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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

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How to minimize cross-border clinical trial mishaps? Conflicts of interest abound. Isn't an international forum the obvious answer? No, for the simple reason that international guidelines have existed for more than 50 years yet they haven't prevented clinical trial mishaps.In 1963 the World Medical Association (WMA) created and endorsed the Declaration of Helsinki (DoH). Purpose of the DoH is to guide the proper ethical conduct of human clinical trials, and to prevent clinical trial mishaps.Has the DoH prevented clinical trial mishaps? Obviously not if one goes by the high profile Phase 4* HPV (Human Papilloma Virus) Vaccine trial in India, a multinational endeavor stopped in 2010 by the Government of India, leading to an Indian Parliamentary inquiry as well as an ongoing PIL (Public Interest Litigation) at the Indian Supreme Court. Let's examine these issues in sequence and see where that leads us.First, let's examine the DoH, the WMA's explicitly drafted recommendations for the proper conduct of human clinical trials.Next, let's examine examine the history of informed consent, particularly how it came into existence. This history teaches us that informed consent can either promote or prevent clinical trial mishaps. Promote mishaps when trial administrators and funders pay lip service to it (tokenism) and aren't held accountable. Prevent them when used sincerely to promote and preserve patient autonomy.Since existing structures appear inadequate to the task, is there another way to prevent or minimize clinical trial mishaps? Yes, public pressure for stricter implementation of existing country-specific laws. Where existing country-specific laws prove inadequate, the citizenry need to push their government to enact clearer and more comprehensive laws. Two compelling reasons for this. For one, citizens of one country are unlikely to be as motivated in seeing justice done for clinical trial mishaps that happen in another country. For another, isn't it morale-boosting and integral to a citizen's identity to hold their government accountable rather than have some foreign entity step in and do so on their behalf? In fact, isn't the alternative shameful? Here, the history of the use of informed consent is a poignant guide, teaching us that the central problem is not absence of adequate laws but rather lack of accountability in the existing system.* A Phase 4 trial is a post-approval surveillance trial where effects are monitored on thousands of people to uncover unforeseen side-effects.The Declaration of Helsinki (DoH)The DoH was the WMA's declaration of ethical principles for medical research involving human subjects.From 1963 till 2013 it has undergone 7 revisions.The history of the DoH is pockmarked with controversy.For example, the 5th revision in 2000 was approved without consensus from national medical associations in the aftermath of the controversial sub-Saharan nevirapine studies on vertical HIV transmission. These studies revealed a blatant double standard in human clinical trial practice. A 1994 US study (1) showed that Zidovudine (AZT) given intravenously prenatally, during delivery and postpartum reduced perinatal (vertical) HIV transmission by ~2/3rds. It then became the standard of care in developed countries. However, when it came time to test whether the 2nd generation drug nevirapine could also minimize or prevent vertical transmission in the high-risk but much poorer sub-Saharan populations, the 1st world trial sponsors chose to give a single nevirapine dose to pregnant women during labor and once to their infants within 72 hours of birth (2). This when it was already 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 (3). Rationale of the trial sponsors? The needed infrastructure, comprehensive perinatal care and drug cost couldn't be adequately provisioned at the trial site. In other words, in a tussle between money and ethics, money won.The 7th revision of the DoH, adopted in October 2013 at the 64th WMA General Assembly in Fortaleza, Brazil, also has its share of controversy. In particular, it says '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' (4). In response, the Latin American and Caribbean Medical Confederations refused to approve this wording of placebo use stating, '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' (5, 6).Another ambiguity of the 7th DoH revision is 'risk of serious or irreversible harm'. Which is it, not treating a simple skin cut or not treating an HIV positive pregnant woman? After all, don't we live with a vast, unbridgeable chasm in health care access between the haves and have-nots so much so that even a simple skin cut could be construed as 'risk of serious or irreversible harm' in the 1st world even as an HIV positive pregnant woman is left untreated in the 3rd world?What is informed consent and why is it essential in human clinical trials?Informed consent stems from the need for patient autonomy.In a clinical trial, patient autonomy is the basic human right of a trial participant to not be subjected to medical research abuse.The egregious Nazi regime medical experiments on concentration camp inmates drove the need to prevent future outright medical research abuse so in 1947 the Nuremberg Code (Nuremberg Code) was created, i.e. research ethics guidelines for human experimentation.Article 1 of the Nuremberg Code explicitly identifies the need for consent, 'The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity' (See