Biospecimens, Research Consent, and Distinguishing Cell Line Research.

Newly revised regulations for human research affecting translational oncology will become effective in January 2019. A substantial component of the debate leading to this revision was how to regulate biospecimen research; specifically, whether all biospecimens should be considered inherently "identifiable," thereby necessitating informed consent for use in research. The famous cases seminal to this discussion involve cancer cell lines, but the unique features of this kind of biospecimen research were largely missing from the regulatory deliberation. However, special aspects of cell line research-at the stages of procurement, generation, evolution, and sharing-alter how society should balance participant interests against the goals of research. Recommendations are offered to cancer researchers and policymakers going forward to enable ethically appropriate regulation of biospecimen research across its diverse spectrum.

Unit 731 and moral repair.

Unit 731, a biological warfare research organisation that operated under the authority of the Imperial Japanese Army in the 1930s and 1940s, conducted brutal experiments on thousands of unconsenting subjects. Because of the US interest in the data from these experiments, the perpetrators were not prosecuted and the atrocities are still relatively undiscussed. What counts as meaningful moral repair in this case-what should perpetrators and collaborator communities do decades later? We argue for three non-ideal but realistic forms of moral repair: (1) a national policy in Japan against human experimentation without appropriate informed and voluntary consent; (2) the establishment of a memorial to the victims of Unit 731; and (3) US disclosure about its use of Unit 731 data and an apology for failing to hold the perpetrators accountable.

Ethics, Human Use, and the Department of Defense Serum Repository.

The Department of Defense Serum Repository (DoDSR) contains a growing archive of sera from service members collected to perform medical surveillance, clinical diagnosis, and epidemiologic studies to identify, prevent, and control diseases associated with military service. The specimens are a mandatory collection under DoD and U.S. regulations and do not include informed consent for uses beyond force health protection. Any use of the specimens for research requires deidentification of the samples and must be approved by Institutional Review Boards. However, as expansion of the DoDSR is contemplated, ethical considerations of sample collection, storage, and use must be carefully reconsidered. Other similar programs for research use of specimens collected for public health purpose are also undergoing similar reviews. It is recommended that at a minimum, service members are informed of the potential storage and use of their specimens and are allowed to opt out of additional use, or a broad informed consent is provided. The DoDSR provides a tremendous resource to the DoD and global health community, and to ensure its continued existence and improvement, the DoD must stay consistent with all principles of research ethics.

First, do no harm: the US sexually transmitted disease experiments in Guatemala.

Beginning in 1946, the United States government immorally and unethically-and, arguably, illegally-engaged in research experiments in which more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases. Many have been left untreated to the present day. Although US President Barack Obama apologized in 2010, and although the US Presidential Commission for the Study of Bioethical Issues found the Guatemalan experiments morally wrong, little if anything has been done to compensate the victims and their families. We explore the backdrop for this unethical medical research and violation of human rights and call for steps the United States should take to provide relief and compensation to Guatemala and its people.

Proper knowledge on toxicokinetics improves human hazard testing and subsequent health risk characterisation. A case study approach.

In the current EU legislative frameworks on chemicals safety, the requirements with respect to information on general kinetic parameters (absorption, distribution, metabolism and excretion or ADME) or integrated toxicokinetic parameters (TK, i.e. plasma concentration-time curve, area under the curve etcetera) in humans and experimental animals vary widely. For agrochemicals and cosmetics, there are regulatory requirements whereas for other frameworks, such as food ingredients, biocides, consumer products and high production volume chemicals (REACH) there are very little or no requirements. This paper presents case studies that illustrate the importance of ADME and TK data in regulatory risk characterisations. The examples were collected by interviewing regulatory risk assessors from various chemicals (non-pharmaceutical) frameworks. The case studies illustrate how (1) applying ADME/TK in an early phase of toxicity testing can be used to improve study design and support the 3R-goals and how (2) increased use of ADME/TK data can improve the final risk assessment.

Survey of users of TOPS, an internet-based system to prevent healthy subjects from over-volunteering for clinical trials.

