ethical concerns regarding research on human subjects

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• v.59(4); 2006 Apr

Ethical and legal issues in research involving human subjects: do you want a piece of me?

The conduct of biomedical research involving the participation of human beings implicates a variety of ethical concerns pertaining to such values as dignity, bodily integrity, autonomy, and privacy. These ethical concerns have been translated into a complex regulatory apparatus in the USA, containing specific legal provisions concerning such matters as participant safety, informed consent, and confidentiality. A topic of particular interest for pathologists is the handling of human tissue specimens that may be used for present, or stored for future, research purposes. This article examines the ethical and legal ramifications of obtaining and storing tissue samples for research purposes, with special attention to the issues of informed consent and confidentiality.

The conduct of biomedical research involving human participants raises a host of ethical and legal issues that have concerned philosophers, lawyers, policy makers, scientists, and clinicians for many years. 1 After briefly enumerating several relevant ethical principles and the legal apparatus that has been developed specifically in the USA to effectuate those principles, I will outline one matter of particular interest to pathologists: the obtaining and retention of human tissue samples for use in current or future research projects.

Underlying ethical principles

Biomedical research is conducted for the purpose of systematically collecting and analysing data from which generalisable conclusions may be drawn that may aid in improving the care of currently unknown beneficiaries in the future. 2 The chief role of human participants in research is to serve as sources of needed data. This is a different situation than ordinarily occurs in clinical medicine, in which diagnostic or therapeutic interventions are suggested or carried out solely to benefit the current patient. 3 Consequently, although many ethical issues overlap between the realms of research and clinical medicine, the ethics concerns in human subjects research are not identical to those arising in the diagnostic and therapeutic context.

The most salient ethical values implicated by the use of human participants in research are beneficence (doing good), non‐maleficence (preventing or mitigating harm), fidelity and trust within the fiduciary investigator/participant relationship, personal dignity, and autonomy pertaining to both informed, voluntary, competent decision making and the privacy of personal information. 4 These (as well as other) ethical concerns are addressed by an extensive regulatory structure pertaining to human subjects research. The historical and philosophical background culminating in the present American system of governmental command and control regulation in this arena has been extensively chronicled elsewhere. 5

General regulatory oversight in the USA

Based largely on the recommendations of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (the Belmont Commission), established by the 1974 National Research Act, American regulations governing the conduct of biomedical research involving human participants were published in 1981 by the federal Department of Health and Human Services (DHHS) (at that time, the Department of Health, Education and Welfare). Most US health care institutions conducting research have now agreed to apply these federal regulations to all of their research protocols regardless of the funding source for a particular study. Additionally, numerous other federal agencies have adopted the DHHS regulations, as subsequently amended, as a Common Rule to protect human participants in any research protocol that those agencies sponsor. 6 Research involving the testing of investigational drugs or medical devices is regulated concurrently by the federal Food and Drug Administration (FDA) 7 ; the Common Rule and FDA requirements overlap considerably but are not completely identical.

Research to which the Common Rule or FDA regulations, or both, apply must be reviewed and approved initially by an institutional review board (IRB) recognised by the federal Office of Human Research Protections (OHRP) within the Office of the Secretary, DHHS. The research activity is then subject to continuing IRB oversight and at least annual reapproval thereafter. To approve (and renew approval for) a protocol, the IRB must determine that each of the following requirements is satisfied:

• Physical and psychological risks to subjects are minimised.
• Physical and psychological risks to subjects are reasonable in relation to anticipated benefits to those subjects and to the importance of the general knowledge that may reasonably be expected to result.
• Selection of subjects is equitable
• -  purposes of the research, its expected duration, and the nature of any interventions/experiments;
• -  anticipated risks and benefits of participation and the reasonable alternatives to participation in the research protocol;
• -  confidentiality provisions relating to the research records;
• -  any compensation and/or treatment available for research related injuries;
• -  the right to not participate and to discontinue participation at any time without penalty.
• Informed consent will be documented appropriately.

The regulatory provisions for informed consent in research are basically a codification and extension of the American common law informed consent doctrine 8 that was developed by the courts in the therapeutic setting.

As a complement to the federal regulation, some individual states have enacted statutes containing protections for human participants, requiring some type of prior review and oversight. 9 The specific content of these state laws varies. Also, private civil lawsuits may be brought by a particular participant against researchers and protocol sponsors for breach of common law tort standards of care (that is, medical malpractice) in the conduct of research involving and harming that participant. 10

Tissue specimens

Uses in research.

Hakimian and Korn 11 observed, “Human biological specimens have been the foundation of pathological inquiry ever since Rudolf Virchow propounded the cellular basis of disease in 1858. Today, the study of human tissue affords unique and increasingly sophisticated molecular and genetic insights that progressively illuminate the detailed mechanisms and pathways of human diseases.”

Tissue specimens may be sought specifically for use in a current research protocol from individuals who are either undergoing non‐experimental diagnostic or therapeutic interventions for a medical problem, or who are currently participating in a different research protocol. Also, with increasing frequency, patients or current research participants are being asked to donate bodily tissue for storage and possible use at some future date as part of human genetic studies whose precise details are not yet known or knowable. 12 It has been noted that the genetic analysis of human tissue samples may result in highly useful information about genetic explanations of human disease. In the light of developments fuelled by the Human Genome Project, “both the number of known target genes and the methods for rapid and inexpensive genetic analysis are increasing, as is our realization of the complexity of the genetic links of common diseases.” 13 Research addressing complex diseases involving many different genes will require the study of tremendous amounts of data on both the genotypes and phenotypes of numerous people. Researchers both in the USA and internationally are looking enthusiastically at the creation of vast database resources to house the human tissues collected to supply this potentially valuable genetic material.

