Research Ethics Board - Guidelines For Writing A Research Consent: Fill & Download for Free

Placebos are used in both clinical trials and general practice. Arguably the most prescribed drug in human history (1), the history of medicine is in large part the history of the placebo (2). What's the ethical dilemma of placebos in clinical trials? To understand this we need to examine the history of informed consent, and understand what's a placebo, where it stands in current biomedical research and how its use creates an ethical dilemma.The problem starts with the definition of placebo. There isn't one. Rather there are many.The word placebo derives from the Latin word, 'placere' meaning 'I will please' or 'I will do good', a word opposite to nocebo derived from the Latin word 'nocere' meaning 'I will harm'. One definition of placebo is 'An inert substance usually prepared to look as similar to the active product investigated in a study as possible' and the placebo effect is 'any (usually beneficial) changes that occur within a group ‘treated’ with placebo' (3). I wrote one definition implying there are many and therein lies one of several ethical issues about placebos. A recent review (4) helpfully collated different definitions of placebo used by many world-renowned biomedical research organizations and health policy-making bodies.From 4Ironically, even different institutes within the same organization, the US-based NIH, have multiple definitions. Why are multiple definitions a problem? Unlike our past or rather because of it, in biomedical research today, safety of patients is sacrosanct. The more ambiguous the definition of a foundational term like placebo, the greater the possibility of misunderstanding and miscommunication. If the experts themselves don't agree on a common definition of placebo, an intervention that requires the approval of clinical trial participants, what chances then that the latter, likely not experts, fully understand what their consent means? Such a pitfall could further undermine public trust in doctors and clinical trials (5).The clinical trial as we now know it is of recent vintage. It starts with the UK's Medical Research Council 1947 study of streptomycin treatment for tuberculosis (6). Since 1947, clinical trial methodology has improved vastly to minimize bias in design, management and interpretation. Now health-care providers need to provide clinical trial participants information necessary for their autonomous decision-making, i.e. informed consent forms are now mandatory. In this mix, we have placebos.By enabling a causal association between treatment and outcome, placebos have been instrumental in making clinical research more rigorous and scientifically sound, with a caveat of course. After all, the 'placebo effect' tells us in no uncertain terms that we don't fully understand how our body, brain and mind work together. The unpredictable 'placebo effect' also negates economic arguments that are typically made in favor of placebo-controlled trials, namely, that it requires fewer participants and is faster compared to trials that compare two or more treatments (e.g., active controlled or superiority or non-inferiority trials) (7).However, why do clinical trials require informed consent (approval by participants) in the first place?Brief history of informed consent in clinical trialsGerman Nazi doctor experiments on concentration camp inmates and the Tuskegee Syphilis Project are representative examples of egregious medical practice abuse. Human autonomy, the overarching victim, thus became the central tenet in modern medical ethics through a convoluted and not simplistically linear process. While the Nuremberg Code established a set of research ethics for human experimentation in 1947, isn't it ironic that the Tuskegee syphilis experiment was conducted continuously from 1932 until 1972? In this study, African-Americans diagnosed with syphilis were deliberately left untreated in order to follow natural disease progression. This example of egregious post-WWII violation of human rights proved that the Nuremberg Code alone was insufficient to prevent wholesale abuse in human experimentation. While public revelation of the Tuskegee project in 1972 drove the creation of new standards in research ethics requiring the treatment of research participants as autonomous agents, it was only in 1997 that US president Bill Clinton apologized to the Tuskegee study participants and their families. However, neither of these two egregious examples of abuse alone suffice to understand how we arrive at today's 'informed consent'. For this we need to delve into the law and lawsuits.The first piece of 'Informed consent'. When and how the phrase came into existence.The US case Salgo v. Leland Stanford, Jr. University Board of Trustees coined the phrase, 'informed consent'. The plaintiff, Mr Salgo underwent a now-defunct treatment 'involving puncturing the aorta through the back in order to inject a radio-opaque dye, and was left with permanent paralysis of the legs. According to the direction given to the jury: “The physician has . . . discretion [to withhold alarming information from the patient] consistent, of course, with the full disclosure of facts necessary to an informed consent” ([1957] 317 P.2d 170 (Cal. Ct. App.) at 181)'(8). In this jury instruction, there is an obvious contradiction of terms between 'discretion to withhold alarming information' and 'full disclosure of facts necessary to an informed consent'. Nevertheless, this and subsequent cases codified that disclosure needed to conform to 'professional practice standard', namely, what a reasonable health-care practitioner would do under similar circumstances (8).The second piece of 'Informed consent': The 'reasonable person standard'.In the US case, Canterbury v. Spence ([1972] 464 F.2d 772 (D.C. Cir.)), the patient fell out of his hospital bed after undergoing a laminectomy (surgical removal of a vertebral bone called the lamina) and suffered major paralysis (8). The patient had not been warned about 'the possibility of this rare outcome'. This case deemed the professional practice standard inadequate in that it failed to respect the patient's self-determination, and it gave way to the patient- centered 'reasonable