OBJECTIVE: To analyse users' experience of TOPS, an internet-based system that helps UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or starting a second trial too soon after the first. METHODS: We sent to all units that currently use TOPS an anonymous questionnaire comprising 18 questions about the effectiveness and ease of use of the system. RESULTS: Of 35 units that currently use TOPS, 31 (85.7 %) returned questionnaires. Most users find TOPS easy to use, had increased their detection rate of over-volunteering, and had rejected subjects as a result of using TOPS. A GP reply alone is not enough to prevent over-volunteering. Ethics committees, the MHRA and sponsors know about TOPS and support its use. CONCLUSIONS: The results confirm that TOPS does prevent healthy subjects from over-volunteering. Consequently, the Health Research Authority has agreed to take over the management of TOPS. Ethics committee approval of a phase 1 trial and MHRA accreditation of the unit will henceforth be conditional on consistent and proper use of TOPS. That should enhance its effectiveness and improve the safety of volunteers in non-therapeutic trials in the UK.

Aspects of vulnerable patients and informed consent in clinical trials.

SCOPE: To discuss the rationale behind informed consent in clinical trials focusing on vulnerable patients from a European and German viewpoint. METHODS: Scientific literature search via PubMed, Medline, Google. RESULTS: Voluntary informed consent is the cornerstone of policies regulating clinical trials. To enroll a patient into a clinical trial without having obtained written and signed consent is to be considered as a serious issue in the conduct of a clinical trial. Development of ethical guidance for physicians started before Christ Era with the Hippocratic Oath. Main function of consent, as articulated in all guidelines developed for clinical research, is to facilitate an individual's freedom of choice, respect autonomy, and thus to ensure welfare of the participants in clinical trials. Minors are unable to provide legally binding informed consent, this issue is addressed through a combination of parental permission and minor's assent. Illiteracy is a critical problem that affects all corners of our earth; it has no boundaries and exists among every race and ethnicity, age group, and economic class. New strategies to improve communication with patients including the use of videotapes or animated cartoon illustrations could be taught. Finally the time with the potential participant seems to be the best way to improve understanding. CONCLUSION: Discovery of life saving and life enhancing new treatments requires partnership that is based on good communication and trust between patients and researchers, sponsors, ethics committees, authorities, lawyers and politicians so that vulnerable patients can benefit from the results of well controlled clinical trials.

Pediatric participation in non-therapeutic research.

United Stated federal regulations allow participation of children in greater than minimal risk research with no potential for direct benefit under narrowly defined circumstances. This type of research is controversial, as it runs contrary to the best interest standard, on which we base most decisions made on behalf of children. I argue that such research is ethically defensible if a fully informed, scrupulous, and virtuous parent would choose to enroll his or her child in the study. Further, I defend the current regulations, which allow local Institutional Review Boards to approve more than minimal risk, nontherapeutic research when the research involves children with the medical condition being studied, but requires federal review for similarly risky studies that involve healthy children. Because families of children with medical diseases tend to be more familiar with the health care system and with medical procedures, they are more able to make informed decisions about the burdens of research participation. Further, parents of children with medical conditions have a morally significant interest in advancing medical knowledge about their child's condition. It is appropriate to take this interest into account when evaluating the ethical status of a research study.

[End of life non-therapeutic intensive care for organ preservation and donation: legal and ethical issues]. / Réanimation non thérapeutique en fin de vie pour préservation des organes en vue d'un don : problèmes éthiques et légaux.

