Ethics Principles that Provide Guidance to Researchers

by Allen Alvarez

Principles maintain a prominent place in legal instruments and guidelines used to regulate research around the world. We can see this prominence in the drafting of codes, declarations and reports in response to abuse of research subjects in the years between 1932 and 1964.

A running history of events that influenced the development of research ethics during and after that period is presented by David Resnik (June 2014).

Examples of ethical violations in history

1947
The Tuskegee Syphilis Study that studied the effects of untreated syphilis in 400 African American men, a study the U.S. Department of Health sponsored between 1932 and 1972, may not be in violation of any research regulation during its first 14 years (1932-1946). In 1947, however, it was clear that it violated key ethical principles after the Nuremberg Code. Even after the Code was issued, the sponsor and researchers continued to run an unethical experiment for the next 25 years (1947-1972).

Based on the 10 requirements of the Code, the Tuskegee Syphilis Study is in clear violation of the following:

1. voluntary informed consent to participate is absolutely essential (1, 9) - the 400 subjects were not told that they were in an experiment and they even believed they were getting treatment
2. the requirement to "avoid all unnecessary physical and mental suffering and injury" (4, 5, 7, 8, 10) - the subjects were withheld treatment even when penicillin became widely available in the 1940s (American Chemical Society 1999);
3. "risk to be taken should never exceed" the expected benefits of the study (6, 2, 3) - the subjects took risks without getting any benefits

1946-1948
Unethical human experiments were conducted by the US government in Guatemala that involved intentionally infecting over 1300 subjects with venereal diseases to test the effectiveness of penicillin (Reverby 2011). 83 participants died in the study. 700 participants were treated with penicillin. All participants were not informed that it was an experiment.

1964
Aside from the Nuremberg Code, the Tuskegee Syphilis Study physicians violated ethical standards of medical research when the Declaration of Helsinki was issued in 1964. The Study violated the Declaration for 8 years (1964-1972). As a non-therapeutic study, the physicians who conducted the study contravened key articles under section III, namely:

• 1.  "...the duty of the doctor to remain the protector of the life and health of that person on whom clinical research is being carried out."
• 2. The nature, the purpose, and the risk of clinical research must be explained to the subject by the doctor.
• 3a. "Clinical research on a human being cannot be undertaken without his free consent..."
• 3c. "Consent should as a rule be obtained in writing."
• 4a. The investigator must respect the right of each individual to safeguard his personal integrity, especially if the subject is in a dependent relationship to the investigator.
• 4b. At any time during the course of clinical research the subject or his guardian should be free to withdraw permission for research to be continued. The investigator or the investigating team should discontinue the research if in his or their judgment it may, if continued, be harmful to the individual. 

1966
It was on this year that Henry Beecher (1966) published an article that revealed 22 studies that were in violation of known ethical standards at that time.

Responses to unethical research

1974-1979     Identification of basic ethical principles
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was convened in 1974 with a two-part mandate:

1. "to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects" and 
2. "to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles" (from the summary of The Belmont Report).

Four years later, the Commission issued the Belmont Report (1978) that:

1. identified the 3 basic ethical principles of (a) Respect for persons, (b) Beneficence and (c) Justice;
2. consideration of 3 requirements that apply those 3 principles. The 3 requirements are (a) Informed Consent, (b) Assessment of Risks and Benefits and (c) the requirement that there be fair procedures and outcomes in the selection of research subjects.

The Commission used the expression "basic ethical principles" to mean "general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions" (p. 4). The source of these basic principles is the cultural tradition of the members of the Commission and these are only 3 of those other principles "generally accepted" in the said cultural tradition that "are particularly relevant to the ethics of research involving human subjects" (p. 4).

Albert Jonsen, who was a member of the Commission, recounts that an original list of 8 principles were identified (Jonsen 2005: 4). Because the commissioners felt that the list should not include too many principles and that whichever included should be universal, they reduced them to three which were suggested by H. Tristram Engelhardt (respect for persons as free agents and concern to support the best interests of human subjects in research) and Tom Beauchamp (distributive justice) (Jonsen 2005: 4).

