.

University policy requires all research involving human subjects to be reviewed by ORSC or the IRB. If the study meets the definition of research involving human subjects, you must submit to the IRB. If you have conducted research involving human participants without IRB approval/determination, please contact the IRB office ( [email protected] ) to work with IRB support staff regarding appropriate reporting and determinations.

Conducting human subjects research without IRB approval/determination is considered noncompliance and requires appropriate corrective action and reporting.

Additional Information and What is Considered Human Subjects Research

You can find a lot of information governing human subject research at the following sites:

• 21 CFR 50 – FDA, Protection of Human Subjects
• 21 CFR 56 – FDA, Institutional Review Boards
• 45 CFR 46 – DHHS, Protection of Human Subjects
• The U.S. Department of Health and Human Services, Office for Human Research Protections .
• The U.S. Department of Health and Human Services, National Institutes of Health .
• The U.S. Food and Drug Administration, Guidance Documents .

Research using data collected for non-research purposes requires IRB review to determine if the proposed research use meets the definitions of research involving human subjects (See FAQ: What qualifies as Human Subjects Research requiring IRB Review? ). In this instance, HRP-UT903 – Template IRB Proposal Secondary Use Submission form would need to be used.

All communication concerning general IRB questions should be submitted directly to the IRB Office at [email protected] . If your research activity has already been submitted, please reach out to your assigned IRB Analyst directly via comment within UTRMS, or by email.

Human Subjects Research

To comply with federal regulations and Miami policies, research involving human subjects requires that researchers be familiar with the ethical issues common to such work. In addition to the required online training, all human subjects research must be reviewed and the methods approved for compliance with the standards of ethical behavior.

Miami University has a Federalwide Assurance (FWA) with the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (DHHS). The Miami University Institutional Review Board for Human Subjects Protections (IRB) also adheres to other federal, state, local, and institutional guidelines as applicable to the responsible conduct of research.

Institutional Review Board (IRB)

The IRB for Miami University has the responsibility to oversee procedures for carrying out the University's commitment to protect human subjects in research. This oversight includes both internal and externally funded research. The IRB is authorized to approve, require modifications in (to secure approval), or disapprove all research activities using human subjects covered by this policy. Qualifying research can be administratively approved by the Miami Research Ethics and Integrity Program (REI)(termed Level 1 review process).

Human Subjects Research Definitions

Human Subject: Human subject means a living individual about whom an investigator (whether professional or student) conducting research:

• Obtains information or biospecimens through intervention or interaction with the individual, and, uses studies, or analyzes the information or biospecimens; or
• Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens. Research: systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Minimal Risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Some activities may appear to be human subjects research, but are not included in the definition. These include:

• Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research, and historical scholarship), including the collection and use of information, that focus directly on the specific individuals about whom the information is collected.
• Public health surveillance activities, including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority.
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for activities authorized by law or court order solely for criminal justice or criminal investigative purposes. Authorized operational activities (as determined by each agency) in support of intelligence, homeland security, defense, or other national security missions.

When activities may include these activities, it is wise to check with the Miami Research Ethics and Integrity Program before conducting the research.

Do I Have to Submit an IRB Application?

This policy applies to all activities which, in whole or in part, involve research with human subjects if:

• The research is sponsored by Miami University, or
• The research is conducted by or under the direction of faculty, staff, or students of Miami University in connection with their institutional responsibilities, or
• The research is conducted by or under the direction of faculty, staff or students of Miami University using any property or facility of the University, or
• The research involves the use of Miami University's nonpublic information to identify or contact human research subjects or prospective subjects. Graduate and undergraduate student research projects which meet the definition of research and are intended for dissemination beyond the classroom are covered by this policy. Student projects designed to provide research training which are not intended for dissemination beyond the classroom are not treated as research projects under this policy.

Required Ethics Training on Human Subjects Research

All researchers who interact with human subjects to collect data must complete a required educational program on ethics and procedures for the use of human subjects in research before the Institutional Review Board may approve a proposal.

Who Should Complete Ethics Training?

The CITI on-line training course must be completed by the principal investigator (PI), co-principal investigators, and other key personnel who are responsible for the design and/or conduct of the study. The requirement applies to subcontractors, consultants, individual fellowship applicants, study coordinators, and persons who conduct invasive procedures, or conduct health or opinion surveys or interviews. Research assistants including graduate and undergraduate students who are collecting data from human subjects including providing explanations or answering questions about the research in relation to recruiting or use of data gathering instruments are also required to complete the training program.

Individuals providing technical services only such as setting up a room, handing out and collecting survey instruments without providing explanations or answering questions about the research or data-gathering instruments, typing data into a data base, transcribing audiotapes, or reviewing videotapes to code behavior, are not covered by this requirement; however, they should receive instruction on maintaining privacy and confidentiality of data.