person standard', i.e. what any reasonable patient would consider necessary and sufficient to know, rather than what professionals might consider necessary to disclose (9). According to the philosopher Peter Singer and his colleague Helga Kuhse, 'this single move served to overcome three main weaknesses of the professional practice standard: first, that agreed professional standards of disclosure were typically set too low to satisfy patient demand for information; second, that there were no agreed standards for new procedures; and, third, that patients were put at a significant disadvantage in having to rely upon expert witnesses (usually other health-care practitioners) in disputes about standards of care' (8).With the adoption of a 'reasonable person standard', patients have greater decision-making control about their own health care. In theory, anyway. What does this mean in practical terms though? Health-care providers have to disclose to the patient the four elements necessary for informed patient consent: the nature (therapeutic/not), risks, alternatives and benefits of the procedure and/or treatment. Disclose the nature of the treatment: Is it therapeutic or not? This is how we arrive at the current ethical dilemma of the placebo. As with many ethical dilemmas that ensue from the tussle between individual rights and collective good, the participants of a placebo-controlled trial bear the risks. Let's examine who benefits.Who benefits from a placebo-controlled trial, public health (the participants, i.e. patients, nation(s)) or the sponsor? Some case studies highlight a) inevitable conflicts of interest and b) developed vs developing world disconnects in access to consistent standard of care.Neither individuals nor public health, only the sponsor. In Bolivia, Discovery labs was testing a new surfactant, Surfaxin, for respiratory distress syndrome (RDS). However, its intent was not to develop the drug to benefit premature Bolivian infants with RDS but to market it in high-income countries (10). Violation of ethics? No doubt.Individuals pay but public health benefits. In the Romanian government-funded, Bucharest Early Intervention Project (11), abandoned children were randomly assigned to either foster or institutional care even though US childcare experts agreed foster care was better. The result helped Romanian policy-makers establish a foster care program in Bucharest, and an ethicist concluded the study had sufficient 'social value' to justify its design (12). Millum and Grady state 'Social value is a fundamental, but under-analyzed, concept in research ethics' (7). I bet the children left to institutional care would vociferously beg to differ. Another fundamental informed consent issue that this case highlights? Presumably, usually parents or caregivers, i.e. individuals, proffer informed consent on behalf of minors. In the case of these and other orphans, presumably the state, manifestly not an individual, consents? Is individual and state informed consent the same thing? The study (11) itself is mum on this issue. Yet another ethical conundrum.Double standards in medical research.The US 076 regimen gave Zidovudine (AZT) intravenously prenatally, during delivery, and postpartum (13). Though it reduced perinatal (vertical) HIV transmission by approximately 2/3rds and had become the standard of care in developed countries, the needed infrastructure, comprehensive prenatal care, and drug cost couldn't be met in developing countries, which had the majority of perinatal HIV infections. Hence controversial placebo-controlled trials in Sub-Saharan Africa gave a single nevirapine dose to pregnant women during labor and their infants within 72 hours of birth (14). What's egregious about that? As Millum et al write, 'it was known at the time that single-dose nevirapine would not be as effective as more comprehensive and much more expensive treatment regimens that also targeted transmission during pregnancy' (15). Like it or not, when it comes to public health, we live in a world of haves and have-nots.According to latest guidelines, when is a placebo currently acceptable?A brief history of the modern clinical trials and the codified set of rules for their conduct, namely, the World Medical Association's 1964 Declaration of Helsinki (DoH) and its subsequent revisions (7 as of 2013) reveal plenty of controversy such as the 5th revision in 2000 which was approved without consensus from national medical associations in the aftermath of the controversial sub-Saharan nevirapine studies on vertical HIV transmission.The 7th version of the DoH, adopted in October 2013 at the 64th WMA General Assembly in Fortaleza, Brazil, says, 'Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects. (Paragraph16)' (15). It also asserts that 'placebos, no intervention or any intervention less effective than the best proven one may be used only when the patients who receive them will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention' (16). 'Less effective than the best proven', a phrase that explicitly codified double standards in medical research. In response, the Latin American and Caribbean Medical Confederations did not approve the wording of placebo use in the DoH 2013 because 'the poor and vulnerable populations, discriminated by their lack of resources, cannot be subjected to biomedical research that have levels of safety less than those applied to more developed societies' (17, 18).Ambiguity about the 'risk of serious or irreversible harm' is another big problem with the latest DoH stance on placebo. Is it risk of serious or irreversible harm to not treat a cut or skin biopsy or to not treat an HIV positive pregnant woman? In the arena of global politics, 'risk of serious or irreversible harm' becomes a vast, seemingly insurmountable chasm between the optimal and the dubious in wealthy and poor countries, respectively. Hellman et al also point out that the 2013 DoH excluded the division between therapeutic and non-therapeutic studies, further increasing participant vulnerability (18).Today, health-care providers need to tell placebo-controlled trial participants they could receive either a treatment or a placebo. Do participants balk? Certainly but it seems to vary by disease type and severity. While