The ethical and regulatory debate

The collection of human tissue specimens for use in current, and especially in potential future, research protocols raises a panoply of ethical concerns about, among other things, consent and confidentiality. These ethical issues manifest themselves in a regulatory context. Debates about these issues have been carried out for a considerable time. 14 More than a decade ago, the National Institutes of Health and the Centers for Disease Control and Prevention jointly issued a Consensus Statement on “Informed Consent for Genetic Research on Stored Tissue Samples.” 15 In August of 1999, the National Bioethics Advisory Commission published a report that looked comprehensively at the uses of human biological materials and issued 23 recommendations generally trying to interpret the language of the existing Common Rule rather than replace it. 16

Informed consent

When a person is having tissue removed (with their consent) as part of a treatment intervention and is asked for permission to allow a piece of that tissue to also be available for use in a related ongoing genetic study, valid consent for the additional research use would require that the participant be told clearly whether the genetic study is an integral part of the treatment protocol or is an entirely separate investigation. Only in the former situation could the investigator legitimately condition receipt of the treatment on the participant's agreement to have tissue analysed for research purposes. If the genetic study is separate, a volunteer may refuse to donate tissue to it without giving up the chance to participate in the treatment protocol.

Whether linked to present patient treatment or totally separate, a current research project can be described to a prospective tissue donor with enough precision to allow for meaningful informed consent. By contrast, it is difficult, if not impossible, for a participant in a research protocol to give meaningful prospective consent to the use of tissue in a possible future research protocol that cannot currently be described. Common practice has been for IRBs to allow investigators to ask patients receiving treatment to give a generic approval for the current banking of tissue, but only on the condition that use of the tissue in specific research protocols in the future would require an additional consent from the patient, based on specific information conveyed about the particular genetic study at that later point in time.

Recent events have fuelled the controversy over the ethical and legal need to obtain a tissue donor's informed consent for the collection, storage, and use of the donor's biological specimen for research purposes. In an August 2004 guidance document, the federal OHRP sought to clarify its position regarding consent requirements when human biological specimens are used in research by “reaffirm[ing] OHRP policy (see OHRP guidance on repository activities and research on human embryonic stem cells) that, under certain limited conditions, research involving only coded private information or specimens is not human subjects research.” (emphasis in original) 17 Under this guidance, tissue collection for present or future research purposes is not subject to the IRB review and informed consent provisions of the Common Rule, as long as there is no personally identifiable information attached to the tissue specimens. The OHRP guidance “recommends that institutions have policies in place that designate the individual or entity authorized to determine whether research involving coded private information or specimens constitutes human subjects research.”

Some confusion remains, however, because, despite OHRP's interpretation exempting collection of non‐identifiable tissue specimens from application of the Common Rule, FDA regulations mandating the obtaining of informed consent for the collection and use of tissue specimens in present or future research protocols involving the testing of investigational drugs or medical devices still do apply with full force. This disharmony in regulatory requirements has been noted critically by commentators 18 and groups representing biomedical investigators. 19 In a letter to OHRP dated 11 January 2006, the Association of American Medical Colleges observed: “Discordant guidance from different agencies puts institutions in an untenable position and creates confusion and anxiety where none should exist.” 20 The problem results because the FDA regulatory definition of human subject differs from the definition of human subject under the Common Rule, with the former including within the definition the use of unidentified tissue specimens.

It is noteworthy that, in recognition of the disruptiveness of the Common Rule/FDA regulatory disharmony on this point, the FDA had published, 21 two days before the date of the AAMC letter, a public notice that it is in the process of preparing a new guidance document to be entitled “Guidance on informed consent for in vitro diagnostic device studies using leftover human specimens that are not individually identifiable.” The regulations themselves would remain intact. However, FDA indicated in its 9 January 2006 Federal Register publication an intent to notify the public, through the issuance of a guidance document, that FDA will “exercise enforcement discretion [that is, refrain from enforcing the regulations] as to the informed consent regulations for clinical investigators, sponsors, and IRBs” when:

• the study uses leftover specimens; that is, remnants of specimens collected for routine clinical care or analysis that would have been discarded if not used in the study;
• the specimens provided to the investigator are accompanied by only minimal clinical information such as age, sex, and existing laboratory results;
• the specimens are not individually identifiable;
• the specimens are provided to the investigator(s) without identifiers and the supplier of the specimens has established policies and procedures to prevent the release of personal information;
• the individuals caring for the patients are different from, and do not share information with, those conducting the investigation; and
• the study has been reviewed by an IRB.

The August 2004 OHRP guidance on this subject has been characterised by at least a few commentators not (as OHRP explicitly claims) as merely a reaffirmation of existing policy, but instead as “a dramatic shift” leaving “an enormous regulatory gap in which, with a minimum of effort, the majority of research involving databanks can be excluded from the Common Rule.” 22 One argument in favour of imposing substantial affirmative informed consent requirements rather than allowing exemption altogether or substituting presumed consent (with an opportunity to object) would focus on the risks involved in donating tissue. This argument is exemplified by the comment, “In human tissue research, genomic technology has not only increased the demand for human tissue, but it has also increased the potential for tissue donors to be subjected to both psychosocial and economic harms.” 23

However, most arguments supporting a specific consent requirement for present or future research uses of human tissue specimens, even if anonymised, rest more on the claim that basic personal interests are at stake for the prospective tissue donor. This is the contention: “There should be no doubt about what is at stake in developing policy for the use of stored samples: the fundamental right to decide whether and how one's body and its parts will be used in research.” 24 As explained by a proponent of requiring informed consent for the conduct of research using non‐identified tissue specimens: “Informed consent is not just about enabling people to decide whether or not to accept certain risks. Seeking permission to use biobanks can be valuable for its own sake as well. The process of asking acknowledges the individual whose information and tissue are obtained therein. In the case of research, informed consent is one part of honoring the contribution that the person is making to advancement of knowledge.” 25

Regulatory proponents additionally cite evidence that at least a significant minority of patients polled want to be informed in advance and afforded the opportunity to consent to or refuse the use of their tissue for research purposes. 26 This desire bolsters the argument that the storage and use of tissue specimens in research protocols is a matter about which people really care and, therefore, strongly want their autonomy rights respected. 25

This part of the proponents' argument is weakened, though, by a number of study findings to the contrary. For instance, some studies of tissue donors' preferences and perceptions have been interpreted to show that most patients do not share professional bioethicists' concern about the potential research related uses of their surplus tissues. Responses to one questionnaire revealed that “only a small number [of patients supplying tissue specimens] report their information levels to be of particular importance when biobank based research is assessed in relation to other issues pertaining to research politics and ethics...This study calls for reconsideration of the importance attributed to informed consent in debates about ethics of biobanks and genomics companies...” 27