page 182 of 7).Did the 1947 Nuremberg Code prevent ongoing and future medical abuse?Obviously not since the Tuskegee syphilis experiment ran uninterrupted in the USA from 1932 until 1972. In this study, African-Americans diagnosed with syphilis were left untreated because the physicians wanted to follow the natural disease progression. This is a painfully compelling example that an international code alone is insufficient in and of itself in preventing future or ongoing outright medical practice abuse, let alone clinical trial mishap.Something more than an international agreement is needed to prevent medical research abuse of human trial participants. History teaches that this something more is lawsuits. In particular, today's informed consent is the legacy of two key US medical malpractice lawsuits.How did informed consent come into existence in human clinical trials? The two landmark US lawsuits that helped create it.The 1st lawsuitThe judge in the first case, Salgo v. Leland Stanford, Jr. University Board of Trustees (1957), coined the phrase 'informed consent' in his jury instruction.The plaintiff Mr. Salgo's now defunct treatment entailed '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).'discretion to withhold alarming information' and 'full disclosure of facts necessary to an informed consent' are obviously contradictory in nature. Regardless, this was the first instance requiring that disclosure to patients needed to conform to 'professional practice standard', i.e. what is expected from a reasonable health-care practitioner (8).The 2nd lawsuitIn the second US case, Canterbury v. Spence ([1972] 464 F.2d 772 (D.C. Cir.), the patient fell out of his hospital bed after undergoing a spinal procedure and suffered major paralysis.Since the patient had not been warned about 'the possibility of this rare outcome', the 'professional practice standard' was deemed inadequate by failing to respect the patient's self-determination.Instead it gave way to the patient-centered 'reasonable person standard', i.e. what a reasonable patient considers necessary and sufficient to know rather than what health-care practitioners 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 a 'reasonable person standard', health-care providers have to disclose to patients or clinical trial participants the four elements necessary for informed patient consent: the nature (therapeutic/not), risks, alternatives and benefits of the procedure and/or treatment. When the patients or clinical trial participants are below the age of consent, the disclosure is given to and consent sought from the parents or legal caregivers.A recent human clinical trial mishap: Phase 4 HPV (Human Papilloma Virus) Vaccine study in IndiaTo generate data to support inclusion of HPV vaccine in India's UIP (Universal Immunization Programme).Actual vaccinations started in 2009 in the Indian states of Andhra Pradesh and Gujarat.Girls aged 10 to 14 years of age, i.e. dependents so consent presumably sought and obtained from parents/caregivers.Two-component trial: Phase 4* HPV vaccine clinical trial and observational research on vaccine delivery.Designed and executed by PATH (Program for Appropriate Technology in Health), a US-based NGO, in collaboration with the ICMR (Indian Council of Medical Research) and the State Governments of Andhra Pradesh and Gujarat.The vaccines: Merck's Gardasil and GlaxoSmithKilne's Cervarix.Funded by the Bill and Melinda Gates Foundation.Trial suspended by the Government of India in April 2010.After the reported post-vaccination deaths of 7 girls in the two states, the Indian Parliament's Standing Committee on Health investigated this study, and released its report in August, 2013 (10).Salient problems identified by the Committee (page 11 of the Committee report, see reference 10):'6.14 The Inquiry Committee, while going through the above report, noticed the following irregularities and discrepancies in the study:The warden/teachers/headmasters were not given written permission by the parents/guardians to sign on behalf of their girls.On many forms witness had not signed and of the forms which are signed, it is not clear whether they are signed by full time government employees, as per rules.Neither the photograph nor the photo ID card of parents/guardians/wardens is pasted in consent form.On many forms investigator has not signed.On some forms signature of parents/guardians is not matching with their names.The date of vaccination is much earlier than the date of signature of parents/guardian in the consent forms. Apparently they were obtained post-facto.In some forms, the name is of the father but signature is of probably mother (lady’s name).'Salient conclusions of the report (pages 14-15 of the Committee report, see reference 10):'(i) Irregularities in obtaining consent forms and actual implementation of the consent process;(ii) Lack of monitoring and preparedness to deal with serious adverse events;(iii) Inclusion of vulnerable and tribal population groups;(iv) Blurring of distinction between Universal Immunization Programme and PATH study;(v) Absence of insurance coverage for the study participants; and(vi) Inclusion of the statement in the consent form that “you will not be charged for your daughter to receive the vaccine” that could be construed as covert inducement.'News reports (11, 12, 13, 14, 15, 16, 17, 18) and sponsor comments (19, 20) about this trial.So whether or not the girls' deaths were attributable to the HPV vaccine, the resulting investigation revealed a thoroughly messed up informed