a study suggests 70% of cancer patients would likely decline to participate in a placebo-controlled trial (19), 24% of hypertension patients are likely to do so (20).Final word: Placebos remain a persistent ethical dilemma. We just added another wrinkle with bureaucracy.Our history teaches us that when we codify processes and develop contingencies to accommodate ethical codes and legal requirements, we tend to become complacent and end up going through the motions without fully comprehending the poignant ethical and moral compulsions that necessitated them. In other words, a definition of bureaucracy. We see a similar effect at play with our current use of placebos in clinical trials. The meager research currently available on how clinical trial participants are informed about placebos and their effects suggests that placebos and their risks are poorly explained (4, 21, 22). This, even without getting into vast global cultural differences. For example, imagine informed consent in cultures that believe evil spirits or witchcraft cause diseases or where the concept of lock and key privacy (...of informed consent forms) is alien or where native healers are accorded respect on par with modern medical practitioners or where illiteracy is prevalent. Given we do live in a world of such enormous cultural, resource and opportunity differences, from benign neglect to active deception, the entire ethical gamut with respect to placebos is still very much at play.BibliographyShapiro, Arthur K., and Elaine Shapiro. "The powerful placebo." From ancient priest to modern (1997).Požgain, Ivan, Zrinka Požgain, and Dunja Degmečić. "Placebo and nocebo effect: a mini-review." Psychiatria Danubina 26.2 (2014): 100-107. Page on hdbp.orgDay, Simon. Dictionary for clinical trials. John Wiley & Sons, 2007.Hernández, Astrid, et al. "The Definition of Placebo in the Informed Consent Forms of Clinical Trials." PloS one 9.11 (2014): e113654. Page on plosone.orgLouhiala, Pekka, Harri Hemilä, and Raimo Puustinen. "Clinical use of placebo treatments may undermine the trust of patients: a response to Gold and Lichtenberg." Journal of medical ethics (2014): medethics-2014. Page on mv.helsinki.fiMarshall, Geoffrey, et al. "Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation." BMJ 2.4582 (1948): 769-782.Millum, Joseph, and Christine Grady. "The ethics of placebo-controlled trials: methodological justifications." Contemporary clinical trials 36.2 (2013): 510-514. The Ethics of Placebo-controlled Trials: Methodological JustificationsA Companion to Bioethics, Second Edition. Helga Kuhse, Peter Singer, editors. A Companion to BioethicsFaden, Ruth R., Tom L. Beauchamp, and Nancy M. King. "A history and theory of informed consent." (1986).Lurie P, Wolfe SM. Commentary 9.2. The Developing World as the “Answer” to the Dreams of Pharmaceutical Companies: The Surfaxin Story. In: Lavery JV, Grady C, Wahl ER, Emanuel EJ, editors. Ethical Issues in International Biomedical Research: A Casebook. Oxford University Press; 2007. pp. 159–170.Nelson, Charles A., et al. "Cognitive recovery in socially deprived young children: The Bucharest Early Intervention Project." Science 318.5858 (2007): 1937-1940. Page on ucsd.eduRid, Annette. "When is research socially valuable? Lessons from the Bucharest Early Intervention Project: commentary on a case study in the ethics of mental health research." The Journal of nervous and mental disease 200.3 (2012): 248-249. Page on bucharestearlyinterventionproject.orgConnor, Edward M., et al. "Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment." New England Journal of Medicine 331.18 (1994): 1173-1180.Marseille, Elliot, et al. "Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa." The Lancet 354.9181 (1999): 803-809.Millum, Joseph, David Wendler, and Ezekiel J. Emanuel. "The 50th anniversary of the Declaration of Helsinki: progress but many remaining challenges." Jama 310.20 (2013): 2143-2144. Page on nih.govWorld Medical Association (WMA). Declaration of Helsinki. Amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. WMA Archives, Ferney-Voltaire, France.Confederacion Medica Latinoamericana y el Caribe (CONFEMEL). Declaracion de Pachuca Sobre la Revision de Helsinki. 22 and 23 November 2013. (Accessed May 5, 2014. Page on confemel.comHellmann, Fernando, et al. "50th Anniversary of the Declaration of Helsinki: The Double Standard Was Introduced." Archives of medical research 45.7 (2014): 600-601.Jefford, Michael, and Rosemary Moore. "Improvement of informed consent and the quality of consent documents." The lancet oncology 9.5 (2008): 485-493.Halpern, Scott D., et al. "Hypertensive patients' willingness to participate in placebo-controlled trials: implications for recruitment efficiency." American heart journal 146.6 (2003): 985-992.Bishop, Felicity L., et al. "Informed consent and placebo effects: a content analysis of information leaflets to identify what clinical trial participants are told about placebos." PloS one 7.6 (2012): e39661. Page on plosone.orgKeränen, Tapani, et al. "Placebo-controlled clinical trials: how trial documents justify the use of randomisation and placebo." BMC medical ethics 16.1 (2015): 2. Page on biomedcentral.com

Clinical trials as we understand them today are a fairly recent invention, starting with the 1947 UK Medical Research Council's study of streptomycin for tuberculosis treatment, the 1st randomized clinical trial (1).Informed consent is of even more recent vintage. Dwelling at the intersection of law and medicine, birthed by the former, imposed on the latter, informed consent and clinical medicine have had an uneasy relationship from the beginning. While landmark cases started shaping its legal doctrine already in the 19th and early 20th century, informed consent's post-WWII legal lineage in the US is easy to track, with milestone rulings starting in the 1950s through to the 1970s (2, 3, 4),The 1957 Salgo v. Leland Stanford Jr. University Board of Trustees (2) established the precedent of patient self-determination with the judge coining the phrase, informed consent, in his jury instruction, the 1st known instance of its explicit use.The 1960 Natanson v. Kline (3) established the negligence standard, as in the physician having an inherent duty to make a