Content uploaded by John Henry Noble Jr
Author content
All content in this area was uploaded by John Henry Noble Jr on Apr 09, 2015
Content may be subject to copyright.
Protecting People With Decisional Impairments and Legal Incapacity Against Biomedical Research Abuse
Abstract
Ethical and legal principles are provided for reviewing the ethics of recent cases of biomedical research abuse involving persons with decisional impairments or legal incapacity who were unable to understand the risks and benefits of the research to which they were subjected. Research abuse continues to occur despite guidance from the Nuremburg Code, the Declaration of Helsinki, the U.S. Belmont Report, extensive federal regulations governing human participant research, and several professional and disciplinary codes of ethics with which, the authors believe, the majority of researchers comply. Contributing to research abuse are weaknesses in the institutional review board and research ethics board review process; conflicting opinions about applicable ethical principles; mounting evidence of pervasive conflicts of interest; and dubious conflated research and marketing practices involving researchers, pharmaceutical and medical device manufacturers, and government research sponsors and regulatory agencies. Several recommendations are made to correct identifiable weaknesses and failures in the governance of biomedical research.
... 191 The development of civil law and, in a related sense, constitutional law resulted in substantial changes in the second half of the twentieth century. In light of the inhumanity and grave abuse of the dictatorships in the 1930s and 1940s, 192 in the second half of the twentieth century, various international legal agreements were established with provisions relating to the rights of persons with disabilities. 193 The initial approach was to ensure the application of the ban on discrimination, but in the 1990s, there was an increasing acceptance that regulations should address disability in a holistic manner. ...
In the second half of the twentieth century, Hungary attempted to develop modern legislation reflecting the interests of people with disabilities. Accordingly, under the Hungarian Civil Code, persons with disabilities with diminished active legal capacity received the ability to proceed in everyday transactions. Hungary was the first country in the world to adopt disability legislation regulating, in a horizontal sense, the rights of persons with disabilities. Hungary was also the second country to ratify the CRPD. In the field of civil law, the partial restriction (restriction according to area of authority) of active legal capacity has been possible since 2001. Even so, Hungarian law has yet to comply fully with the provisions of the United Nations Convention – provisions, which are based on the common law system approach to legal capacity. In Hungary, the right of a person to active legal capacity is still subject to limitations. In this respect, the adoption of a new Hungarian Civil Code would result in a significant change. Combining the common law and civil law models will abolish guardianship excluding active legal capacity and it will also introduce several legal institutions that ensure the effective implementation of the rights of persons with psychosocial disabilities while placing no restrictions on active legal capacity. The adoption of the new Hungarian Civil Code will ensure that Hungarian law complies with the provisions of the United Nations Convention, thereby establishing a legal framework that attends to the specific circumstances, interests, and needs of people with disabilities.
... 24 These concerns, in addition to the possibility of conflicts of interest within families, have led some to argue that family member authorization should not be the exclusive means of ensuring consideration and protection of the prospective research subject's interests. Rather, independent advice to substitute decision-makers 6 and/or independent oversight (for instance, by a research ombudsperson in addition to REBs) 34 have been suggested as essential supplements to authorization by a family member or other. ...
... The World War II war crimes tribunal enacted the Nuremberg Code in 1947 in reaction to the unethical use of subjects by Nazi physicians on concentration camp inmates before and during the war. 12 The Nuremberg Code of Ethics in Medical Research contained ten principles safeguarding subjects in research. Among others, it states that the human participant should be able to give voluntary informed consent to take part without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. ...
... Other examples include statistical manipulations of test data to convince regulators that the product is safer than it actually is, or using incoherent psychiatric patents to test new drugs that induce severe emotional states. 11 Biomedical ethicists have offered a number of solutions to minimize the risks of immoral design investments in synthetic biology and microbial engineering. For example, Arthur Caplan has argued that synthetic microorganisms need to be branded with genetic "watermarks," as Craig Venter demonstrated in practice. ...
... 24 These concerns, in addition to the possibility of conflicts of interest within families, have led some to argue that family member authorization should not be the exclusive means of ensuring consideration and protection of the prospective research subject's interests. Rather, independent advice to substitute decision-makers 6 and/or independent oversight (for instance, by a research ombudsperson in addition to REBs) 34 have been suggested as essential supplements to authorization by a family member or other. ...
In Canada, as in the United States, the legal frameworks governing research involving adults incapable of providing informed consent are beset by gaps and ambiguities. In both countries, federal laws and policies relevant to the regulation of research involving decisionally incapable adults interact in complex ways with provincial or state laws. To alert researchers to these complexities and to urge law reform, this review provides a comprehensive account of the federal and provincial/ territorial legal frameworks relevant to research involving decisionally incapable adults in Canada.