Ethical Principles: The Belmont Report

A vital component of all human subjects ethics training are the ethical principles regarding all research involving humans as subjects. These principles have been set forth in the report published by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research entitled, "Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." Some of these principles include respect for persons, beneficence (including minimization of risks and maximization of benefits), and justice. Belmont Report

Submitting an IRB Application for Review

Researchers who propose to conduct research involving humans as subjects shall prepare and submit an Application for Approval of Research Involving Human Subjects to the IRB. Applications must be approved prior to any subject recruitment or contact with subjects. Researchers must complete the required education program on research ethics for human subjects research prior to approval of an application (see section IV).

The objective of committee review is to ensure that the rights and welfare of the subjects are adequately protected and that all activities involving human subjects are in compliance with University policies and Federal regulations to assure that:

• Selection of research subjects is equitable
• Informed consent is obtained and documented where appropriate
• Risks to subjects are minimized
• Risks are reasonable in relation to anticipated benefits to subjects and others
• Privacy and confidentiality are protected
• Data handling and safety monitoring provisions are adequate
• Vulnerable subjects are provided special safeguards against undue influence or coercion to participate in the research

Types of Protocol Review

• New Protocol Review -- All new research projects involving human subjects shall be reviewed by the IRB prior to beginning the project. For initial review by the IRB, investigators shall submit the cover page, research description and supporting materials as specified in the guidance document.
• Revisions to an Approved Protocol -- Any changes in an approved protocol, including subject population, study location, procedures, or project personnel must be reviewed and approved by the IRB prior to initiating changes. Investigators shall submit the Modification Application Cover Page, a description of the proposed changes, and the revised protocol that incorporates the proposed changes.
• Continuing Project Review -- All research involving human subjects approved by the IRB (level 2) must be re-reviewed periodically, at least every twelve months or more frequently as specified in the original approval notification. This applies to studies for which data are continuing to be collected or for which research data are being maintained with personal identifiers that can be linked to individual subject responses. For review of continuing projects, investigators shall submit a Human Subjects Research: Continuing Research Status Report including a status report and personnel form. Research projects are not eligible for continuing review if the project's approval has lapsed more than two years from the approval date. Level 1 approvals (Exempt Certifications) do not require an annual status report.

Researcher Responsibilities for Responsible Conduct of Research

Researchers shall obtain approval for proposed human subjects research prior to recruiting subjects or collecting data from subjects. This applies to preliminary and pilot studies which are developing or testing instruments and procedures, as well as the full study.

Researchers shall explain to subjects, prior to their decision about whether or not to participate, the objectives of the research, the procedures to be followed and the potential risks and benefits. Researchers shall not use individuals as subjects unless satisfied that they, and/or others legally responsible for their well-being, fully understand the consequence of participation and freely consent to participate in the research. The IRB may waive these requirements for written informed consent only when persuaded that the research cannot otherwise be done, that its potential value outweighs the indignity to the subject, and that the subject runs no further risk or harm in participating. Researchers shall seek consent from subjects to participate only under circumstances that provide the prospective subject sufficient opportunity to consider and decide freely whether or not to participate. Subjects shall be given a copy of the informed consent materials to keep.

Researchers shall make clear to subjects that participation is voluntary and that they are free to withdraw from active participation in the research at any time. Subjects who indicate a desire to withdraw shall be allowed to do so promptly and without penalty or loss of benefits to which the subject is otherwise entitled. Any payment to subjects must be reasonable and prorated with partial payment in the event subjects discontinue participation during the course of the study.

Researchers shall respect the privacy of subjects. They shall protect confidential information given them, advising subjects in advance of any limits upon their ability to ensure that the information will remain confidential.

Researchers shall obtain approval from the IRB prior to making any changes in the research procedures. This approval shall be done in a timely manner.

Student Researchers

• Student Research Projects designed to add to generalizable knowledge through dissemination of results in publications or presentations beyond the classroom are covered by this policy on human subjects research. Faculty members who assign or supervise research conducted by students are responsible for ensuring that the proposed research is reviewed and conducted in accordance with University policy and the student is qualified to safeguard adequately the well-being of the subjects.
• Class Projects designed to provide hands-on experience or research training to students are not treated as research projects in this policy and do not require formal IRB review. Projects in this category are expected to be confined to the specific class and end at the termination of that class. If it is anticipated that the research project will be used in other classes or published or presented beyond the classroom, the project should be submitted to the IRB for review. Faculty members who assign research learning experiences are responsible for assuring that people used in such projects are treated ethically. Faculty members must provide information to students on University policies and guidelines on human subjects research and develop class procedures in a manner that protects the privacy, dignity, and welfare of participants.

Research Subjects Under Age 18

In almost all cases, consent from parent(s) or legal guardian(s) is required for children under age 18. College students who are under age 18 must have parental or guardian consent to participate as research subjects. In addition to parental or guardian consent, children should also be asked for their assent to participate in the research project in language appropriate to the subject's age and maturity.