Ethical principles are social and relational. These refer to what we, as members of society, value as important in relation to other members of society. Ethical principles are different from personal values although we sometimes call these values 'our principles'. Personal values of specific individuals may or may not be social but they are personal in the sense that these are valued regardless of its implications to others. Ethical principles, on the other hand, are valued on the basis of our relation to others and because we relate to others. 

1991     Legislation
The U.S. government published the Federal Policy for the Protection of Human Subjects (45 CFR part 46, subpart A), a.k.a.  the “Common Rule” in 1991. The Common Rule is codified in separate regulations by 15 Federal departments and agencies. Subpart B of 45 CFR 46 requires additional protections for pregnant women, human fetuses, and neonates; subpart C, additional protections for prisoners; and subpart D, additional protections for children. The Common Rule outlines the basic provisions for Institutional Review Boards (IRBs), informed consent, and Assurances of Compliance. Since 1991, all researchers of government funded studies, including those conducted in foreign countries, and researchers in government institutions are legally required to comply with the requirements of the Common Rule. The current version (2009) of 45 CFR 46 with all its subparts are available here and here. It is continuously being updated to meet the changing demands of protecting research subjects.

21 CFR, especially 50 (Protection of Human Subjects), 54 (Financial Disclosure by Clinical Investigators), 56 (IRBs), and 58 (Good Laboratory Practice for nonclinical laboratory studies), are issued to govern Food and Drug Administration (FDA) regulated research activities and clinical trials. Other related FDA regulations are listed here.

1992    Promotion of responsible research from within scientific practice
The National Academy of Sciences (NAS) published Responsible Science: Ensuring the Integrity of the Research Process (NAS 1992). The book referred to misconducts in research that goes beyond the requirements of earlier regulations intended to govern research involving human subjects (NAS 1992, pp. 135-136). It is noteworthy to quote what the NAS thought about the role of guidelines it is contemplating to develop to promote responsible conduct:

Guidelines for the conduct of research differ from institutional policies [emphasis added] that are designed to address misconduct in science or conflict of interest or that, in response to regulatory requirements, govern research involving human subjects [emphasis added], hazardous materials, or recombinant DNA.¹¹ Research conduct guidelines are intended to promote responsible conduct of research and, to the extent that questionable practices and misconduct in science are linked, to reduce the amount of misconduct in science. However, although there are positive advantages associated with the adoption of such guidelines, this approach, by itself, may not be effective in fostering responsible research conduct. The imposition of guidelines also carries certain risks and limitations in the collegial academic environment. 

Responsible Science also estimated the incidence of misconduct, discussed some of the causes of misconduct, proposed a definition of misconduct, and recommended ways to prevent misconduct in research. Bernard Gert, who was critical of the principle-based approach to bioethics, is listed on the Panel on Scientific Responsibility and the Conduct of Research (or the Panel).

Ten years later, NAS followed up with another book Integrity In Scientific Research: Creating An Environment That Promotes Responsible Conduct (2002). This was prepared by its Committee on Assessing Integrity in Research Environments. It defines integrity from an individual and institutional point of view:

For individuals, it is an aspect of moral character and experience.¹ For institutions, it is a matter of creating an environment that promotes responsible conduct by embracing standards of excellence, trustworthiness, and lawfulness that inform institutional practices. (NAS 2002, p.34)

The document highlights a combination of making the institutional environment conducive to promotion of integrity through the establishment of explicit procedures, systems and codes of conduct (NAS 2002, pp. 49-71), establishing an institutional performance-based assessment and benchmarking (NAS 2002, pp. 72-83),  integrating an educational program into the training curricula (NAS 2002, pp.84-111, cf. NAS 1992, pp. 130ff) and evaluation by self-assessment approach (NAS 2002, pp. 112-123).