reasonable disclosure of risks and hazards of treatment or face possible malpractice liability.The 1972 Canterbury v. Spence (4) established the reasonable person standard, i.e., the need to disclose what any reasonable person would consider necessary and sufficient to know.According to Ruth R. Faden, Tom L. Beauchamp and Nancy M.P. King, who published the definitive text-book on it in 1986 (5), how informed consent was planted in clinical medicine, how it grew, in other words its clinical medicine lineage, that's largely lost to time. This is perhaps an unavoidable difference because medicine already walks an uneasy tightrope between patient autonomy and welfare. Absence of early peer-reviewed medical studies only emphasizes the initial reluctance with which clinical medicine incorporated informed consent, and is also emblematic of the unease with which the two co-exist. Part of the reason for this unease is the perennial existence of grey areas.Why perennially grey areas? Because the young, the elderly, the frail, the poor, the poorly educated, the intellectually impaired, and the seriously ill are a part of us, a part of us that's much more dependent and thus much more vulnerable to manipulation. As Robert Q. Marston, the then-Director of the US NIH noted in an influential speech on the subject of informed consent, 'Whether or not consent is in fact informed is admittedly difficult to assess. We often are in an uncertain situation in which inadequate information, communication problems, and the inability of the subject to comprehend-or to read-or to listen-can be misleading' (6).Pre-informed consent Clinical Medicine helps understand why it's Important, nay Critical, in Clinical TrialsAs recently as 1964-1966, a study in the US found that >50% of physicians, 53% to be exact, thought it was 'ethically appropriate for a physician not to tell a cancer patient that she had been enrolled in a double blind clinical trial of an experimental anticancer drug and was currently receiving a placebo' (5, page 89).Two of the most prominent egregious abuses in human medical research, namely, Nazi human experimentation during the Holocaust and the Tuskegee Syphilis Study* certainly cast a long shadow, necessitating clear, formal, legally binding guidelines for human experimentation. While case law verdicts helped shape the legal framework for informed consent, the cultural framework, at least in the US, arose from several other cases that drove public debate, illuminated gaps in physician understanding of informed consent, and highlighted the roles and responsibilities of research committees and funders. Careful examination of the details and circumstances of some of these prominent cases helps drive home why informed consent is not only important but indeed critical. Two of several prominent US examples that were crucial in fleshing out informed consent as it exists today are elaborated here.The Jewish Chronic Disease Hospital CaseConducted at the Jewish Chronic Disease Hospital (JCDH) in Brooklyn, New York, and funded by Sloan-Kettering Institute for Cancer Research, the American Public Health Service and the American Cancer Society. With 10 years of research on anti-cancer immune responses under his belt, in July 1963, chief investigator Dr. Chester M. Southam convinced the hospital medical director Emmanuel E. Mandel to permit injection of a suspension of foreign, live cancer cells into 22 JCDH patients.The research question? Do cancer patients reject cancer transplants or not? Obviously comparison with response of cancer-free patients, the controls, was also required.The informed consent aspect? Some were informed orally they were involved in an experiment, but not that they would be injected with live cancer cells. No written informed consent.The final insult to injury, some patients were incompetent to give informed consent.The non-cancer patients, i.e., the controls, weren't informed either that they were getting injected with live cancer cells.The grounds? Might unnecessarily agitate the participants.The defense? That it was customary in medical research that consent 'not be documented even in far more dangerous research' (5, page 161), something that sounds utterly indefensible in the year 2015.As the New York Post reported in 2013, three young physicians, Drs. Avir Kagan, David Leichter and Perry Fersko, courageously went against the prevailing status quo and refused to participate in this study (7). They also brought it to the attention of attorney William Hyman, one of JCDH's Board of Directors, who filed a suit to access hospital records to learn more about the study (8). Hyman's concerns ranged from potential patient abuse, potential reputation damage to the hospital and its possible liability. The Hyman-driven review revealed (5, page 162),The study wasn't presented to the hospital's' research committee.Physicians directly responsible for patient care of subjects involved in the research weren't consulted about the cancer cell injections.Three physicians who had been consulted by Dr. Mandel were against the research arguing 'subjects were incapable of giving appropriate consent'.In 1966, the Board of Regents of the State University of New York censured Drs. Southam and Mandel, finding them guilty of deceit, fraud and unprofessional conduct, writing in its judgment (5, page 162, 9, see Regent' decision from 10 below),'A physician has no right to withhold from a prospective volunteer any fact which he knows may influence the decision. It is the volunteer's decision to make. . . . There is evidenced in the record in this proceeding an attitude on the part of some physicians . . . that the patient's consent is an empty formality. Deliberate nondisclosure of the material fact is no different from deliberate misrepresentation of such a fact. . . . The alleged oral consents that they obtained after deliberately withholding this information were not informed consents and were, for this reason, fraudulently obtained'.The Willowbrook State School CaseAn institution on Staten Island, New York, it was then classified in a manner unthinkable today, a mere 60 years later, namely, as a place for 'defective children'. Originally designed to house 3000, by 1963 it housed >6000. With the children's severe