Surveys, interview procedures, or participant observations are not eligible for exempt status (Level 1 Review) when persons under age 18 are involved as subjects.

If you have any further questions about the IRB application materials, training requirements, review procedure or other issues, please contact the REI Office at 529-3600 or email us at [email protected] .

ResearchMatch

ResearchMatch has a simple goal – to bring together two groups of people who are looking for one another:

• People who are trying to find research studies, and
• Researchers who are looking for people to participate in their studies.

ResearchMatch is a confidential, free, and secure registry that has been developed to involve you in their mission to help improve health and wellbeing through research.

Jennifer Sutton

Director of Research Ethics and Integrity

102 Roudebush Hall [email protected]   513-529-0454

Dr. Sherrill Sellers

207D McGuffey Hall [email protected]  

Assistant Director of Research Ethics and Integrity

102 Roudebush Hall [email protected]   513-529-3735

To report an adverse event involving research subjects or non-compliance with protocols: Contact Jennifer Sutton 513-529-0454 as soon as possible.

Multi-Agency Federal Wide Assurance: FWA 00000397 Expires 31 Aug 2027 MU IORG ID: 0000563 Expires 09/20/2025 MU IRB Registration ID: 00000895

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Research and Economic Development

Hipaa & human subjects research mockup, implementation of hipaa and the privacy rule by ucr.

The Health Insurance Portability and Accountability Act (HIPAA) , defines the scope of Protected Health Information, known as “PHI.” HIPAA sets standards to protect patients from inappropriate disclosures of their PHI through the “Privacy Rule.” HIPAA also sets standards for the creation, storage, and transmission of electronic PHI through the “Security Rule.” Together, the Privacy Rule and Security Rule both serve to protect patients against unauthorized uses and disclosures of PHI that may cause harm to their insurability, employability, reputation, and/or their privacy rights.

What is PHI (Protected Health Information)?

All forms of health information that are associated with any of the 18 identifiers specifically defined by HIPAA and are maintained by a covered entity , are considered to be PHI subject to HIPAA regulations. PHI is information created or received by a covered entity relating to:

• The past, present or future physical or mental health or condition of a patient
• Payment for the provision of healthcare to a patient that is transmitted or maintained in any form or medium
• Contains identifiers that can identify a patient or for which there is a reasonable basis to believe the information can be used to identify a patient

To access this information as part of research, authorization or written permission is normally required. The following conditions dictate when PHI may be utilized for Research Purposes:

• When the PI obtains an individual’s HIPAA authorization for use of their PHI
• When the PI obtains a waiver of HIPAA authorization from the IRB for use of PHI
• As part of a Limited Data Set & Data Use Agreement
• When PHI has been De-identified prior to being obtained and utilized
• As part of activities that are considered to be ‘preparatory to research’
• Research on the Deceased

HIPAA Regulations Apply

 if study data are....

• Derived from a medical record
• Added to the hospital or clinical medical record
• Created or collected as part of health care
• Used to make health care decisions

HIPAA Regulations do not apply

• Obtained only from the subject, including interviews, questionairres
• Obtained from a foreign country or countries only
• Obtained from records open to the public

How to utilize PHI within these categories, prior to engaging in research with PHI

When researchers need to apply to the irb (institutional review board).

Most Studies involving human participants will require application to the UCR IRB at [email protected] . Researchers planning to use PHI held by an outside institution are also required to submit an application to the IRB for review and must also follow the HIPAA requirements of the institution(s) holding those records (e.g., Riverside University Health Systems, Riverside Community Hospital, Saint Bernadine’s Medical Center, etc.). Research is subject to HIPAA privacy requirements when it is conducted together with the provision of health care information or services.

Examples include research involving the review of medical records, or research, (such as surveys), which obtain PHI from patients receiving treatment. If an IRB application is determined not to meet federal requirements for “Human Subjects Research,” but still involves the use, disclosure or creation of any PHI, this guidance still applies. The IRB will request that you submit the appropriate HIPAA forms to the UCR School of Medicine’s Health Sciences Compliance office for guidance on a case-by-case basis.

Obtaining an Individual’s HIPAA Authorization

The Principal Investigators (PI) or their designee can obtain authorization from individual participants, or their representatives, for utilization of their PHI for research purposes. This form, along with the Informed Consent Form, can be approved for utilization by the UCR IRB. A single Authorization form for the utilization of PHI for multiple study activities may be used, so long as the authorization is fully vetted by an accredited IRB and contains the same level of information found in the UCR IRB forms.