While I frame the four approaches identified by NAS (2002) as attempts to respond to previous unethical conduct in research, I do not mean to imply that these responses are mutually exclusive.

1994-1998     Institutional initiatives
In Canada, the three major public research funding bodies (the Social Sciences and Humanities Research Council (SSHRC), the Medical Research Council (MRC which was replaced in 2000 by the Canadian Institutes of Health Research, CIHR), and the Natural Sciences and Engineering Research Council (NSERC)) consulted to develop a common ethics policy statement (Greene 2002).  The process produced the Tri-Council Policy Statement (TCPS): Ethical Conduct for Research Involving Humans in 1998. TCPS required researchers and their institutions to follow the policy's ethical principles when their project is funded by any of the three agencies.

Here is Ian Greene's summary of seven of the 8 guiding ethical principles in TCPS (1998):
1.  Respect for Human Dignity
2.  Respect for Free and Informed Consent
3.  Respect for Vulnerable Persons
4.  Respect for Privacy and Confidentiality
5.  Respect for Justice and Inclusiveness
6.  Balancing Harms and Benefits
7.  Minimizing Harm

It is understandable if Greene may have left out principle 8, i.e. Maximizing Benefit, since that principle is closely related to TCPS principle 7. In fact, both can be considered specifications of the Belmont Report's principle of Beneficence.

2009     Adoption of institutional initiatives
The  Health Canada Research Ethics Board published its Administrative Policy and Procedures Manual (Ethics Review of Research Involving Humans) in January 2009. The Manual lists all 8 of the TCPS (1998) Guiding Ethical Principles in its Appendix A including principle 8-Maximizing Benefit.

2010
The TCPS, 1st edition (1998), was revised in 2010 as TCPS2. The changes are listed here. It is noteworthy to mention that TCPS 1998's "8 Guiding Ethical Principles" (Context of an Ethics Framework. C.) was replaced by TCPS2 2010's "3 Core Principles" (Chapter 1.B) which are essentially the same as the 3 principles in the Belmont Report (1978).

2014
The TCPS2 (2010) was revised once again in 2014 as TCSP2 (2014). The changes are listed here. The 3 Core Principles are retained and are the same as in TCPS2 (2010).

Declaration of Helsinki (2013) 

After the year 2000, the Declaration of Helsinki was amended again in 2002, 2004, 2008 and 2013. The 2013 version lists 12 general principles (articles 3 - 15) and several others specific to risks, burdens and benefits, vulnerable groups and individuals, scientific requirements and research protocols, research ethics committees, privacy and confidentiality, informed consent, use of placebo, post-trial provisions, research registration and publication and dissemination of results and
unproven interventions in clinical practice.

Part of the process that influenced revisions since 2002 onward is the 1997 publication of Peter Lurie and Sidney Wolfe's (1997) claim that the NIH, WHO, UN and CDC designed unethical clinical trials on the prevention of mother-child transmission of HIV in developing countries.

The Lurie & Wolfe (1997) New England Journal of Medicine Sounding Board paper has been widely cited, raising the awareness about the need to develop regulation and ethics review capacity across international borders, especially when clinical trials are done through multi-country collaboration between scientists in different countries, including low income countries where the risk of research injustice is high.

All the institutions called out responded with initiatives that would address the ethical violations Lurie & Wolfe (1997) identified. NIH funded capacity building projects to train researchers and members of ethics review committees in low income countries in reviewing and regulating research to assure compliance to high ethical standards. NIH's Fogarty International Center launched the International Research Ethics Education and Curriculum Development Award which helped train local bioethicists in different countries and enhanced their capacity to develop local research ethics review guidelines. One example is the Philippines' National Ethical Guidelines for Health and Health Related Research (pages 13-267).