developmental impairments amplified by poor oversight, large numbers weren't even properly toilet trained. Unsurprisingly, such conditions not just predisposed to but also facilitated easy spread of fecal-borne infections. For example, in 1954, many children contracted hepatitis (presumably hepatitis A) within 6 to 12 months of living at Willowbrook.In 1956, Saul Krugman and colleagues started a series of experiments to develop an effective prophylactic. Funded by the US Armed Forces Epidemiological Board, the US Army Medical Research and Development Command, the Health Research Council of the City of New York, and several committees at New York University School of Medicine, including its Committee on Human Experimentation, they deliberately infected newly admitted patients with isolated hepatitis virus strains. Of the 10,000 children admitted to Willowbrook after 1956, ~ 750 to 800 were sent to Krugman's special hepatitis unit. Wards of the state never included in the studies, the children's parents had given written consent. At first, parents were informed by either letter or personal interview. Later, informed consent entailed groups discussions with parents of prospective parents.From the beginning, these studies were on the radar of Henry K. Beecher. With a decidedly murky ethical background himself, nevertheless, by the 1960s he'd emerged a pioneer of informed consent with his publication in 1959 of 'Experimentation in Man'. Beecher first listed the Willowbrook study in 1966 as one of 22 'ethically dubious' experiments. His repeat highlighting of this study in his 1970 book, Research and the Individual, brought the matter to the public's attention. Criticism gained momentum with the theologian Paul Ramsey joining in and with Stephen Goldby publishing a sharply critical letter in the Lancet in April 1971 (11), with the full support of the Lancet editors who publicly apologized for having previously overlooked the issue of informed consent.Such public scrutiny forced the researchers to defend themselves in the public arena. Their defense? Since most of the children recruited in the study would contract hepatitis anyway, they weren't placed in greater danger compared to the other institutionalized children. Optimal isolation, better attention, administered the best available anti-hepatitis therapy then available, the researchers asserted that their attempt to give the selected children sub-clinical hepatitis infections would immunize them against specific hepatitis viruses (12). That's not all. Influential editors of several prestigious medical journals, namely JAMA, NEJM, Journal of Infectious Diseases, agreed with this defense, arguing such research was valuable for understanding hepatitis, had potential value to such institutionalized children, had sufficient consent provisions, didn't expose the children to unnecessary risks and was performed by competent investigators (13).The rebuttal? The studyIncreased the children's later life risk for chronic liver disease.Unlike other Willowbrook residents, study children didn't receive protective doses of gamma globulin (14).Both process and legitimacy of consent obtained for the study were also easy to challenge. Consent forms used suggested the children would receive a vaccine against the virus, some parents were only contacted by letter. A key change happened in late 1964. Willowbrook became so overcrowded that new patient admissions ceased while Krugman's special research unit continued accepting children whose parents 'volunteered' them for the study, suggesting implicit coercion into the study as a means for parents getting their children admitted to Willowbrook (15). Study reviewers and we ourselves could easily conclude that social pressures under which such parents gave their consent, especially post-1964, undermined their ability to act in the best interests of their children.As Faden, Beauchamp and King note in their book (5, page 164), while Krugman's research unit was eventually closed, debate about the ethics of the Willowbrook study never resolved satisfactorily (16) and we see remarkable parallels regarding the ethics of informed consent issues here and in the 2009 PATH-ICMR HPV (Human Papilloma Virus) clinical trial**, ***. In both, the subjects of research were minors and parents/guardians offered informed consent on their behalf, one of the perennial grey areas I referenced earlier.The Road to Today's Informed Consent Becomes ClearerWith such recent examples of egregious medical research abuses as the backdrop, in 1973, Robert Q. Marston, the then-Director of the US NIH made an influential speech (6) that highlighted the central role of informed consent in clinical trials, 'That the committee determine that the rights and welfare of the subjects involved are adequately protected, that the risks of an individual are outweighed by the potential benefits to him or by the importance of the knowledge to be gained, and that informed consent is to be obtained by methods that are adequate and appropriate', and that 'if, in a specific case, I were forced to choose between the individual and the general welfare of society, I would choose to protect the individual'.He emphasized (6) that review committees that oversee human experimentation needed to strictly adhere to three basic criteria, namely,' Protection of the rights and welfare of the subjects.Weighing of risks against benefits.Determination that informed consent is to be obtained by methods that are adequate and appropriate.'In the US, it was in 1981 that the Judicial Council of the American Medical Association (AMA) first took an explicit stance on Informed Consent (5, page 96),'INFORMED CONSENT.The patient's right of self-decision can be effectively exercised only if the patient possesses enough information to enable an intelligent choice. The patient should make his own determination on treatment. Informed consent is a basic social policy for which exceptions are permitted (1) where the patient is unconscious or otherwise incapable of consenting and harm from failure to treat is imminent; or (2) when risk-disclosure poses such a serious psychological threat of detriment to the patient as to be medically contraindicated. Social policy does not accept the paternalistic view