Because UCR researchers may be working with non-affiliated hospitals and clinics, such non-affiliated institutions may also require use of their version of the HIPAA authorization form to access their medical records. The authorization form originates from the covered entity that owns the PHI. If a covered entity does not have their own authorization form, UCR researchers must still utilize the UCR HIPAA Research Authorization form when obtaining informed consent for research that involves PHI.

Both the UCR HIPAA Authorization Form and the UCR Informed Consent Guide can be found on our forms webpage .

Obtaining a Waiver of a HIPAA Authorization

A PI can request a waiver of an individual participants’ HIPAA authorization as part of their IRB application. There are several important components that go into requesting a waiver. The UCR IRB has the jurisdiction to request changes or deny a HIPAA waiver form if the required components are insufficient to ensuring human subjects protections.

Both the HIPAA Waiver Form and the IRB application form can be found on our forms webpage .

Use of a Limited Data Set

The covered entity and PI can also agree to use a Limited Data Set for research purposes so long as a Data Use Agreement has been executed between both parties. In these cases, with the establishment of an appropriate data use agreement (i.e., meets HIPAA requirements, including limiting further use or disclosure of PHI) between the holder of the PHI and the researcher, a limited data set may be used or disclosed for research purposes without obtaining either an Authorization or Waiver. A Limited Data Set is PHI that excludes the following direct Identifiers of the individual or of relatives, employers, or household members of the individual:

• Postal address information, other than town or city, State, and zip code;
• Telephone numbers, fax numbers, electronic mail addresses;
• Social security numbers, medical record numbers, health plan beneficiary numbers, account numbers, certificate/license numbers, vehicle identifiers and serial numbers (including license plate numbers);
• Device identifiers and serial numbers;
• Web Universal Resource Locators (URLs), Internet Protocol (IP) address numbers;
• Biometric identifiers, including finger and voice prints; and
• Full face photographic images and any comparable images

For more information about Data Use Agreements please visit the Material Transfer Agreements website and an MTA officer can assist you with this process.

Use of De-Identified PHI

De-identified health information is a record in which identifying information has been removed to render the health information not subject to HIPAA’s Privacy Rule. Researchers may use or disclose de-identified health information, without restriction, since it is not PHI and thus is not protected by the Privacy Rule.

However, in order to be used as part of a research study this information must be de-identified prior to it being obtained by the researcher . This is typically done by the covered entity before being released for use. The covered entity seeking to release health information to researchers must determine that the information has been de-identified using either of the following methods:

• By removing all 18 identifiers that could be used to identify the individual or the individual's relatives, employers, or household members, or
• By using statistical methods to establish de-identification, which requires the use of a qualified expert.

Activities that are “Preparatory to Research”

For activities involved in preparing for research, PHI may be used or disclosed to a researcher without an individual’s authorization, a waiver or an alteration of authorization, or a data use agreement. However, this type of access must be requested prior to the actual review or use as part of the IRB application. As part of the IRB application, the UCR IRB must obtain representations from the researcher that:

• The use or disclosure is requested solely to review PHI as necessary to prepare a research protocol or for similar purposes preparatory to research,
• The PHI will not be removed from the covered entity in the course of review, and
• The PHI for which use or access is requested is necessary for the research
• Researchers may not use this information to contact potential study participants.

The preparatory to research provision permits covered entities to use or disclose protected health information for purposes preparatory to research, such as to aid study recruitment. However, this does not permit the researcher to remove protected health information from the covered entity’s site. As such, a researcher who is an employee or a member of the covered entity’s workforce could use protected health information to contact prospective research subjects.

This preparatory to research provision would allow such a researcher to identify prospective research participants for purposes of seeking their authorization to use or disclose protected health information for a research study. In addition, this rule permits a covered entity to disclose protected health information to the individual who is the subject of the information.

Research on Decedents

California law requires local IRBs to review research using State of California-produced death data files containing personal identifying information. State of California-produced death data files which require IRB review include:

• All files that can be linked to other death files using the certificate number (e.g., Death Address Files, Multiple Cause of Death Files); and
• All files that are provided with personal identifiers (e.g., Death Statistical Master Files, Merged Death Files, Fetal Death Statistical Master Files).
• Access to State of California-produced death data files that include personal identifying information also requires review by the State of California Committee for the Protection of Human Subjects (CPHS). Researchers apply for CPHS review when ordering the data from the State of California.
• Research involving State of California-produced death data files that do not contain personal identifying information does not need to be reviewed by the IRB.

As part of the research plan, PIs should contact the Office of Research Integrity directly at [email protected] as an IRB application may be required. The State of California requires that researchers have a "valid scientific interest" in order for the IRB to approve such a study.