INTRODUCTION: Stroke is presently the first cause of brain death in France. In this context, the question of elective non-therapeutic ventilation and resuscitation arises, aiming at enabling the patients for whom a decision to stop all the therapeutics has been made to evolve towards brain death and organ donation. In 2010, the French society of intensive care has released guidelines regarding stroke management including strategy on this topic. The question has also been referred to the Ethics Committee of Nancy university hospital by a chief-nurse of our hospital and we report here its conclusions and propositions. METHOD: A workgroup was appointed and has tackled the major issues: the justification, the risks for the patient and the society, the expression of the patient's consent, the legality of this care benefiting only a third party, and the practical details. CONCLUSIONS AND PROPOSITIONS: Elective intensive care following decision to stop any treatment after severe stroke seems to be justified with regard to public health as well as individual or collective ethics, providing the patient has expressed his/her consent or his/her non-opposition before stroke occurrence. In France there is no legal frame regulating this practice, no information of the general public, and a public debate has yet to be initiated. Regarding the practical details, a priori agreement of the organ procurement organisation, patient's consent, and approval of the consultant required by the law of April 22, 2005 relating to Patients' rights and to the end of life to rule out any conflict of interest, have to be checked before referring the patient to ICU. Advance directives drafting must be developed and their scope extended to organ donation and elective resuscitation. Therefore, fair information of the general public and clarity and transparency of the procedures are needed. The prolongation of the French moratorium on Maastricht III type non-heart beating organ donation - grounded on fears of possible conflicts on interest - seems obsolete with regard to the increasing respect of the patient's autonomy and to the risk of harmfulness entailed by elective resuscitation before death.

Swabbing students: should universities be allowed to facilitate educational DNA testing?

Recognizing the profound need for greater patient and provider familiarity with personalized genomic medicine, many university instructors are including personalized genotyping as part of their curricula. During seminars and lectures students run polymerase chain reactions on their own DNA or evaluate their experiences using direct-to-consumer genetic testing services subsidized by the university. By testing for genes that may influence behavioral or health-related traits, however, such as alcohol tolerance and cancer susceptibility, certain universities have stirred debate on the ethical concerns raised by educational genotyping. Considering the potential for psychosocial harm and medically relevant outcomes, how far should university-facilitated DNA testing be permitted to go? The analysis here distinguishes among these learning initiatives and critiques their approaches to the ethical concerns raised by educational genotyping.

TOPS: an internet-based system to prevent healthy subjects from over-volunteering for clinical trials.

AIM: Our aim was to set up a system to help UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or from starting a second trial too soon after the first. METHODS: TOPS (The Over-volunteering Prevention System) is internet-based, simple and quick to use, free to users and a charity run by a Board of Trustees. Users enter only two or three pieces of information: (1) 'National Insurance number' (NINO) of UK citizens, or 'passport number' and country of origin of non-UK citizens, as their identifier, (2) 'date of last dose' of trial medicine or (3) 'never dosed'. Subjects must consent, but TOPS collects only non-personal data, so it does not require Ethics Committee approval and is not covered by the Data Protection Act. RESULTS: A total of 55 research units (29 clinical research organisations, 5 pharmaceutical companies, 13 universities and 8 hospitals) throughout the UK have registered to use TOPS, and have entered 124,906 volunteers since we launched it. All commercial and many non-commercial units now use TOPS. In our unit, no subject has to the best of our knowledge participated in two trials simultaneously. TOPS has reduced to <1% the incidence of subjects attempting to volunteer within 3 months of completing another trial elsewhere, and very few have to our knowledge succeeded. CONCLUSION: TOPS is widely used and effective, and helps research units to comply with UK clinical trial regulations.

Limits on risks for healthy volunteers in biomedical research.

Healthy volunteers in biomedical research often face significant risks in studies that offer them no medical benefits. The U.S. federal research regulations and laws adopted by other countries place no limits on the risks that these participants face. In this essay, I argue that there should be some limits on the risks for biomedical research involving healthy volunteers. Limits on risk are necessary to protect human participants, institutions, and the scientific community from harm. With the exception of self-experimentation, limits on research risks faced by healthy volunteers constitute a type of soft, impure paternalism because participants usually do not fully understand the risks they are taking. I consider some approaches to limiting research risks and propose that healthy volunteers in biomedical research should not be exposed to greater than a 1% chance of serious harm, such as death, permanent disability, or severe illness or injury. While this guideline would restrict research risks, the limits would not be so low that they would prevent investigators from conducting valuable research. They would, however, set a clear upper boundary for investigators and signal to the scientific community and the public that there are limits on the risks that healthy participants may face in research. This standard provides guidance for decisions made by oversight bodies, but it is not an absolute rule. Investigators can enroll healthy volunteers in studies involving a greater than 1% chance of serious harm if they show that the research addresses a compelling public health or social problem and that the risk of serious harm is only slightly more than 1%. The committee reviewing the research should use outside experts to assess these risks.