that the physician may remain silent because divulgence might prompt the patient to forego needed therapy. Rational, informed patients should not be expected to act uniformly, even under similar circumstances, in agreeing to or refusing treatment'.And this is more or less the landscape we've operated in ever since, with adequate and appropriate methods for obtaining informed consent remaining a perennially grey area, especially as clinical trials globalize and involve research subjects with vastly different cultural, linguistic and educational norms.Bibliography1. Marshall, Geoffrey, et al. "Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation." BMJ 2.4582 (1948): 769-782.2. Salgo v. Leland Stanford Jr. University Board of Trustees, 317 P.2d 170, 181 (1957).3. Natanson v. Kline, 350 P.2d 1093, 186 Kan. 393, 186 Kansas 393 (1960).4. Canterbury v. Spence, 464 F.2d 772 (D.C. Cir. 1972).5. Faden, Ruth R., Tom L. Beauchamp, and Nancy M. King. "A history and theory of informed consent." (1986). Oxford University Press.6. Marston, Robert Q. "Medical science, the clinical trial and society." Hastings Center Report 3.2 (1973): 1-4.7. The New York Post, Allen M. Hornblum, Dec 28, 2013. NYC's forgotten cancer scandal8. MATTER OF HYMAN v. Jewish Hosp., 15 N.Y.2d 317, 206 N.E.2d 338, 258 N.Y.S.2d 397 (1965).9. Katz, Jay, Alexander Morgan Capron, and Eleanor Swift Glass. Experimentation with human beings: The authority of the investigator, subject, professions, and state in the human experimentation process. Russell Sage Foundation, 1972.10. Langer, Elinor. "Human Experimentation: New York Verdict Affirms Patient's Rights." Science 151.3711 (1966): 663-666.11. Goldby, Stephen. "Experiments at the Willowbrook state school." The Lancet 297.7702 (1971): 749.12. Krugman, Saul, Joan P. Giles, and Jack Hammond. "Infectious hepatitis: Evidence for two distinctive clinical, epidemiological, and immunological types of infection." Jama 200.5 (1967): 365-373.13. Is Serum Hepatitis Only A Special Type of Infectious Hepatitis? JAMA. 1967;200(5):406-407. doi:10.1001/jama.1967.03120180094017.14. Annas, George J., Leonard H. Glantz, and Barbara F. Katz. Informed consent to human experimentation: The subject's dilemma. Ballinger Pub. Co., 1977.15. Goldman, Louis. "The Willowbrook Debate." World Med 7 (1971): 23-25.16. Ingelfinger, F. J. "Ethics of experiments on children." New England Journal of Medicine 288.15 (1973): 791-792.More details on the journey to, the process of, and grey areas in informed consent available in these answers:* Tirumalai Kamala's answer to Do you believe placebos are morally permissible? Why or why not?** Tirumalai Kamala's answer to Should we have an international forum to resolve clinical trial mishaps?*** Tirumalai Kamala's answer to Is it true that Bill Gates faced trial in India for illegally testing tribal children with vaccines?Thanks for the A2A, Kritika Gupta.

This answer may contain sensitive images. Click on an image to unblur it.'Was anyone ever held accountable for the Tuskegee syphilis study?'When a reprehensible and unethical human experiment runs uncontested for 40 years, the contours of accountability seem porous and gray rather than clear-cut or black and white since responsibility falls far and wide, not just on individuals but on institutions, the government itself as well as an entire biomedical research community. After all, funded and operated by the United States Public Health Service - Wikipedia (USPHS), a US government agency, results of the Tuskegee syphilis study (TSS) researchers were even published in leading biomedical journals.Poor, rural, mostly illiterate black men in Macon county, Alabama, were recruited for a study with an inherently problematic, even indefensible goal; to examine in excessive detail the course of untreated syphilis. Promising them burial insurance, physical exams, hot meals and transportation to and from the hospital plus false promises of treatment for 'bad blood', the researchers lied to the participants to gain their credulous permission for detailed post-mortem autopsy as well as painful, unsafe and potentially dangerous spinal taps performed under the guise of treatment, even as they arranged for their military deferments to keep them in the study. Preemptively stripping them of their dignity, the researchers evidently considered their research subjects as akin to doltish brutes shorn of any capacity to knowingly consent to their participation in a medical study.Whatever reckoning was to be had could only ever be too little, too late for those directly damaged by this study. Of the original 399, only 74 were even alive in 1972, 28 having died directly of syphilis, 100 of related complications, 40 wives had been infected and 19 children born with syphilis. Survivor numbers had dwindled to a mere 6 by the time President Clinton offered an official apology for the TSS on May 16, 1997 (1).This answer briefly coversThe legal and regulatory consequences following public knowledge of the TSS.The biomedical research community knowledge of the TSS.The researcher cast of the TSS.The TSS aftermath in the form of continuing adverse health consequences for black men in the US.Legal & Regulatory Consequences following Public Knowledge of the Tuskegee Syphilis StudyMedia coverage of a whistleblower, a by now familiar drill, the TSS was first reported by Jean Heller - Wikipedia of the Associated Press in the Washington Star on July 25, 1972, after she indirectly heard the account of Peter Buxtun - Wikipedia, a former PHS (Public Health Service) VD (venereal disease) interviewer, who came forward as a whistle blower. One day later the New York Times carried the same story on its first page (2), and the rest as they say is history.In a way, even more so than the Nuremberg trials - Wikipedia, the aftermath of the TSS, ‘America's own Nuremberg’ (3), largely shaped the Informed consent - Wikipedia regimen under which human biomedical research operates today.The US CongressPassed the National Research Act - Wikipedia in 1974.Established the Office for Human Research Protections - Wikipedia through which guidelines for research involving human subjects were strengthened.This ActMandated the by-now familiar IRBs (Institutional review board - Wikipedia) to