Additional HIPAA Resources

• Investigators, research staff, coordinators and administrators who need to know HIPAA research procedures are requested to take the UCR HIPAA Training. You will need to register in order to complete the tutorial.  
• This tutorial has been targeted to research investigators - just fill in the requested information to begin. At the end of the session, you will be able to download a certificate of completion to attach to your UCR IRB application.  
• SOM researchers: In addition to the information provided here, SOM researchers should also be familiar with the UCR Health Sciences Compliance Program as it applies to the practice of medicine as a whole.  
• See the UCOP Policy on Research Use of Protected Health Information for important information on how HIPAA can apply to a research project.  
• For more information about HIPAA requirements as they pertain to review of three or fewer case studies, please review the HIPAA & Case Report Guidance .

Data that is not subject to HIPAA Regulations and is not PHI

Some research studies do not use, disclose or create PHI and are not subject to HIPAA regulations.

For example, some studies use individually identifiable health information that includes personal identifiers such as name, date of birth or address. However, it is not considered to be PHI because the data is not:

• Obtained or generated as part of a health care service (treatment, payment, operations, medical records)
• Entered into a medical record, or
• Used to make treatment decisions

Examples of studies that use research (only) generated health information and are not subject to HIPAA:

• Studies that obtain data from subjects during interviews or surveys, and the investigators do not review or alter the subjects' health records or make treatment decisions as part of the research.
• Studies that obtain data from records open to the public or existing research records.
• Studies that use tests that do not go into the medical record because they are part of a basic research study and the results will not be disclosed to the subject.

Also, health information by itself without the 18 identifiers is not considered to be PHI. For example, a dataset of vital signs by themselves do not constitute PHI. However, if the vital signs dataset includes medical record numbers, then the entire dataset must be protected since it contains an identifier.

Data that is not subject to HIPAA is still regulated by other human subjects protection regulations and may also be subect to other privacy regulations (e.g., the Family Educational Rights and Privacy Act (FERPA) or California's Confidentiality of Medical Information Act (CMIA)).

   Committees

Institutional review board, institutional animal care and use committee, promoting research objectivity committee, stem cell research oversight committee, dual use research of concern, related links.

• Research Misconduct (RM) Allegations
• Responsible Conduct of Research (RCR) Requirements
• Research Participant/Subject Resources
• HIPAA & Human Subjects Research
• IRB Workshops & Outreach

• Policy & Compliance
• Human Subjects Research - Home Page

Human Subjects Research - Home page

Find useful information about proposing and conducting NIH extramural research involving human subjects, including policies, regulations, training and resources.  Learn about considerations for human subjects research when planning and submitting a research application or contract proposal, and throughout the extramural funding cycle.

Definition of Human Subjects Research

Are you planning on conducting human subjects research? Learn more about research that meets the definition human subjects research, Federal regulation requirements, and whether your project may be considered exempt. Also, learn about NIH-specific considerations and become more familiar with NIH policies, and other regulations as it relates to human subjects research protections.

Pre-Award and Post-Award Processes

Learn about the process of applying for a grant, cooperative agreement, or R&D contract, as it relates to the involvement of human subjects research. Find useful resources on how to prepare your Protection of Human Subjects section, and learn about next steps after submitting your grant application or proposal.

Certificates of Confidentiality (CoC)

Learn more about the NIH Certificates of Confidentiality policy. Determine if your research is eligible for receiving a CoC and use our online system to get a certificate. 

Clinical Trial Requirements for Grants and Contracts

If you are submitting a grant application or responding to a contract proposal to NIH that includes a clinical trial, or are involved with conducting, managing, or overseeing clinical trials, learn about NIH policies, and find resources to guide you in your work.

Inclusion Policies

NIH is committed to supporting clinical research that benefits individuals of all sexes/genders, races, ethnicities, and ages. The information provided on this website is designed to assist the extramural community in addressing inclusion, including the Inclusion of Women and Minorities policy and the Inclusion Across the Lifespan policy, in NIH grant applications and progress reports.

NIH Single IRB Policy

Learn about the NIH single IRB policy for NIH-funded domestic multi-site studies involving non-exempt human subjects studies. Find key resources to understand the policy expectations and the process for requesting exceptions. 

Policies & Regulations

Find information about human subjects research policies, and NIH-specific requirements for humans subjects research studies.

Training & Resources

Training and tools to learn about human subjects research, exemptions, and NIH requirements for human subjects research.

This page last updated on: February 28, 2019

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March 22, 2024

Can AI Replace Human Research Participants? These Scientists See Risks

Several recent proposals for using AI to generate research data could save time and effort but at a cost

By Chris Stokel-Walker

zepp1969/Getty Images

In science, studying human experiences typically requires time, money and—of course—human participants. But as large language models such as OpenAI’s GPT-4 have grown more sophisticated, some in the research community have been steadily warming to the idea that artificial intelligence could replace human participants in some scientific studies .

That’s the finding of a new preprint paper accepted for the Association for Computing Machinery’s upcoming Conference on Human Factors in Computing Systems (CHI), the biggest such gathering in the field of human-computer interaction, in May. The paper draws from more than a dozen published studies that test or propose using large language models (LLMs) to stand in for human research subjects or to analyze research outcomes in place of humans. But many experts worry this practice could produce scientifically shoddy results.