Other surveys demonstrate that most individuals who have had tissue removed for other purposes have no objection to the unlimited use of excess tissue in future research studies. These findings—as well as the position that the law appears not to recognise donors' personal ownership rights pertaining to surplus tissue specimens taken from those individuals for diagnostic or therapeutic purposes 11 —underpin the contention by some that a patient's valid consent for future research uses of previously collected tissue specimens should be made on the basis of a binary choice (either authorising all future research uses or none at all) rather than requiring investigators in every new research protocol to track down and obtain specific consent from every tissue donor, even if the specimen is identified only by a code. 28 Other bioethics scholars go further, arguing that the “data [regarding what matters actually are important to patients] suggest applying a tentative general framework for obtaining consent for research using stored biological samples. Consent should be required for research using clinically derived, identified samples, but waived for additional research using research derived, anonymized samples.” 29

An active ethical/social policy discussion about the parameters of informed consent for research uses of surplus human tissue specimens undoubtedly will persist in the USA for the foreseeable future, as we delve ever further into the genomic era of biomedical progress. For the time being, the regulatory approach to this question has been resolved by OHRP and FDA in the respective manners described above. Whether the present approach of OHRP to exclude the research use of coded tissue specimens from the classification of human subjects research, subject to the requirements of the Common Rule, constitutes a serious gap in legal protection for vulnerable individuals, or whether a realistic recognition that the ability to give or withhold informed consent in this context is not an especially important value to most potential tissue donors remains to be seen.

Policy makers in the USA also should closely monitor the legal and ethical approaches of the international community to the informed consent question in this context. In the United Kingdom, the well publicised Alder Hey and Bristol Royal Infirmary inquiries, revealing systematic retention of postmortem organs from children for educational and research purposes, without obtaining authorised informed consent, engendered substantial debate about the role of informed consent in research related tissue specimen collection. 12 , 30 , 31 Various informative surveys of relevant public and professional attitudes have been conducted in Europe 26 , 32 and Asia. 33 Pertinent laws and customs have been developed in different countries to address this matter, accompanied by various degrees of controversy about how they balance patients' rights and society's interest in having research conducted. 34 Inconsistent national laws contribute to confusion and inhibit collaborative research efforts, 35 but conflicting ethical, cultural, and religious perspectives will continue to make international regulatory harmonisation a highly difficult challenge. 36

Medical privacy requirements

Because possible unfair discrimination against an individual by a present or potential employer, insurer, educator, or other party on the basis of genetic information derived from a scientific analysis of the individual's tissue specimen is a major risk of allowing one's tissue to be available for research purposes, it is necessary to consider the confidentiality implications of collecting and storing tissue to be used in the research context. In the USA, medical confidentiality rules derive from, and may be enforced under, common law tort doctrine and any applicable state statutes and regulations. However, the chief American source of pertinent legal authority is the federal Standards for Privacy of Individually Identifiable Health Information (Privacy Rule). 37 This regulation became effective in 2003 after being promulgated by DHHS under the legislative authority of the Health Insurance Portability and Accountability Act (HIPAA). 38

The Privacy Rule requires specific written permission from a patient before anyone may use or disclose “protected health information” (PHI) about that person for non‐routine purposes such as research. PHI is defined as any “individually identifiable health information” transmitted or maintained by a “covered entity” (for example, a health care provider, health insurance plan, or data processing firm).

In the context of research using stored tissue specimens, the reach of the HIPAA Privacy Rule is somewhat constrained. First, tissue repositories such as biobanks are not “covered entities” subject to the Rule unless they conduct some other kind of activity that brings them within the “covered entity” definition. The Privacy Rule would be implicated only with regard to a covered entity, such as a hospital, that discloses PHI for the creation or stocking of the research repository. 39 “It is the act of the health care provider sending a specimen to a commercial sponsor while knowing that it will be retained in a repository that triggers the HIPAA written authorisation form requirement, not the sponsor's actions in maintaining the repository.” 40

Moreover, the Privacy Rule would only apply to a covered entity that sends to a repository tissue that is accompanied by clinical information containing specific patient identifiers. “The Privacy Rule permits covered entities to release data that have been de‐identified without obtaining an Authorization and without further restrictions upon use or disclosure because de‐identified data is not PHI and, therefore, not subject to the Privacy Rule.” 39 “The Privacy Rule permits covered entities under the Rule to determine that health information is de‐identified even if the health information has been assigned, and retains, a code or other means of record identification, provided that: (1) the code is not derived from or related to the information about the individual; (2) the code could not be translated to identify the individual; and (3) the covered entity under the Privacy Rule does not use or disclose the code for other purposes or disclose the mechanism for re‐identification.” 17

Conclusions

Pathologists everywhere involved in various aspects of research involving human participants must be cognisant of the regulatory environment impacting their activities in their particular jurisdiction and the ethical principles underlying the applicable local legal rules. In this article I have outlined the salient boundaries of the regulatory environment for biomedical research. I have devoted particular attention to current approaches and controversies about informed consent and the ramifications of medical confidentiality when obtaining human tissue specimens for use in current research protocols or storing them for use in future protocols, the details of which cannot be predicted or described to the potential tissue donors.

Abbreviations

AAMC - Association of American Medical Colleges

HIPAA - Health Insurance Portability and Accountability Act

IRB - institutional review board

OHRP - Office of Human Research Protections

PHI - protected health information

How to Address Ethical Issues in Human Subjects Research

Industry Advice Regulatory Affairs

In highly regulated industries such as medical devices, pharmaceuticals, biotechnology, and food safety, companies must constantly balance the demands of bringing new products to market quickly while also testing those products in a safe manner. Many of these products are tested on human subjects, and successful studies can improve human health while helping researchers learn more about diseases, human behavior, and learning patterns. 

A mix of national regulations and international declarations offer numerous principles for human subjects research ethics. “The most important thing is to protect the people participating. It goes back to how vulnerable groups have been taken advantage of,” says Mary Dronitsky, a professor in the College of Professional Studies . 

This article provides a closer look at three key documents that define the principles of human subjects research ethics—the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report—and offers a set of best practices for regulatory affairs professionals who manage the development, marketing approval, and utilization of highly regulated products.