approve all human subject studies using US federal funds.Created a commission, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research - Wikipedia to study and write regulations governing human subject studies.Five years later this commission published the Belmont Report - Wikipedia enshrining respect for persons, beneficence and justice as the founding beliefs for modern American bioethics (4).Ciivil rights attorney Fred Gray (attorney) - Wikipedia and the NAACP - Wikipedia filed a class-action lawsuit in 1973 on behalf of the Tuskegee syphilis study participants. The case (Pollard v.United States, 5) settled out of court with a $10 million settlement awarded to the study's participants. In addition, free health care was provided to participants still living as well as their infected wives, widows and children (see below from 6).Biomedical Research Community Knowledge of the Tuskegee Syphilis StudyThough the public at large may have remained unaware of this study during its four decades, it was obviously well-known within the biomedical research community, with not one but several peer-reviewed studies published in various medical journals including the highly prestigious JAMA (journal) - Wikipedia.Peer-review means peers within the biomedical community analyzed the study results and deemed them worthy of publication. Contours of accountability thus expand even further to fellow researchers and the journals' editorial staff who reviewed these manuscripts and noticed nothing untoward about a study that left patients with syphilis untreated for years, especially in the years after penicillin was accepted as a treatment of choice all the way back in 1945.Vonderlehr, Raymond A., et al. "Untreated syphilis in the male Negro: a comparative study of treated and untreated cases." Journal of the American Medical Association 107.11 (1936): 856-860.Rivers, Eunice, et al. "Twenty years of followup experience in a long-range medical study." Public Health Reports 68.4 (1953): 391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2024012/pdf/pubhealthreporig00184-0037.pdfPeters, Jesse J., et al. "Untreated syphilis in the male Negro: pathologic findings in syphilitic and nonsyphilitic patients." Journal of Clinical Epidemiology 1.2 (1955): 127-148.Olansky, Sidney, et al. "Untreated syphilis in the male Negro: X. Twenty years of clinical observation of untreated syphilitic and presumably nonsyphilitic groups." Journal of chronic diseases 4.2 (1956): 177-185.Rockwell, Donald H., ANNE ROOF YOBS, and M. Brittain Moore. "The Tuskegee study of untreated syphilis: the 30th year of observation." Archives of Internal Medicine 114.6 (1964): 792-798.Researcher Cast of the Tuskegee Syphilis StudyRunning four decades from 1932 until 1972 obviously meant a rotating cast of players. No one lost their job, their grant funding and/or professional accreditation.Fred Gray asserts the two black Tuskegee administrators, Robert Russa Moton - Wikipedia, head of the Tuskegee University - Wikipedia, who died in 1940, and Eugene Dibble - Wikipedia, who died in 1968, were misled to believe the study participants would receive treatment for participating in the study and that they were never aware of the study's atrociously unethical basis.The chief architects of the study, Hugh S. Cumming - Wikipedia, Taliaferro Clark, Raymond A. Vonderlehr, were dead by 1972, a careful analysis of their backgrounds showing ' similar cultural, intellectual, and institutional backgrounds' (7), especially one strongly steeped in the eugenics that dominated thinking within the USPHS in the early decades of the 20th century.Other study boosters were also dead, Joseph Earle Moore of the Johns Hopkins University Medical School dying in 1957 and Oliver Clarence Wenger of the USPHS dying in 1958.Some researchers who got involved later and were still alive in 1972 and beyond brazenly defended the study and their role in it.John R. Heller Jr. ran the TSS from 1933 to 1934. He died in 1989. When the story first broke, Heller evinced no indication he was even aware of his gross misconduct let alone his rank bias (see below from 8, emphasis mine).'Soon after the story broke, John R. Heller, the director of the TSS from 1933 to 1934, was questioned in an interview for the ethics of his study, but he declared that “there was nothing in the experiment that was unethical or unscientific.”48 He then claimed that the withholding of treatment was not required by the Study, and that all of the men in the study received some form of treatment. He also responded to the accusations that his study should have provided all test subjects with penicillin by saying that penicillin would not have been effective during the late stages of syphilis, and then later even admitted that the thought to provide penicillin never even 49 “‘occurred to us to ask because the demand was so great for other people who needed it much more than they did -- the armed forces and people in civilian life’ with other serious diseases.”'John Charles Cutler - Wikipedia died in 2003. He defended his involvement in the TSS when interviewed by PBS Nova in 1993 (see below from 9).'Cutler: The Tuskegee study has been grossly misunderstood and misrepresented this way. And the fact was that it was concern for the black community, trying to set the stage for the best public health approach possible and the best therapy, that led to the study being carried out….We were dealing with a very important study that was going to have the long-term results of which were actually to improve the quality of care for the black community so that these individuals were actually contributing to the work towards the improvement of the health of the black community rather than simply serving as merely guinea pigs for the study. And of course I was bitterly opposed to killing off the study for obvious reasons.'Still alive in 1992, Sidney Olansky offered a startling and entirely unrepentant accounting to ABC's PrimeTime Live of his participation in conducting this heinous medical malfeasance (see below from 10, emphasis mine)'A February 1992 story aired by ABC's PrimeTime Live offers telling -- and chilling -- insight into the thinking behind the continuation of the Tuskegee Study. Correspondent Jay Schadler interviewed