We identified the federal and provincial/territorial laws and policies pertinent to this review by updating previous work on substitute decision-making about research in Canada and then performing keyword searches on a Canadian legal information database (CanLii) to identify further laws of relevance. Our analysis of identified laws focused on three questions: 1) What (if any) preconditions-including permissible risk and/or benefit thresholds-are imposed on research involving persons who lack capacity to consent? 2) What provisions (if any) are in place for identification of the legally authorized representative for research decision making? and 3) What factors, if any, are stipulated as mandatory relevant considerations for the legally authorized representative's decision-making process?
Across Canada, laws relating to substitute decision-making are highly variable, and often ambiguous or uncertain, on each of the matters targeted in our analysis.
Researchers and research institutions should be aware of federal and provincial/territorial legal requirements for research involving persons who lack capacity to consent in Canada. The relevant governments should undertake coordinated efforts at law reform to clarify, and potentially harmonize, these requirements.
Decades ago, pharmacogenetic research established that one's genetic profile might predict efficacy and safety of medicines. Polymorphic expression of isoenzymes of the cytochrome P-450 enzyme system explains a significant amount of the variability of inter-individual responses to medicines. In Alzheimer's disease, the highly variable clinical response to cholinesterase inhibitors metabolized by the liver is explained on this basis. More recently, translation of basic pharmacogenomic research through the drug development process has led to the approval of "personalized" medicines, for example, in the field of oncology, cardiology and psychiatry, based on an individual's underlying genotypic variance of phenotypically expressed pathogenic targets and pathways. Translational pharmacogenomic research in Alzheimer's disease has emerged as a viable alternative to the study of large populations with similar phenotypic expression of symptoms through stratification of sub-groups based on ApoE carrier status in clinical trials.When initiating a global research protocol, it is incumbent upon sponsors to actively engage stakeholders in developing and underdeveloped countries, including local government authorities, regulatory bodies, ethics review boards, community representatives and participants, to address all aspects of the clinical trial, especially informed consent, which may be more challenging in countries where local customs and practices dictate the need for innovative approaches. Implementation of pharmacogenomics in the clinical trial requires further attention to ethical detail related to what kind of informed consent is needed for use of stored DNA samples for future, unforeseen related or unrelated research, whether and to whom to disclose current and future study results, and ways by which the benefits of current and future discoveries are shared by stakeholders in developed and underdeveloped or developing countries.
In February, the online magazine Slate published an article with the title, "Go Away, Ethics Police; Leave the NIH Alone." The author of the piece was Richard Epstein, a law professor at the University of Chicago and a senior fellow at the Maclean Center for Clinical Medical Ethics. The "ethics police" to whom Epstein objected were the critics who had pushed the National Institutes of Health (NIH) into adopting a strict new set of conflict-of-interest regulations. Last year, a muckraking series of reports in the Los Angeles Times revealed that some NIH scientists had parlayed their elite scientific positions into lucrative consulting contracts with the pharmaceutical industry. Several NIH scientists had received more than 600,000 from Schering AG and other companies at the same time that his institute conducted studies for Schering and pledged it 114,000 from the makers of cholesterol-lowering drugs.
Many critics of U.S. regulation to protect human subjects of biomedical and behavioral research deem the system inherently unworkable and variously inadequate or unnecessary. Many deem its rationale, the Belmont Report, outdated and philosophically deficient. Some would scrap or revamp the system. These criticisms and prescriptions are challenging factually, legally, and ethically. Similar minimalist, audited self-regulation operates smoothly elsewhere in life science. Events suggest Belmont's continuing validity in its administrative-law role as interpretive touchstone for human subjects protection regulations. U.S. human subjects protection and related regulations are constitutionally grounded and consistent with U.S. obligations under human rights law. Criticisms that the system is inconvenient do not respond to ethical and legal duties--to acknowledge the innate dignity of human subjects of research, to recognize and squarely face ethical issues in human subjects research, to heed applicable domestic and international law, to say no to projects when no is warranted, to foster researcher involvement in the system, to focus on substance rather than form, and to resist automaticity. If the system is to function protectively and reasonably efficiently, then the legitimacy of the pertinent law and Belmont's legal role should be recognized as the primary resource for interpreting the human subjects regulations; the system and proposed changes should be viewed critically for efficacy rather than convenience; and policy and practice should emphasize (a) predictability, stability, and clarity of the regulatory system, and (b) resources and will to comply and enforce.