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Principles of Human Subjects Research Ethics

National and international organizations have issued declarations on human subjects research ethics in response to medical experiments throughout history that were done on participants who did not consent to being treated, Dronitsky says. These include experiments on prisoners of war in German concentration camps in World War II, the Tuskegee Syphilis Study in the United States from 1932 to 1972, and various vaccine or pain study trials that took advantage of persons with mental disabilities or other underrepresented groups. The three major declarations each consist of several principles of research that act as scientific and moral guidelines for treating people who have agreed to be part of a research study.

Nuremberg Code

Issued by the three judges who presided over the trials of German doctors conducting experiments in World War II, the Nuremberg Code consisted of 10 principles for research trials involving human subjects. First and foremost, the code declares that participant consent is “absolutely essential” and that participants are “at liberty” to bring the experiment to an end at any time. 

Additional principles state that experiments must be conducted “for the good of society,” should not cause physical and mental injury to participants, and should not be more risky or dangerous than the problem they are trying to solve. 

In a 50th anniversary retrospective, the New England Journal of Medicine noted that the Nuremberg Code has had a “profound” impact on human rights laws and medical ethics even though the code itself has never been adopted as law. For example, its guidelines on informed consent have been the basis for United Nations law and World Health Organization guidelines. 

Declaration of Helsinki

Initially adopted by the World Medical Association in 1964 and amended several times since, the Declaration of Helsinki has influenced legislation and regulation worldwide. The document’s principles similarly state that the health of participants must be a physician’s “first consideration.” The document also states that it is the responsibility of healthcare professionals to protect research subjects, even though participants consent to participating.

The Declaration of Helsinki also calls for all research experiments to include a research protocol that indicates how principles of human subjects research ethics are being addressed, along with information about who is funding or otherwise sponsoring the research. 

Belmont Report

Written in 1978 in response to the Tuskegee study—in which 400 Black men with syphilis were neither informed of their diagnosis nor treated for the disease for decades—the Belmont Report provides guidance for the treatment of human subjects in research trials in the United States. The report builds on both the Nuremberg Code and the Declaration of Helsinki and consists of three key principles.

• Autonomy : This principle is based on the concept of informed consent , Dronitsky says. “When individuals are asked to participate in a clinical study, they need to be doing it voluntarily and should not face undue pressure. They must also be given sufficient information.” 
• Beneficence : The risks of an experiment cannot outweigh the rewards. In addition, the risks and rewards should be clear enough that they can be interpreted by the general public, not just trial participants.
• Justice : The recruitment of volunteers must be impartial, all participants in an experiment must be treated fairly, and participants should not be exploited. “You need or provide full access to all individuals to have the opportunity to be in clinical trials—not just prisoners, those with mental disabilities, or the economically disadvantaged,” Dronitsky says.

Best Practices for Human Subjects Research Ethics

To adhere to these key principles for human subjects research ethics, organizations need to abide by rules established by the U.S. Food and Drug Administration (FDA) and regulatory agencies in any counties where a trial is taking place. A series of simple but critical best practices will help organizations ensure that a trial meets these requirements and can proceed without revisions or other delays.

1. Review consent forms.

Under FDA rules, a clinical trial that requires human subjects must have a consent form that is reviewed and approved by an Ethics Committee or Institutional Review Board (IRB). These rules also apply to physicians working in private practice, who are required to submit research proposals to a hospital, medical school, or local or state government agency. Ultimately, the IRB serves as a “check and balance” for the study, Dronitsky says, ensuring that the needs of the participants and the research teams are aligned.

FDA guidance for IRBs includes specific recommendations for obtaining informed consent, such as conducting informed consent interviews and informing participants of changes to the research study. 

The FDA also provides compensation guidelines for trial participants, which the IRB must also review and accept. The agency suggests that payment should be “just and fair” without presenting undue influence that may coerce a participant to provide certain feedback, remain in a study when they would otherwise withdraw, or otherwise interfere with their ability to give voluntary, informed consent. 

2. Review recruitment materials.

In the United States, the FDA also requires the IRB to look at the trial’s recruitment materials. “The IRB wants to make sure they are not unduly influencing patients or making promises that the drug will work,” Dronitsky says.

FDA guidance for recruiting human subjects stipulates that advertising material should not include terms such as “new treatment” or “new drug” without indicating that the treatment is experimental. In addition, recruitment material should not promise “free medical treatment” when the standard is not to charge participants to take part in a trial.

The recruitment material that’s reviewed should also include any information that’s given to the office personnel who first speak to potential trial participants, the FDA says. This material should help office personnel address the ways that personal, medical, and financial information are protected as well as take the necessary steps to protect that information.  

3. Clearly define participant criteria. 

One of the emerging trends in biotechnology is the personalized treatment of rare diseases, made possible through highly targeted treatment plans and therapies that are, in some cases, based on a patient’s genetic and molecular makeup.

These treatments are more effective than generic therapies, and the reduced cost of genetic sequencing has driven down the drug development cost. However, organizations may have difficulty finding participants who meet the very specific criteria for these clinical trials. This roadblock presents safety and ethical issues because organizations must avoid enrolling participants who do not qualify. Not only is the research’s validity in doubt, but the participants may be at a higher risk of an adverse reaction to the treatment, Dronitsky points out.

It’s often not enough to simply recruit patients who have the disease, she continues. Most research study protocols should have a set of inclusion and exclusion criteria that more specifically define and narrow the patient population that’s being recruited. These criteria can include a specific age range, other preexisting conditions, or other medications that someone is taking.

4. Monitor the trial’s progress.

As the experiment continues, investigators must monitor what’s happening to participants. The trial protocols that an IRB approves must include specific requirements for ongoing assessments. Trials that receive funding or other assistance from the National Institutes of Health are also subject to additional oversight, Dronitsky notes.

Assessments may vary depending on the nature of the trial. In a medical device trial, for example, trial organizers need to look at the data that a device generates. If numbers appear to be off, they must further investigate to see if the issue is with the way the device collects and reports data—as with a heart rate monitor in a smartwatch that’s worn incorrectly—or is indicative of a problem that requires medical attention.

In drug trials, meanwhile, the FDA offers guidance for adverse event reporting , which refers to unanticipated problems that arise in patients taking a drug. According to the FDA, certain adverse events must be reported to an IRB, while others do not—but all require investigators to intervene on behalf of a patient’s health and safety. 

5. Consider additional expert help.

The sooner that a drug goes to market, the sooner that patients realize clinical benefits and companies enjoy financial benefits for their employees, investors, and shareholders. This can put pressure on investigators to complete a trial quickly, especially if other companies are developing similar drugs or devices.