This new review, led by William Agnew, who studies AI ethics and computer vision at Carnegie Mellon University, cites 13 technical reports or research articles and three commercial products; all of them replace or propose replacing human participants with LLMs in studies on topics including human behavior and psychology, marketing research or AI development. In practice, this would involve study authors posing questions meant for humans to LLMs instead and asking them for their “thoughts” on, or responses to, various prompts.

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One preprint , which won a best paper prize at CHI last year, tested whether OpenAI’s earlier LLM GPT-3 could generate humanlike responses in a qualitative study about experiencing video games as art. The scientists asked the LLM to produce responses that could take the place of answers written by humans to questions such as “Did you ever experience a digital game as art? Think of ‘art’ in any way that makes sense to you.” Those responses were then shown to a group of participants, who judged them as more humanlike than those actually written by humans.

Such proposals often cite four main benefits of using AI to synthesize data, Agnew and his co-authors found in their new review. It could increase speed, reduce costs, avoid risks to participants and augment diversity—by simulating the experiences of vulnerable populations who otherwise might not come forward for real-world studies. But the new paper’s authors conclude that these research methods would conflict with central values of research involving human participants: representing, including and understanding those being studied.

Others in the scientific community are also skeptical about AI-synthesized research data.

“I’m very wary of the idea that you can use generative AI or any other kind of automated tool to replace human participants or any other kind of real-world data,” says Matt Hodgkinson, a council member of the Committee on Publication Ethics, a U.K.-based nonprofit organization that promotes ethical academic research practices.

Hodgkinson notes that AI language models may not be as humanlike as we perceive them to be. One recent analysis that has not yet been peer-reviewed studied how scientists refer to AI in 655,000 academic articles and found the level of anthropomorphism had increased 50 percent between 2007 and 2023. But in reality, AI chatbots aren’t all that humanlike; these models are often called “ stochastic parrots ” that simply remix and repeat what they have learned. They lack any emotions, experiences or true understanding of what they’re asked.

In some cases, AI-generated data could be a helpful complement to data gathered from humans, says Andrew Hundt, who studies deep learning and robotics at Carnegie Mellon University. “It might be useful for some basic preliminary testing” of a research question, he adds, with the synthetic data set aside in favor of human data once a real study begins.

But Hundt says using AI to synthesize human responses likely won’t offer much benefit for social science studies—partly because the purpose of such research is to understand the unique complexities of actual humans. By their very nature, he says, AI-synthesized data cannot reveal these complexities. In fact, generative AI models are trained on vast volumes of data that are aggregated, analyzed and averaged to smooth out such inconsistencies.

“[AI models] provide a collection of different responses that is basically 1,000 people rolled up into one,” says Eleanor Drage, who studies AI ethics at the University of Cambridge. “They have no lived experience; they’re just an aggregator of experience.” And that aggregation of human experience can reflect deep biases within society. For example, image- and text-generating AI systems frequently perpetuate racial and gender stereotypes .

Some of the recent proposals identified in the new review also suggested that AI-generated data could be useful for studying sensitive topics such as suicide. In theory, this could avoid exposing vulnerable people to experiments that might risk provoking suicidal thoughts. But in many ways, the vulnerability of these groups amplifies the danger of studying their experience with AI responses. A large language model role-playing as a human could very well provide responses that do not represent how real humans in the group being studied would think. This could erroneously inform future treatments and policies. “I think that is so incredibly risky,” Hodgkinson says. “The fundamental [problem] is that an LLM or any other machine tool is simply not a human.”

Generative AI may already be weakening the quality of human study data, even if scientists don’t incorporate it directly into their work. That’s because many studies use Amazon’s Mechanical Turk or similar gig work websites to gather human research data. Already Mechanical Turk–based responses are often seen as subpar because participants may be completing assigned experimental tasks as fast as possible to earn money rather than focusing closely on them. And there are early indications that Mechanical Turk workers are already using generative AI to be more productive. In one preprint paper, researchers asked crowd workers on the site to complete a task and deduced that between 33 and 46 percent of respondents used an LLM to generate their response.

Because there is no scientific precedent for using AI-generated rather than human data, doing so responsibly will require careful thought and cross-field cooperation. “That means thinking with psychologists—and it means thinking with experts—rather than just having a bunch of scientists have a go themselves,” Drage says. “I think there should be guardrails on how this kind of data is created and used. And there seem to be none.”

Ideally those guardrails would include international guidelines set by academic bodies on what is and isn’t acceptable use of LLMs in research or guidance from supranational organizations on how to treat findings reached from the use of AI-powered data.