consent process and seriously inadequate process for reporting adverse events. But wait a minute? Isn't all this thoroughly covered by the overarching DoH? Let's examine the relevant DoH provisions to make sure.In any case, so far the government actions have resulted in predictable shake-ups, committees, new procedures, even though existing procedures appear to be adequate on paper.What about accountability? Who is responsible? When human clinical trials are outsourced and off-shored, who bears responsibility for adverse events, especially for seemingly unanticipated adverse events, as happened in this Phase 4 Indian HPV vaccine trial? Let's examine a relevant landmark and precedent-setting judgment (18).In 2012, a judge in Argentina upheld fines against GlaxoSmithKline, the sponsor of an Argentinian clinical trial testing the safety of the vaccine Synflorix against pneumococcal disease in children.Issues of informed consent?In some instances, consent was given by parents who were minors themselves.Grandparents who were not authorized to give consent for their grandchildren.A child vaccinated even after mother explicitly refused her consent.Signatures on consent forms not matching those of the individuals giving consent.GlaxoSmithKline appealed the fine using the defense that alleged errors and poor documentation in the informed consent process were a mere formality that didn't pose actual risks to trial participants.The judge rejected this defense and upheld the fine, against both the investigators and the sponsor.His rationale? Even minor deficiencies in trial procedure could later become relevant since adverse health effects might appear only in the future.This precedent-setting judgment bestows supervisory duty on the trial sponsor regarding informed consent. It also paves the way for hope. For example, the Indian Supreme Court is well-known to be highly responsive to PILs, using them as tools to demand improvements in state laws and regulations (Public interest litigation in India). Currently, it's considering one such PIL with respect to the Phase 4 HPV trial (18). In India, PILs arise when the State is perceived to have violated constitutional and/or statutory provisions, and they have served as indispensable bulwark protecting essential rights of Indian citizens.Further, since this case involved US and UK trial sponsors and manufacturing companies, this PIL includes an amicus brief (21) submitted by the European Center for Constitutional and Human Rights 'outlining the legal framework on clinical trials in the respective home countries' (18), in order to cover obvious gaps in judicial precedents.Finally, and more importantly, in our globalized age of cross-border, outsourced and off-shored clinical trials, an obvious and perhaps steep learning curve lies ahead for all entities involved in them, namely, government regulatory bodies, sponsors, investigators and other health-care staff. Especially these latter need to be rigorously trained in the ethical and legal aspects of human clinical trials. It then becomes a natural and necessary mandate for each and every national medical association and department of health to help ensure that such training becomes part and parcel of each country's health care practice (22), i.e. that it no longer remains the select purview of developed countries' health care infrastructure. Now, wouldn't that be leveling of a playing field that actually matters, one of autonomous life and death?BibliographyConnor, 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. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human SubjectsConfederacion 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.http://www.loc.gov/rr/frd/Military_Law/pdf/NT_war-criminals_Vol-II.pdfA Companion to Bioethics, Second Edition. Helga Kuhse, Peter Singer, editors. A Companion to Bioethics; A Companion to Bioethics, Second EditionFaden, Ruth R., Tom L. Beauchamp, and Nancy M. King. "A history and theory of informed consent." (1986).Page on 100.47.5Mudur, Ganapati. "Human papillomavirus vaccine project stirs controversy in India." BMJ 340 (2010).Mudur, Ganapati. "Row erupts over study of HPV vaccine in 23 000 girls in India." BMJ 345 (2012).Sharma, Dinesh C. "Rights violation found in HPV vaccine studies in India." The Lancet Oncology 14.11 (2013): e443. Page on thelancet.comSuba, Eric J., and Stephen S. Raab. "Cervical cancer mortality in India." The Lancet 383.9931 (2014): 1804. Page on thelancet.comCalls in India for legal action against US charityClinical trials in India: ethical concernsIndia Outlines Plans for Upgrading Clinical Trial ProceduresTerwindt, Carolijn. "Health Rights Litigation Pushes for Accountability in Clinical Trials in India." Health and human rights 16 (2014): 2. Health Rights Litigation Pushes for Accountability in Clinical Trials in IndiaLaMontagne, D. Scott, and Jacqueline D. Sherris. "Addressing questions about the HPV vaccine project in India." The Lancet Oncology 14.12 (2013): e492. Page on thelancet.comStatement from PATH: cervical cancer demonstration project in IndiaAmicus curiae brief concerning non-state actor responsibility in clinical trials, November 22, 2013, submitted to the Supreme Court of India by the European Center for Constitutional and Human Rights and the Essex Business and Human Rights Project in Writ Petition (Civil) No. 558 of 2012, on file with ECCHR.Poongothai, Subramani, et al. "Why are clinical trials necessary in India?." Perspectives in clinical research 5.2 (2014): 55. Why are clinical trials necessary in India?Thanks for the A2A, Kritika Gupta.