WHO and UN collaborated to launch initiatives in ethics review capacity building through TDR and SIDCER's Strategic Initiative for Developing Capacity in Ethical Review which supported researchers in different countries in Asia-Pacific to organize their respective Forums for Ethics Review Committees in Asian and Western Pacific countries (FERCAP).

The European Commission (EC) also contributed to to the global response to research injustice following Lurie & Wolfe's (1997) exposé by funding capacity building initiatives including the multi-country project CTC-ETHICS - Ethical issues in clinical trial collaborations with developing countries from 2000 to 2002. CTC Ethics organized capacity building events to train researchers in ethics review of multi-country research and conducted studies in research ethics leading to publications in peer-reviewed journals. Reidar Lie, the Principal Investigator of that project, hired a research assistant, Allen Alvarez, to interview members of ethics review committees in the Philippines (including FERCAP members) about the use of placebo in clinical trials when an effective treatment already exists. The interview study results got published in the journal Bioethics (2005). Lie and Alvarez's collaboration later led to Alvarez completing his PhD (University of Bergen, 2009) under Lie's supervision. 

Optimism and skepticism toward the role of principles in fostering compliance to non-legal requirements and guidelines

Beyond legally enforceable regulatory instruments, the issue of compliance to ethical standards for research in non-legally binding guidelines, is important to address. Parallel to corporate efforts (Trevino, et al. 1999) in managing ethics in relation to legal compliance, regulation of research according to ethical aspirations embodied by principles require that we identify the core principles contained in legal instruments and guidelines.

However, there are doubts whether imposition of guidelines that enforce these principles can be effective in "fostering responsible research conduct" since the "imposition of guidelines also carries certain risks and limitations in the collegial academic environment" (NAS 1992, pp.135-136). In particular, the Panel (1992, pp.136-137) listed 10 disadvantages of institutional guidelines, namely:

1. "Many scientists believe that research conduct guidelines are unnecessary and ineffective research practices are often too complex and too varied to be governed by a few general principles (emphasis added)"
2. "adopting such principles is a time-consuming process that requires the efforts of active researchers who are already burdened by other obligations"
3. "focusing on guidelines diverts attention from the consideration of complex ethical issues and genuine dilemmas in the research environment"
4. "research guidelines cuts against faculty autonomy and other values associated with academic freedom as ideals of the academic environment"
5. "guidelines may encourage implementation of rules and rigid regulations, as well as “cookbook” approaches to scientific endeavors" 
6. "guidelines that describe appropriate research conduct will expose them to additional litigation and administrative vexations (Nobel, 1990)"
7. "Many scientists believe that explicit guidelines can add little of substance to the material already included in publications such as On Being A Scientist and Honor in Science"
8. "guidelines may not be necessary because the norms of science are self-evident and because existing policies provide abundant advice to determine how to conduct research responsibly"
9. "the effort needed to bring to the attention of faculty and students any research conduct guidelines that have been adopted" is a drawback" 
10. "If research conduct policies are not appropriately implemented, they can be viewed as empty gestures or “window dressing” that will serve little purpose." 

The Panel concluded that "Written guidelines are unlikely to influence academic research behavior if they are imposed from above or from outside (emphasis added)" (NAS 1992, p.137).

The effective strategy they endorse is an integrated bottom-up (rather than top-down) approach to developing guidelines, i.e.

To be effective, guidelines must be incorporated into the process of research and education and become an operational part of day-to-day activities. If faculty desire to develop guidelines for the conduct of research, such policies should be formulated by those who will be directly affected and should be adapted to specific research fields and protocols.

Institutional guidelines are likely to be less effective than ones formulated at the group or laboratory level. However, research institutions may wish to adopt an overarching set of general principles for their members to provide a common frame of reference. (NAS 1992, p.138)

The Panel noted that academic or scientific freedom is too important that any imposition to restrict it must be justified. Thus, guidelines or regulatory interventions that restrict such freedom are only needed when misconduct is likely to persist: "steps that might restrict scholarly or scientific independence were taken only when there was clear evidence that inappropriate behaviors or hazardous situations might persist in the absence of institutional policies" (NAS 1992, pp.136-137). They caution that "care should be taken to avoid adopting constraints that could be damaging to the research process" (NAS 1992, p.138).