To facilitate participant recruitment while still adhering to the principles of human subjects research ethics, some organizations opt to hire consultants who specialize in clinical trial recruitment, Dronitsky notes. These individuals can help investigators develop materials to bring in more potential participants—through the use of social media, for example—as well as a more diverse group of participants. 

Prepare for a Future in Regulatory Affairs

Professionals in regulatory affairs roles must balance the historical precedents for human subjects research ethics with the reality of rapidly changing regulations in the United States and abroad. 

A Master of Science in Regulatory Affairs from Northeastern University helps prepare these professionals to manage the product life cycle in industries such as biotechnology, pharmaceuticals, and medical devices while better understanding the laws and standards that apply to each step of that life cycle.

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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.

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Ethical Principles in Healthcare Research

Human Research Ethics Guidelines in Australia

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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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Henk ten Have

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Gefenas, E. (2016). Research: Human Subjects. In: ten Have, H. (eds) Encyclopedia of Global Bioethics. Springer, Cham. https://doi.org/10.1007/978-3-319-09483-0_372

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Federal Policy for the Protection of Human Subjects ('Common Rule')

The current U.S. system of protection for human research subjects is heavily influenced by the Belmont Report , written in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report outlines the basic ethical principles in research involving human subjects. In 1981, with this report as foundational background, HHS and the Food and Drug Administration revised, and made as compatible as possible under their respective statutory authorities, their existing human subjects regulations.

The Federal Policy for the Protection of Human Subjects or the “Common Rule” was published in 1991 and codified in separate regulations by 15 Federal departments and agencies, as listed below. The HHS regulations, 45 CFR part 46 , include four subparts: subpart A, also known as the Federal Policy or the “Common Rule”; subpart B, additional protections for pregnant women, human fetuses, and neonates; subpart C, additional protections for prisoners; and subpart D, additional protections for children. Each agency 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 part 46, subpart A. For all participating departments and agencies the Common Rule outlines the basic provisions for IRBs, informed consent, and Assurances of Compliance. Human subject research conducted or supported by each federal department/agency is governed by the regulations of that department/agency. The head of that department/agency retains final judgment as to whether a particular activity it conducts or supports is covered by the Common Rule. If an institution seeks guidance on implementation of the Common Rule and other applicable federal regulations, the institution should contact the department/agency conducting or supporting the research.

The list below displays the agencies and departments that have signed onto the Common Rule and their CFR numbers. Hyperlinks are to areas of a department or agency Web site that have been suggested to HHS as entry points for those interested in human subject protection activities of the department or agency.

General information:

• Of these, 15 agencies are official signatories with the rule codified in their own Code of Federal Regulations (CFR) sections
• 4 departments and agencies follow the Pre-2018 Common Rule because of executive order or statutory mandate (Department of Homeland Security, Social Security Administration, Office of the Director of National Intelligence, and Central Intelligence Agency)
• There is 1 new signatory to the revised Common Rule (Department of Labor)
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• 1 original signatory (Department of Justice) intends to become an official signatory to the revised Common Rule
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For additional details about the agencies and departments that have signed onto the Common Rule, including contact information and links to relevant webpages/resources, please visit https://www.hhs.gov/ohrp/education-and-outreach/revised-common-rule/common-rule-departments-agencies/index.html .

Responsible Conduct of Research

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This website is for educational purposes only. Please contact the Office of Research Integrity Assurance for information about applicable policies and regulations regarding research activities involving human beings or animals.

Historically, the term “human subject” largely referred to a person participating in medical, psychological, or other health-related research. Yet the term can apply to a broad range of research activities outside of those realms. Regardless of the type of research, significant ethical issues can emerge if human participants are involved.

A key ethical concept associated with human subjects research is called “informed consent.” Informed consent has three fundamental components:

• subjects being asked to participate in research should be adequately informed about the benefits and risks that may be associated with the research;
• subjects should not be coerced into making decisions about participating in the research, nor should they be forced to remain in the research if they decide to withdraw from it; and
• subjects must be competent to make decisions regarding their participation in research, which is in part determined by their age and mental capacity.

In general, each of the three components must be satisfied before a human being is enrolled in research. At a minimum, researchers should discuss the research protocol with potential subjects. Usually, they should also provide participants with a consent form, a document which is supposed to explain the proposed research in clear and thorough detail.

When conducting human subjects research, it is essential that researchers are familiar with the ethical principles delineated in the Belmont Report . These principles are: respect for persons , beneficence , and justice .

In accordance with federal regulations, each institution that receives federal funds for human subjects research must have at least one institutional review board (IRB). An IRB is responsible for reviewing the scientific, legal, and ethical merits of a research protocol involving human participants before the research starts and, depending on the type of research, while it is ongoing.

Researchers must check with an IRB before proceeding with a protocol involving human participants in order to ensure that those participants are adequately protected.

Georgia Tech Links

• Office of Research Integrity Assurance: About the Institutional Review Boards

Other Links & Resources

• The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
• The Common Rule: Protection of Human Subjects (Title 45 Code of Federal Regulations Part 46)
• Federal Aviation Administration: Aerospace Medical and Human Factors Research
• FDA: Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs
• National Institutes of Health (NIH): Office of Behavioral and Social Science Research
• National Institutes of Health (NIH): Training & Resources - Human Subjects
• NIH Required Education in the Protection of Human Research Participants, June 5, 2000
• National Science Foundation: Human Subjects
• The Nuremberg Code
• U.S. Department of Education: Protection of Human Subjects in Research
• U.S. Department of Energy: Human Subjects Protection Program
• U.S. Department of Health and Human Services: Health Information Privacy
• U.S. Department of Health and Human Services: Office for Human Research Protections
• World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects

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Cultural Relativity and Acceptance of Embryonic Stem Cell Research

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There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities.

INTRODUCTION

Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve.

Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes. [1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research. [2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.” [3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops. [4]  Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture.

I.     Global Cultural Perspective of Embryonic Stem Cells

Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense, [5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research. [6] Consequently, global engagement in ESC research depends on social-cultural acceptability.

a.     US and Rights-Based Cultures

In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism, [7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.” [8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed. [9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field. [10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture. [11]

b.     Ubuntu and Collective Cultures

African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama , which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,” [12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth. [13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole . Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value. [14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society.

Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.” [15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail.

Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable. [16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus. [17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines. [18]

Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim. [19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research. [20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF.  Their use is conditioned on consent, and available only to married couples. [21] The community's receptiveness to stem cell research depends on including communitarian African ethics.

c.     Asia

Some Asian countries also have a collective model of ethics and decision making. [22] In China, the ethics model promotes a sincere respect for life or human dignity, [23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life. [25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research. [26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions. [27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency. [28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021. [29] However, issues still need to be addressed in implementing effective IRB review and approval procedures.

The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy, [30] research ethics should also adapt to ensure respect for the values of its represented peoples.

Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies. [31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells. [32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval, [33] and in another instance, the oocyte source was unclear and possibly violated ethical standards. [34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust.

d.     Middle East

Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells, [35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research. [36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors. [37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so. [38]

Jordan has a positive research ethics culture. [39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial. [40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation. [41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.” [42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes.

e.     Europe

In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected. [43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44]

For example, in Germany, Lebenzusammenhang , or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.” [45]  Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount. [46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007. [47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization. [48] Spain’s approach differs still, with a comprehensive regulatory framework. [49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility. [50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices. [51]

II.     Religious Perspectives on ESC

Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives.

The Qur'an states:

“And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.” [52]

Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception. [53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible. [54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research. [55]

In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided. [56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden. [57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all. [58] Acceptance varies on applied beliefs and interpretations.

Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero, [59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all. [60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime. [61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit. [62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets. [63]

Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life. [64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception: [65]

“If she is found pregnant, until the fortieth day it is mere fluid,” [66]

Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation. [67] Stem cell research is accepted due to application of these religious laws.

We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory , which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions. [68] We only wish to show that the interaction with morality varies between cultures and countries.

III.     A Flexible Ethical Approach

The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities.

While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe. [69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation.

For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent. [70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context, [71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders.  This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research.

Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values. [72]

An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions. [73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion.

IV.     Concerns

Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values. [74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions.

Other concerns include medical tourism, which may promote health inequities. [75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments. [76]

For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.” [77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices. [78]

The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.” [79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds. [80]

While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research.

For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society.

This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model.

[1] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice.  Orthopedic reviews ,  14 (3), 37498. https://doi.org/10.52965/001c.37498

[2] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice.  Orthopedic reviews ,  14 (3), 37498. https://doi.org/10.52965/001c.37498

[3] International Society for Stem Cell Research. (2023). Laboratory-based human embryonic stem cell research, embryo research, and related research activities . International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk ; Kimmelman, J., Hyun, I., Benvenisty, N.  et al.  Policy: Global standards for stem-cell research.  Nature   533 , 311–313 (2016). https://doi.org/10.1038/533311a

[4] International Society for Stem Cell Research. (2023). Laboratory-based human embryonic stem cell research, embryo research, and related research activities . International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk

[5] Concerning the moral philosophies of stem cell research, our paper does not posit a personal moral stance nor delve into the “when” of human life begins. To read further about the philosophical debate, consider the following sources:

Sandel M. J. (2004). Embryo ethics--the moral logic of stem-cell research.  The New England journal of medicine ,  351 (3), 207–209. https://doi.org/10.1056/NEJMp048145 ; George, R. P., & Lee, P. (2020, September 26). Acorns and Embryos . The New Atlantis. https://www.thenewatlantis.com/publications/acorns-and-embryos ; Sagan, A., & Singer, P. (2007). The moral status of stem cells. Metaphilosophy , 38 (2/3), 264–284. http://www.jstor.org/stable/24439776 ; McHugh P. R. (2004). Zygote and "clonote"--the ethical use of embryonic stem cells.  The New England journal of medicine ,  351 (3), 209–211. https://doi.org/10.1056/NEJMp048147 ; Kurjak, A., & Tripalo, A. (2004). The facts and doubts about beginning of the human life and personality.  Bosnian journal of basic medical sciences ,  4 (1), 5–14. https://doi.org/10.17305/bjbms.2004.3453

[6] Vazin, T., & Freed, W. J. (2010). Human embryonic stem cells: derivation, culture, and differentiation: a review.  Restorative neurology and neuroscience ,  28 (4), 589–603. https://doi.org/10.3233/RNN-2010-0543

[7] Socially, at its core, the Western approach to ethics is widely principle-based, autonomy being one of the key factors to ensure a fundamental respect for persons within research. For information regarding autonomy in research, see: Department of Health, Education, and Welfare, & National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1978). The Belmont Report. Ethical principles and guidelines for the protection of human subjects of research.; For a more in-depth review of autonomy within the US, see: Beauchamp, T. L., & Childress, J. F. (1994). Principles of Biomedical Ethics . Oxford University Press.

[8] Sherley v. Sebelius , 644 F.3d 388 (D.C. Cir. 2011), citing 45 C.F.R. 46.204(b) and [42 U.S.C. § 289g(b)]. https://www.cadc.uscourts.gov/internet/opinions.nsf/6c690438a9b43dd685257a64004ebf99/$file/11-5241-1391178.pdf

[9] Stem Cell Research Enhancement Act of 2005, H. R. 810, 109 th Cong. (2001). https://www.govtrack.us/congress/bills/109/hr810/text ; Bush, G. W. (2006, July 19). Message to the House of Representatives . National Archives and Records Administration. https://georgewbush-whitehouse.archives.gov/news/releases/2006/07/20060719-5.html

[10] National Archives and Records Administration. (2009, March 9). Executive order 13505 -- removing barriers to responsible scientific research involving human stem cells . National Archives and Records Administration. https://obamawhitehouse.archives.gov/the-press-office/removing-barriers-responsible-scientific-research-involving-human-stem-cells

[11] Hurlbut, W. B. (2006). Science, Religion, and the Politics of Stem Cells.  Social Research ,  73 (3), 819–834. http://www.jstor.org/stable/40971854

[12] Akpa-Inyang, Francis & Chima, Sylvester. (2021). South African traditional values and beliefs regarding informed consent and limitations of the principle of respect for autonomy in African communities: a cross-cultural qualitative study. BMC Medical Ethics . 22. 10.1186/s12910-021-00678-4.