Dr. Sidney Olansky, who directed the experiment from 1950 to 1957, when penicillin was the standard of care for syphilis . . . but not for the men in the Tuskegee Study. Asked if the experiment could have been conducted on a group of white men, Olansky replied, "I think it could have been if we'd had white men in the same general category. Say if we had a bunch of hillbillies up in West Virginia that had a lot of syphilis." Pressed by Schadler about the lies that the men were told, Olansky said, "The fact that they were illiterate was helpful too, because they couldn't read the newspapers. If they were not, as things moved on they might have been reading newspapers and seen what was going on." When Schadler presented statements from survivors who thought that the diagnostic spinal taps they received were treatments, the doctor replied, smiling, "I don't know what they were told. I mean, sometimes people will say things that they don't really mean or don't really believe in order to accomplish something they want." In response to a question about why, if the government doctors had done nothing wrong, they were no longer trusted by the men, Olansky replied, "Someone got them all heated up. They were easily swayed. They were like a pack of sheep." Finally, Olansky's summary of what was learned: "Syphilis isn't too bad a disease." 'Eunice Rivers Laurie - Wikipedia died in 1986 having never accounted for her unwavering support for this travesty of a study (11, 12). A black nurse who gained the trust of the study participants over the years, historical analysis suggests her role was crucial in keeping it alive at every turn that could have ended it (see below from 13).'Key to the cooperation of the men in the Tuskegee Study was the African-American PHS nurse assigned to monitor them. She quickly gained their trust. She dealt with their problems. The physicians came to respect her ability to deal with the men. She not only attempted to keep the men in the study, many times she prevented them from receiving medical care from the PHS treatment clinics offering neoarsphenamine and bismuth (the treatment for syphilis) during the late 1930s and early 1940s. She never advocated treating the men. She knew these treatment drugs had side affects. As a nurse, she had been trained to follow doctor’s orders. By the time penicillin became available for the treatment of syphilis, not treating these men had become a routine procedure, which she did not question. She truly felt that these men were better off because of the routine medical examinations, distribution of aspirin pink pills that relieved aches and pains, and personal nursing care. She never thought of the men as victims...'Tuskegee Syphilis Study Aftermath: Adverse Health Consequences for Black MenNot surprisingly, the Tuskegee Syphilis study further poisoned the hearts and minds of generations of blacks against the US biomedical research community, an effect that continues till date. Even today, researchers attribute to TSS the racial disparities in avoiding or delaying seeking medical care, much lower participation rates in clinical trials and overall worse health outcomes in black men in America (14).Congressional testimony of survivors made clear the sense of violation of trust ran deep (see below from 8, 15),'The participants in this study are firmly convinced that the United States Government in the manner in which this study was conducted violated their Constitutional rights.They feel that the Government knew they had syphilis and failed to treat them.Second, they feel that Public Health Service failed to fully disclose to them that they had syphilis, that they were participating in a study, and that treatment was available for syphilis.They further feel that Public Health Service led many participants to believe that they were being properly treated for whatever diseases they had when in fact they were not being treated at all...Last, but we think very importantly, the study was racially motivated and it discriminated against blacks in that no whites were selected to participate in the study and only those recruited were poor, uneducated, rural blacks...They have no faith, trust, nor confidence that the Public Health Service will properly examine them and give them proper treatment. 57'Bibliography1. Presidential Apology2. Syphilis Victims in U.S. Study Went Untreated for 40 Years3. Robert Levine4. Childress, James F. Belmont revisited: Ethical principles for research with human subjects. Georgetown University Press, 2005.5. https://scholar.google.com/scholar_case?case=5681775705869466920&q=Pollard+v.+United+States&hl=en&as_sdt=400066. Tuskegee Study - Timeline - CDC - NCHHSTP7. Lombardo, Paul A., and Gregory M. Dorr. "Eugenics, medical education, and the Public Health Service: Another perspective on the Tuskegee syphilis experiment." Bulletin of the History of Medicine 80.2 (2006): 291-316. http://www.antimicrobe.org/h04c.files/history/BullHxMed-Lombardo-PublicHealthServ-06.pdf8. Wong, Kristin X. "The Pivotal Role that Race Plays in Medical Research: The Tuskegee Syphilis Study." (2018). https://pdxscholar.library.pdx.edu/cgi/viewcontent.cgi?article=1158&context=younghistorians9. https://historynewsnetwork.org/article/13206110. http://www.thebody.com/content/art30946.html11. Reverby, Susan M. "Rethinking the Tuskegee Syphilis Study." Nursing History Review 7 (1999): 3-28. http://ftp.columbia.edu/itc/hs/pubhealth/p9740/readings/reverby.pdf12. Reverby, Susan M. "More than fact and fiction: Cultural memory and the Tuskegee syphilis study." Hastings Center Report 31.5 (2001): 22-28. http://thehastingscenter.org/uploadedFiles/Bioethics_Forum/Reverby.pdf13. Fourtner, Ann W., Charles R. Fourtner, and C. Freeman Herreid. "Bad blood-A case study of the Tuskegee syphilis project." Journal of College Science Teaching 23 (1994): 277-277. http://andreawise.cmswiki.wikispaces.net/file/view/Bad+Blood+Case+Study.pdf/547944124/Bad+Blood+Case+Study.pdf14. Alsan, Marcella, and Marianne Wanamaker. "Tuskegee and the Health of Black Men." The Quarterly Journal of Economics 133.1 (2017): 407-455. https://economics.stanford.edu/sites/default/files/tuskegee_22may2016-1.pdf15. https://ia800701.us.archive.org/31/items/qualityofhealthc00unit/qualityofhealthc00unit_bw.pdf