“If AI chatbots are used haphazardly, it could deeply undermine the quality of scientific research and lead to policy changes and system changes based on faulty data,” Hodgkinson says. “The absolute, fundamental bottom line is the researchers need to validate things properly and not be fooled by simulated data—[or think] that it’s in some way a substitute for real data.”

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Not unique to humans but uniquely human: researchers identify factor involved in brain expansion in humans

What makes us human? According to neurobiologists it is our neocortex. This outer layer of the brain is rich in neurons and lets us do abstract thinking, create art, and speak complex languages. An international team led by Dr. Mareike Albert at the Center for Regenerative Therapies Dresden (CRTD) of TUD Dresden University of Technology has identified a new factor that might have contributed to neocortex expansion in humans. The results were published in the EMBO Journal .

The neocortex is the characteristic folded outer layer of the brain that resembles a walnut. It is responsible for higher cognitive functions such as abstract thinking, art, and language. "The neocortex is the most recently evolved part of the brain," says Dr. Mareike Albert, research group leader at the CRTD. "All mammals have a neocortex, but it varies in size and complexity. Human and primate neocortices have folds while, for example, mice have a completely smooth neocortex, without any creases."

The folds characteristic of the human brain increase the surface area of the neocortex. The human neocortex has a greater number of neurons that support complex cognitive functions.

The molecular mechanisms driving neocortex evolution are still largely unknown. "Which genes are responsible for inter-species differences in neocortex size? What factors have contributed to brain expansion in humans? Answering these questions is crucial to understanding human brain development and potentially addressing mental health disorders," explains Dr. Albert.

The Power of Brain Organoids

To search for factors influencing brain expansion, the Albert group compared developing brains of mice and humans. "Stem cells in mice don't divide as much and don't produce as many neurons compared to primates. Humans, on the other hand, have a large number of stem cells in the developing brain. This highly expanded pool of stem cells underlies the increase in number of neurons and brain size," explains Dr. Albert.

The team found a factor that is present in humans but not in mice. Using 3D cell culture technology, the group tested if the newly identified factor could influence the expansion of the neocortex. "Thanks to the research awarded with the Nobel prize in 2012, it is possible to turn any cell into a stem cell. Such a stem cell can then be transformed into a three-dimensional tissue that resembles an organ, e.g., a brain. Human stem cells make it possible to study development and diseases directly in human tissues," explains Dr. Albert.

These 3D brain cultures, or brain organoids, may not resemble brains to an untrained eye, but they mimic the cellular complexity of developing brains. "Most of the cell types of the developing brain are present. They interact, signal, and are similarly arranged as in an actual human brain," says Dr. Albert.

Using 3D brain organoids, the group was able to show that a growth factor, known as epiregulin, indeed promotes the division and expansion of stem cells in the developing brain.

All About the Amount

"Knowing that epiregulin drives expansion of human neocortical stem cells, we looked back at the gene that codes for epiregulin and tried to trace it through the evolutionary tree," says study lead author Paula Cubillos, a doctoral candidate at the CRTD. The gene is not unique to humans, but also present in other primates and even in mice. "Epiregulin is not produced in the developing mouse brain, however, because the gene is permanently shut off and not being used. We were intrigued to understand whether there are any differences in how epiregulin works in humans and other primates," explains Paula Cubillos.

The researchers turned again to the 3D culture technology. Using gorilla stem cells, the researchers generated gorilla brain organoids. "Gorillas are endangered species. We know very little about their brain development. Organoids made from stem cells offer a way to study their brain development without interacting with the species at all," says Dr. Albert.

Comparing the effect of epiregulin in human and gorilla brain organoids, the team found that adding epiregulin to gorilla brain organoids can further promote the expansion of stem cells. However, adding even more epiregulin to human brain organoids did not have the same effect. This might be because the human neocortex has already expanded to a very large extent.

"Unlike previously identified factors, epiregulin as such seems not to be unique to humans. Instead, the amount of the growth factor seems to be the crucial regulator for the inter-species differences," concludes Dr. Albert.

This study not only advances our understanding of human uniqueness but also highlights the importance of new technologies that offer ethical and non-invasive complements to animal research.

The study was performed in collaboration with King's College London, the Medical Faculty Carl Gustav Carus of TU Dresden, the Max Planck Institute of Molecular Cell Biology and Genetics, and Hannover Medical School.

• Brain-Computer Interfaces
• Neuroscience
• Brain Injury
• Intelligence
• Language Acquisition
• Disorders and Syndromes
• Learning Disorders
• Neocortex (brain)
• Memory-prediction framework
• Multiple sclerosis
• Mirror neuron
• Neurobiology

Story Source:

Materials provided by Technische Universität Dresden . Note: Content may be edited for style and length.