Furthermore, "development of such guidelines should be left to the discretion and initiative of individual faculty and research institutions" (NAS 1992, p.138).

What do you think should be our approach to fostering ethical research? Approach A. others review research protocol to regulate and reduce misconduct? Approach B. researchers take initiative in self-regulating their research practice so that they can avoid misconduct? or Approach C. combine review and self-regulation?

References:

Beecher, H. K. (1966). Ethics and Clinical Research. New England Journal of Medicine, 274(24), 1354-1360. http://dx.doi.org/10.1056/NEJM196606162742405

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (1998). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS). Available at: http://www.pre.ethics.gc.ca/eng/archives/tcps-eptc/Default/. Date modified: December 18, 2014. 

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (2010). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS2). Available at: http://www.pre.ethics.gc.ca/eng/archives/tcps2-eptc2-2010/Default/

CIHR, NSERC, SSHRC (Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada) (2014). Tri-Council Policy Statement: Ethical Conduct For Research Involving Humans. Tri-Council policy statement: Ethical conduct for research involving humans (TCPS2 2014). Available at: http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/. Date modified: February 13, 2015.

Greene, I. (2002). Summary of the Guiding Ethical Principles for Research Ethics. Available at: http://www.yorku.ca/igreene/tricoun.htm. Published: February 1, 2002. Last accessed: December 15, 2015

Health Canada (2009). Available at: http://www.hc-sc.gc.ca/sr-sr/pubs/advice-avis/reb-cer/index-eng.php#t12_a. Last accessed: December 15, 2015.

Jonsen, A. R. (2005). On the origins and future of the Belmont Report. In Childress, J. F., Meslin, E. M., & Shapiro, H. T. (Eds.). Belmont revisited: Ethical principles for research with human subjects. Georgetown University Press. pp. 3-11. https://books.google.ca/books?id=4U6iStmnQlYC&lpg=PP1&pg=PA3#v=onepage&q&f=false

Lurie, P., & Wolfe, S. M. (1997). Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries. New England Journal of Medicine, 337(12), 853-856. http://dx.doi.org/doi:10.1056/NEJM199709183371212

Reverby, S. M. (2011). “Normal Exposure” and Inoculation Syphilis: A PHS “Tuskegee” Doctor in Guatemala, 1946–1948. Journal of Policy History, 23(01), 6-28. http://dx.doi.org/doi:10.1017/S0898030610000291

NAS (1992). Institute of Medicine, National Academy of Sciences, and National Academy of Engineering. Responsible Science, Volume I: Ensuring the Integrity of the Research Process.   Washington, DC: The National Academies Press, 199 pages. Available at: http://www.nap.edu/read/1864/. Published online: March 1, 2003. Last accessed: December 15, 2014.

NAS (2002). Committee on Assessing Integrity in Research Environments. Integrity In Scientific Research: Creating An Environment That Promotes Responsible Conduct. Washington, DC: The National Academies Press, 202 pages. Available at: http://www.nap.edu/read/10430/ Published online: October 1, 2002. Last accessed: December 15, 2015.

Nobel, J. J. (1990). Comparison of research quality guidelines in academic and nonacademic environments. JAMA, 263(10), 1435-1437. http://dx.doi.org/10.1001/jama.1990.03440100159023

Resnik, D. (2014). Research Ethics Timeline (1932-Present). Available at: http://www.niehs.nih.gov/research/resources/bioethics/timeline/. Published online: November 17, 2004. Revised: June 2, 2014. Last accessed: December 15, 2015.

Trevino, L. K., Weaver, G. R., Gibson, D. G., & Toffler, B. L. (1999). Managing ethics and legal compliance: What works and what hurts. California Management Review, 41(2), 131.