[13] Source for further reading: Tangwa G. B. (2007). Moral status of embryonic stem cells: perspective of an African villager. Bioethics , 21(8), 449–457. https://doi.org/10.1111/j.1467-8519.2007.00582.x , see also Mnisi, F. M. (2020). An African analysis based on ethics of Ubuntu - are human embryonic stem cell patents morally justifiable? African Insight , 49 (4).

[14] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics , 22 (2), 112–122. https://doi.org/10.1111/dewb.12324

[15] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324

[16] Jackson, C.S., Pepper, M.S. Opportunities and barriers to establishing a cell therapy programme in South Africa.  Stem Cell Res Ther   4 , 54 (2013). https://doi.org/10.1186/scrt204 ; Pew Research Center. (2014, May 1). Public health a major priority in African nations . Pew Research Center’s Global Attitudes Project. https://www.pewresearch.org/global/2014/05/01/public-health-a-major-priority-in-african-nations/

[17] Department of Health Republic of South Africa. (2021). Health Research Priorities (revised) for South Africa 2021-2024 . National Health Research Strategy. https://www.health.gov.za/wp-content/uploads/2022/05/National-Health-Research-Priorities-2021-2024.pdf

[18] Oosthuizen, H. (2013). Legal and Ethical Issues in Stem Cell Research in South Africa. In: Beran, R. (eds) Legal and Forensic Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32338-6_80 , see also: Gaobotse G (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[19] United States Bureau of Citizenship and Immigration Services. (1998). Tunisia: Information on the status of Christian conversions in Tunisia . UNHCR Web Archive. https://webarchive.archive.unhcr.org/20230522142618/https://www.refworld.org/docid/3df0be9a2.html

[20] Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[21] Kooli, C. Review of assisted reproduction techniques, laws, and regulations in Muslim countries.  Middle East Fertil Soc J   24 , 8 (2020). https://doi.org/10.1186/s43043-019-0011-0 ; Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[22] Pang M. C. (1999). Protective truthfulness: the Chinese way of safeguarding patients in informed treatment decisions. Journal of medical ethics , 25(3), 247–253. https://doi.org/10.1136/jme.25.3.247

[23] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences , 8(1).  https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199

[24] Wang, Y., Xue, Y., & Guo, H. D. (2022). Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction.  Frontiers in pharmacology ,  13 , 1013740. https://doi.org/10.3389/fphar.2022.1013740

[25] Li, X.-T., & Zhao, J. (2012). Chapter 4: An Approach to the Nature of Qi in TCM- Qi and Bioenergy. In Recent Advances in Theories and Practice of Chinese Medicine (p. 79). InTech.

[26] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students.  Stem cells international ,  2021 , 6667743. https://doi.org/10.1155/2021/6667743

[27] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students.  Stem cells international ,  2021 , 6667743. https://doi.org/10.1155/2021/6667743

[28] Zhang, J. Y. (2017). Lost in translation? accountability and governance of Clinical Stem Cell Research in China. Regenerative Medicine , 12 (6), 647–656. https://doi.org/10.2217/rme-2017-0035

[29] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences , 8(1).  https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199

[30] Chen, H., Wei, T., Wang, H.  et al.  Association of China’s two-child policy with changes in number of births and birth defects rate, 2008–2017.  BMC Public Health   22 , 434 (2022). https://doi.org/10.1186/s12889-022-12839-0

[31] Azuma, K. Regulatory Landscape of Regenerative Medicine in Japan.  Curr Stem Cell Rep   1 , 118–128 (2015). https://doi.org/10.1007/s40778-015-0012-6

[32] Harris, R. (2005, May 19). Researchers Report Advance in Stem Cell Production . NPR. https://www.npr.org/2005/05/19/4658967/researchers-report-advance-in-stem-cell-production

[33] Park, S. (2012). South Korea steps up stem-cell work.  Nature . https://doi.org/10.1038/nature.2012.10565

[34] Resnik, D. B., Shamoo, A. E., & Krimsky, S. (2006). Fraudulent human embryonic stem cell research in South Korea: lessons learned.  Accountability in research ,  13 (1), 101–109. https://doi.org/10.1080/08989620600634193 .

[35] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

[36] Association for the Advancement of Blood and Biotherapies.  https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia

[37] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia.  BMC medical ethics ,  21 (1), 35. https://doi.org/10.1186/s12910-020-00482-6

[38] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics , 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics , 23 (3), 260–268. https://doi.org/10.1111/dewb.12355 ; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know . Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know

[39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[40] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[41] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[42] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France.  Biotechnology Law Report ,  32 (6), 349–356. https://doi.org/10.1089/blr.2013.9865

[45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf

[47] Regulation of Stem Cell Research in Germany . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany

[48] Regulation of Stem Cell Research in Finland . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland

[49] Regulation of Stem Cell Research in Spain . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain

[50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered:

Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110.

Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ...  Revista do Colegio Brasileiro de Cirurgioes ,  41 (5), 374–377. https://doi.org/10.1590/0100-69912014005013

Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India . Routledge.

For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe   

[51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights.  Cultura (Iasi, Romania) ,  14 (2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent?  Research Ethics ,  13 (1), 23-41.  https://doi.org/10.1177/1747016116650235

[52] The Qur'an  (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23

[53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life . Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/

[54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics , 31: 399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386

[55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association , 12 (4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf.

[56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52.  https://doi.org/10.5372/1905-7415.0801.260

[57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation.  Journal of Religion and Health ,  30 (1), 35–41. http://www.jstor.org/stable/27510629 ; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva . A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm

[59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. (( King James Bible . (1999). Oxford University Press. (original work published 1769))

Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…”

In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David.

Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…”

These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth.

[60] It should be noted that abortion is not supported as well.

[61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day . Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html

[62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells . Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html ; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology . Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf.

[63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed . Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/

[64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. Journal of halacha and contemporary society , (43), 49–68.; Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[65] Schenker J. G. (2008). The beginning of human life: status of embryo. Perspectives in Halakha (Jewish Religious Law).  Journal of assisted reproduction and genetics ,  25 (6), 271–276. https://doi.org/10.1007/s10815-008-9221-6

[66] Ruttenberg, D. (2020, May 5). The Torah of Abortion Justice (annotated source sheet) . Sefaria. https://www.sefaria.org/sheets/234926.7?lang=bi&with=all&lang2=en

[67] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[68] Gert, B. (2007). Common morality: Deciding what to do . Oxford Univ. Press.