Journal Reference :

• Paula Cubillos, Nora Ditzer, Annika Kolodziejczyk, Gustav Schwenk, Janine Hoffmann, Theresa M Schütze, Razvan P Derihaci, Cahit Birdir, Johannes EM Köllner, Andreas Petzold, Mihail Sarov, Ulrich Martin, Katherine R Long, Pauline Wimberger, Mareike Albert. The growth factor EPIREGULIN promotes basal progenitor cell proliferation in the developing neocortex . The EMBO Journal , 2024; DOI: 10.1038/s44318-024-00068-7

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Sea surface temperature research provides clear evidence of human-caused climate change

by Woods Hole Oceanographic Institution

New oceanic research provides clear evidence of a human "fingerprint" on climate change and shows that specific signals from human activities have altered the seasonal cycle amplitude of sea surface temperatures (SST).

"This is breakthrough evidence that there is a human-caused climate change signal in ocean temperatures associated with CO 2 increases," according to co-author Benjamin Santer, an adjunct scientist and distinguished scholar in the Physical Oceanography Department at Woods Hole Oceanographic Institute (WHOI).

"We show that a human-caused signal in the seasonal cycle of sea surface temperature (SST) has emerged from the noise of natural variability. Geographical patterns of changes in SST seasonal cycle amplitude (SSTAC) reveal two distinctive features: an increase at Northern Hemisphere mid-latitudes related to mixed-layer depth changes and a robust dipole pattern between 40˚S and 55˚S which is mainly driven by surface wind changes," according to the journal published in Nature Climate Change .

"The evidence we found is very clear. Our research is based on four different observational data sets of sea surface ocean temperature. We analyzed data from various monitoring systems, including satellite records and ocean measurements that WHOI has been collecting from ships and floats since 1950."

"All of this data provided the same story and the same conclusion: that the human-caused signal in SSTAC is very strong and has a very distinctive pattern," reported co-lead author Dr. Jia-Rui Shi, Postdoc with WHOI.

The model-predicted pattern of SSTAC change is identifiable with high statistical confidence in four different observed SST products and in 51 individual model realizations of historical climate evolution. Simulations with historical changes in individual forcing reveal that greenhouse gas increases are the primary driver of changes in SSTAC, with smaller but distinct contributions from anthropogenic aerosol and ozone forcing.

The research was motivated by earlier work by Santer, who has worked on climate fingerprinting for more than 30 years. Previous studies used satellite records to identify human fingerprints in the changing seasonal cycle of mid-to-upper tropospheric temperature. However, this is the first fingerprinting study that reveals detailed patterns of climate change in seasonal sea surface temperatures.

"The seasonal cycle amplitude of sea surface temperature is changing and becoming stronger. One of our biggest findings is that warming is greater in the summer than in the winter. In both the northern and southern hemispheres, the mixed-layer depths of the ocean are becoming thinner, which can significantly amplify summer temperatures," stated Shi.

"The warming in the northern hemisphere is more extreme, associated with smaller ocean basin sizes. In the southern hemisphere, we discovered that sea surface temperature changes are largely driven by wind shift patterns caused by atmospheric warming."

"This research rebuts claims that recent temperature changes are natural, whether due to the sun or due to internal cycles in the climate system. A natural explanation is virtually impossible in terms of what we are looking at here: changes in the seasonal temperatures of the ocean," stated Santer. "This research further rules out the claim that we don't need to treat climate change seriously because it is natural."

"This robust human fingerprint in the seasonal cycle of ocean surface temperature is expected to have wide-ranging impacts on marine ecosystems. This can dramatically influence fisheries and the distribution of nutrients," said Shi. "Gaining insight into the anthropogenic influence on seasonality is of scientific, economic, and societal importance."

In 2023, the upper ocean heat content was the highest on record, leading to strong concern in the scientific community . The ocean absorbs roughly 90% of the Earth's excess heat from global warming and plays a vital role in regulating planetary climate systems.

"Ocean temperatures are literally off the charts. A lot of people want to know what is happening," said Santer. "A big part of the answer is that human activities have gradually warmed the world's oceans. The scientific community has been focused on changes in the ocean's annual average temperature. This paper shows that it's also critically important to perform fingerprinting with seasonal changes," said Santer.

The ocean is a vital carbon sink, absorbing 25% of the carbon dioxide that we produce by burning fossil fuels. However, the ability of the ocean to absorb CO 2 is temperature-dependent. As the ocean warms, it is critical that we understand how the ability of the oceans to absorb CO 2 is affected.

"As oceans absorb carbon dioxide , it creates widely reported acidification, which can negatively impact marine organisms. If we start altering the pH of the ocean, we risk affecting the structural integrity of organisms at the base of the food chain," said Shi.

"We now face important decisions, in the United States and globally, on what to do about climate change. Those decisions be based on our best scientific understanding of the reality and seriousness of human effects on average climate and on the seasons," stated Santer.

Provided by Woods Hole Oceanographic Institution

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