EDITOR—Polman and Uitdehaag present a clinical review of drug treatment of multiple sclerosis that is unsystematic and makes no attempt to take account of existing systematic reviews of the evidence.1 In consequence, it has several important deficiencies as an assessment of the drugs available to help patients with this serious disease. Firstly, the authors say that “the amount of [magnetic resonance imaging] lesions in the early phase of the disease predicts future disability” but make no comment about the conclusion of a recent meta-analysis of nine longitudinal studies that [gadolinium enhanced magnetic resonance imaging] “is not a strong predictor of the development … of disability.”2 Secondly, they dismiss the older immunosuppressive drugs, saying that they have limited efficacy and considerable toxicity. They make no reference, however, to a recent systematic review of the randomised evidence about these drugs that puts them in context.3 Thirdly, they include a short paragraph about the cost utility of interferon beta, with one single reference. A recent systematic review of relevant studies from across the world addressing this question found three looking at relapsing-remitting and two at secondary progressive disease. In each case the cost per quality adjusted life year was high, which raises the question of whether people with multiple sclerosis might derive more benefit from resources invested in services other than interferon beta.4 The assessment of health technologies requires an unbiased and systematic assessment of the totality of the available evidence. People with multiple sclerosis are not helped by incomplete reviews—neither are healthcare decision makers. Footnotes Competing interests All the authors were authors of a recent rapid review of the effectiveness, costs, and utility of a range of disease modifying drugs in multiple sclerosis. They also work for the National Coordinating Centre for Health Technology Assessment, which manages the health technology assessment programme on behalf of the NHS.
BACKGROUND
Informed consent is critical to the ethical conduct of pediatric cancer clinical research. Research regarding such consent has been limited.METHODS
After conducting a background survey of institutional practice from principal investigators (PIs) at 113 Childrens Cancer Group (CCG) centers, the authors obtained more detailed data regarding informed consent from 23 parents of children recently enrolled in CCG research trials and from 23 clinician-investigators at 5 CCG institutions.RESULTSApproximately 73% of PIs responded to the background survey, providing context in which to interpret the more detailed information. Parents reported that they found the informed consent process helpful, although somewhat confusing. Satisfaction with informed consent was not related to ethnicity or education level. Parents found discussion with staff more helpful than the consent document, and the majority reported that the amount of information conveyed was appropriate. Although only 3 parents (13%) reported that too much information was given, nearly 50% of the investigators believed too much information usually is provided. All investigators believed that patients benefit from participation in CCG studies; the majority recommend that the child be enrolled on study, and the majority believe the major obstacle to good informed consent is parents' "state of shock."CONCLUSIONS
Parents expressed general satisfaction with the consent process. By contrast, clinician responses indicate dissatisfaction with the informed consent process. Future research must include more centers and larger numbers of parents of children who we enrolled as well as those who declined to participate in CCG studies, examine consent in minority subgroups, and further investigate the role of clinician-investigators and their interaction with parents and children during the informed consent process. Cancer 1998;82:2467-2481. © 1998 American Cancer Society.
Carlos, FerrandoMarina, SoroJaume, CanetMa Carmen, UnzuetaFernando, SuárezJulián, LibreroSalvador, PeiróAlicia, LlombartCarlos, DelgadoIrene, LeónLucas, RoviraFernando, RamascoManuel, GranellCésar, AldecoaOscar, DiazJaume, BalustIgnacio, GaruttiManuel, de la MattaAlberto, PensadoRafael, GonzalezMª Eugenia, DuránLucia, GallegoSantiago García, del ValleFrancisco J, RedondoPedro, DiazDavid, PestañaAurelio, RodríguezJavier, AguirreJose M, GarcíaJavier, GarcíaElena, EspinosaPedro, CharcoJose, NavarroClara, RodríguezGerardo, TusmanFrancisco Javier, Belda. (2015) Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE): study protocol for a randomized controlled trial. Trials 16
CrossRef
Andrés, EstebanFernando, Frutos-VivarAlfonso, MurielNiall D., FergusonOscar, PeñuelasVictor, AbrairaKonstantinos, RaymondosFernando, RiosNicolas, NinCarlos, ApezteguíaDamian A., VioliArnaud W., ThilleLaurent, BrochardMarco, GonzálezAsisclo J., VillagomezJavier, HurtadoAndrew R., DaviesBin, DuSalvatore M., MaggiorePaolo, PelosiLuis, SotoVinko, TomicicGabriel, D’EmpaireDimitrios, MatamisFekri, AbrougRui P., MorenoMarco Antonio, SoaresYaseen, ArabiFreddy, SandiManuel, JibajaPravin, AminYounsuck, KohMichael A., KuiperHans-Henrik, BülowAmine Ali, ZeggwaghAntonio, Anzueto. (2013) Evolution of Mortality over Time in Patients Receiving Mechanical Ventilation. American Journal of Respiratory and Critical Care Medicine 188, 220-230