[69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA , 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association .; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979).  The Belmont report: Ethical principles and guidelines for the protection of human subjects of research . U.S. Department of Health and Human Services.  https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

[70] Zakarin Safier, L., Gumer, A., Kline, M., Egli, D., & Sauer, M. V. (2018). Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.  Journal of assisted reproduction and genetics ,  35 (7), 1219–1225. https://doi.org/10.1007/s10815-018-1171-z https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063839/ see also: Riordan, N. H., & Paz Rodríguez, J. (2021). Addressing concerns regarding associated costs, transparency, and integrity of research in recent stem cell trial. Stem Cells Translational Medicine , 10 (12), 1715–1716. https://doi.org/10.1002/sctm.21-0234

[71] Klitzman, R., & Sauer, M. V. (2009). Payment of egg donors in stem cell research in the USA.  Reproductive biomedicine online ,  18 (5), 603–608. https://doi.org/10.1016/s1472-6483(10)60002-8

[72] Krosin, M. T., Klitzman, R., Levin, B., Cheng, J., & Ranney, M. L. (2006). Problems in comprehension of informed consent in rural and peri-urban Mali, West Africa.  Clinical trials (London, England) ,  3 (3), 306–313. https://doi.org/10.1191/1740774506cn150oa

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[74] Msoroka, M. S., & Amundsen, D. (2018). One size fits not quite all: Universal research ethics with diversity.  Research Ethics ,  14 (3), 1-17.  https://doi.org/10.1177/1747016117739939

[75] Pirzada, N. (2022). The Expansion of Turkey’s Medical Tourism Industry.  Voices in Bioethics ,  8 . https://doi.org/10.52214/vib.v8i.9894

[76] Stem Cell Tourism: False Hope for Real Money . Harvard Stem Cell Institute (HSCI). (2023). https://hsci.harvard.edu/stem-cell-tourism , See also: Bissassar, M. (2017). Transnational Stem Cell Tourism: An ethical analysis.  Voices in Bioethics ,  3 . https://doi.org/10.7916/vib.v3i.6027

[77] Song, P. (2011) The proliferation of stem cell therapies in post-Mao China: problematizing ethical regulation,  New Genetics and Society , 30:2, 141-153, DOI:  10.1080/14636778.2011.574375

[78] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[79] International Society for Stem Cell Research. (2024). Standards in stem cell research . International Society for Stem Cell Research. https://www.isscr.org/guidelines/5-standards-in-stem-cell-research

[80] Benjamin, R. (2013). People’s science bodies and rights on the Stem Cell Frontier . Stanford University Press.

Mifrah Hayath

SM Candidate Harvard Medical School, MS Biotechnology Johns Hopkins University

Olivia Bowers

MS Bioethics Columbia University (Disclosure: affiliated with Voices in Bioethics)

Article Details

This work is licensed under a Creative Commons Attribution 4.0 International License .

• Alumni Colloquium Series 2022-23

Research Ethics and Policy Series (REPS): "Regulatory and Ethical Perspectives on Pragmatic Trials: Lessons from Three Cases"- Mark Neuman, MD, MSc

12:00pm - 1:00pm • Hybrid: RCH B102AB, Richards Bldg., 3700 Hamilton Walk (and virtual via Zoom)

Regulatory and Ethical Perspectives on Pragmatic Trials: Lessons from Three Cases

Mark neuman, md, msc.

Director, Research Partnerships , Leonard Davis Institute of Health Economics Associate Professor, Anesthesiology and Critical Care , Perelman School of Medicine Director, Penn Center for Perioperative Outcomes Research and Transformation (CPORT) , Perelman School of Medicine | University of Pennsylvania

Mark Neuman, MD, MSc, Professor of Anesthesiology at Penn, will discuss regulatory and ethical issues raised in the process of designing, implementing, and reporting multi-center pragmatic trials, with a focus on 3 recently completed or planned studies focusing on aspects of anesthesia care for older surgical patients:

REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture; NCT02507505), DROP-Benzo (De-adopting Routine Preoperative Benzodiazepines for Older Surgical Patients; NCT05436392); and My Anesthesia Choice-Hip Fracture ( www.myanesthesiachoice.org ; registration pending).

Key areas of discussion will include:

• Navigating clinician attitudes towards comparators and questions around equipoise
• Implementing single IRB processes
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Virome Sequencing Identifies H5N1 Avian Influenza in Wastewater from Nine Cities

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Avian influenza (serotype H5N1) is a highly pathogenic virus that emerged in domestic waterfowl in 1996. Over the past decade, zoonotic transmission to mammals, including humans, has been reported. Although human to human transmission is rare, infection has been fatal in nearly half of patients who have contracted the virus in past outbreaks. The increasing presence of the virus in domesticated animals raises substantial concerns that viral adaptation to immunologically naïve humans may result in the next flu pandemic. Wastewater-based epidemiology (WBE) to track viruses was historically used to track polio and has recently been implemented for SARS-CoV2 monitoring during the COVID-19 pandemic. Here, using an agnostic, hybrid-capture sequencing approach, we report the detection of H5N1 in wastewater in nine Texas cities, with a total catchment area population in the millions, over a two-month period from March 4 th to April 25 th , 2024. Sequencing reads uniquely aligning to H5N1 covered all eight genome segments, with best alignments to clade 2.3.4.4b. Notably, 19 of 23 monitored sites had at least one detection event, and the H5N1 serotype became dominant over seasonal influenza over time. A variant analysis suggests avian or bovine origin but other potential sources, especially humans, could not be excluded. We report the value of wastewater sequencing to track avian influenza.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by S.B. 1780, 87th Legislature, 2021 Reg. Sess. (Texas 2021) (E.B., A.W.M., and J.F.P.), NIH/NIAID (Grant number U19 AI44297) (A.W.M.), Baylor College of Medicine Melnick Seed (A.W.M) and Alkek Foundation Seed (J.F.P.), and Pandemic Threat Technology Center (P.A.P.).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data Availability

All data produced are available online at https://zenodo.org/doi/10.5281/zenodo.11175923 and NCBI SRA BioProject: PRJNA966185

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