CrossRef
L. Y., ZhaoJ. K., LuY., XuX. S., LiuE. M., QingC., LiuS., MinK., WeiD., LiuJ., LuoP., LiJ., DongX.- b., LiuC., LiuS., MinK., WeiD., LiuJ., LuoP., LiJ., DongX.- b., LiuK., XieY., YuH., ChenH., HanX., SunG., WangY. L., LiZ. H., HuangD. M., QuX. S., XueB. W., YuH. Y., WangZ. T., WenC. X., WangY., WeiG. L., WangW., YangZ., YueX., CuiY., GuoL., ZhangH., ZhouW., LiY., ZhangK. X., LiuT., YuL., LiuS., MinW., LiK., WeiJ., CaoJ., LuoB., WangJ., CaoQ. S., LiL., LiuK., WeiP., LiJ., DongS., MinY., LuJ., YuC., DongH., ChenK., XieH., HanG., WangW., WangY., YuY., MaoE., GuX., SuZ.- y., GengY.- l., ZhengX., FangL., HouW., LiJ., DengZ. P., FangQ. Z., YangC., LeiY., ChenX., ChenX., LiS., ChenH. L., DongL., XiongD. X., LeiH., TianL., YueX. L., JiangX. R., Song. (2013) Abstracts of a joint meeting of the Anaesthetic Research Society and the Chinese Society of Anesthesiologists. British Journal of Anaesthesia 110, 146-160
CrossRef
No one wholly dominates another in a democracy. This central limiting principle in democratic political conflict does more than prohibit imprisonment or murder of political opponents; it also proscribes the total and permanent defeat of opponents' self-defined ideological or economic interests. This constraint has varied expressions in American democratic theory and practice-the assumed permanent existence of some form of opposing political parties, the ideological tenet that respect for minority rights always limits majority rule, and the prohibition of slavery. There is, however, a problem with this supposed democratic constraint: Some political disputes simply moot it. In some disputes, victory for one side necessarily amounts to total, annihilating defeat for the other-at least as the losers construe that defeat. In this circumstance, democratic principles cannot explain why the loser should accept the legitimacy of his defeat. Even if the loss followed from a majority vote in a popular election, the majority's action would not necessarily attain legitimacy under democratic theory. This is because equality is a bedrock substantive principle of democratic theory and, insofar as the majority is free to disregard the wishes of members of the losing minority and thereby to treat them as less than equals, majority rule is intrinsically at odds with the egalitarian principle.
For
Kenneth J Rothman (KRothman@bu.edu), professora, Karin B Michels, assistant professorba Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston University Medical Center, Boston, MA 02118-2526, USAb Harvard Medical School Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA 02115, USADepartment of Surgery, University College London, London W1P 7LDCorrespondence to: K J Rothman
Actions that penalise some for the good of others are defended under the utilitarian banner of doing the greatest good for the greatest number. For this reason we justify imposing quarantine to prevent the spread of infectious illness. In the same spirit some scientists and regulators would ask patients who participate in medical research to make sacrifices for the greater good. Their position puts them at odds with the Declaration of Helsinki, which does not mince words in choosing between the greatest good for the greatest number and the rights of the individual patient: “In research on man, the interest of science and society should never take precedence over considerations related to the well being of the subject.”1 This ethical choice of the patient's rights over the good of society in general is now up for re-examination as the World Medical Association deliberates the next revision of the declaration.
Under pressure from the FDA
Why would the World Medical Association consider stepping back from its strong support for the rights of the patient? It is under pressure to do so from several critics, 2 3 notably the United States Food and Drug Administration. The Food and Drug Administration mandates many human experiments as part of the approval …
Bioethics is currently witnessing unprecedented debate over the moral and legal norms governing the conduct of clinical research. At the center of this debate is the duty of care in clinical research, and its most widely accepted specification, clinical equipoise. In recent work, we have argued that equipoise and cognate concepts central to the ethics of clinical research have been left unnecessarily vulnerable to criticism. We have suggested that the vulnerability lies in the conspicuous absence of an articulated foundation in moral and legal theory of the physician-researcher's duty of care to the patient-subject. We have repeatedly suggested that the requisite foundation is in the ethics of trust and the law of fiduciaries.
Curiously, despite the absence of a published thorough exposition of our position, some have preemptively criticized our suggestion that the relationship between physician-researcher and patient-subject is fiduciary. Others have offered their own accounts of the implications of fiduciary law for the relationship.