Jun 10, 2021

“what is being done by suppressing open disclosure and debate
concerning the profile of adverse events
associated with these vaccines
violates fundamental bioethical principles for clinical research.
This goes back to the Geneva convention and the Helsinki declaration”.

I provide this brief essay for the TrialSite community because you are involved or at least interested in human subject clinical research. By way of background, please understand that I am a vaccine specialist and advocate, as well as the original inventor of the mRNA vaccine (and DNA vaccine) core platform technology. But I also have extensive training in bioethics from the University of Maryland, Walter Reed Army Institute of Research, and Harvard Medical School, and advanced clinical development and regulatory affairs are core competencies for me.

Written by: Robert W Malone, MD, MS¹

Before examining the bioethical foundations of current policy and practice which underpin experimental COVID vaccine deployment in many western nations, allow me to begin by sharing some “real world” first-hand evidence.

I was on a call with a Canadian primary care physician last week for a couple of hours. He related the story of the six (in his mind) highly unusual clinical cases of post-vaccination adverse events that he has personally observed in his practice involving vaccination of his patients with the Pfizer mRNA vaccine product. Keep in mind that it was Canadian physicians – acting of their own accord – who filed the FOIA to gain access to the Pfizer vaccine IND (see https://trialsitenews.com/did-pfizer-fail-to-perform-industry-standard-animal-testing-prior-to-initiation-of-mrna-clinical-trials/).

What was most alarming to me was that my clinical primary practice physician colleague told me that each of these cases were reported as per the proper channels in Canada, and each was summarily determined to not be vaccine related by the authorities without significant investigation. Furthermore, he reported to me that any practicing physician in Canada who goes public with concerns about vaccine safety is subjected to a storm of derision from academic physicians and potential termination of employment (state-controlled socialized medicine) and loss of license to practice.

This is one face of censorship in the time of COVID (see https://www.embopress.org/doi/full/10.15252/embr.202051420). But what are official public health leaders afraid of? Why is it necessary to suppress discussion and full disclosure of information concerning mRNA reactogenicity and safety risks? Let’s analyze the vaccine-related adverse event data rigorously. Is there information or patterns that can be found, such as the recent finding of the cardiomyopathy signals, or the latent virus reactivation signals? We should be enlisting the best biostatistics and machine learning experts to examine these data, and the results should- no must- be made available to the public promptly. Please follow along and take a moment to examine the underlying bioethics of this situation with me.

I believe that adult citizens must be allowed free will, the freedom to choose. This is particularly true in the case of clinical research. These mRNA and recombinant adenovirus vaccine products remain experimental at this time. Furthermore, we are supposed to be doing rigorous, fact-based science and medicine. If rigorous and transparent evaluation of vaccine reactogenicity and treatment-emergent post-vaccination adverse events is not done, we (the public health, clinical research and vaccine developer communities) play right into the hands of anti-vaxxer memes and validate many of their arguments. The suppression of information, discussion, and outright censorship concerning these current COVID vaccines which are based on gene therapy technologies cast a bad light on the entire vaccine enterprise. It is my opinion that the adult public can handle information and open discussion. Furthermore, we must fully disclose any and all risks associated with these experimental research products.

In this context, the adult public are basically research subjects that are not being required to sign informed consent due to EUA waiver. But that does not mean that they do not deserve the full disclosure of risks that one would normally require in an informed consent document for a clinical trial. And now some national authorities are calling on the deployment of EUA vaccines to adolescents and the young, which by definition are not able to directly provide informed consent to participate in clinical research – written or otherwise.

The key point here is that what is being done by suppressing open disclosure and debate concerning the profile of adverse events associated with these vaccines violates fundamental bioethical principles for clinical research. This goes back to the Geneva convention and the Helsinki declaration. See https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. There must be informed consent for experimentation on human subjects. The human subjects – you, me, and the citizens of these countries – must be informed of risks. As a community, we have already had a discussion and made our decision – we cannot compel prisoners, military recruits, or any other population of humans to participate in a clinical research study. For example, see the Belmont report, which provided the rationale for US federal law Code of Federal Regulations 45 CFR 46 (subpart A), referred to as “The Federal Policy for the Protection of Human Subjects” (also known as the “Common Rule”).

Quoting from the Belmont Report:

“Informed Consent. — Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied.

While the importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an informed consent. Nonetheless, there is widespread agreement that the consent process can be analyzed as containing three elements: information, comprehension and voluntariness.”

https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

Information, comprehension, and voluntariness. To my eyes, it appears that in many regions public health leadership has stepped over the line and is now violating the bedrock principles which form the foundation upon which the ethics of clinical research are built. I believe that this must stop. We must have transparent public disclosure of risks – in a broad sense – associated with these experimental vaccines. It is either that, or the entire modern bioethical structure which supports human subjects research will have to be re-thought.

I really think we need to

“stop, children, what’s that sound – everybody look what’s going down”
(For What it’s Worth, Buffalo Springfield)

Furthermore, as these vaccines are not yet market authorized (licensed), coercion of human subjects to participate in medical experimentation is specifically forbidden. Therefore, public health policies which meet generally accepted criteria for coercion to participate in clinical research are forbidden.

For example, if I were to propose a clinical trial involving children and entice participation by giving out ice cream to those willing to participate, any institutional human subjects safety board (IRB) in the United States would reject that protocol. If I were to propose a clinical research protocol wherein the population of a geographic region would lose personal liberties unless 70% of the population participated in my study, once again, that protocol would be rejected by any US IRB based on coercion of subject participation. No coercion to participate in the study is allowed. In human subject clinical research, in most countries of the world this is considered a bright line that cannot be crossed. So, now we are told to waive that requirement without even so much as open public discussion being allowed?

In conclusion, I hope that you will join me; stop to take a moment and consider for yourself what is going on. The logic seems clear to me. 1) An unlicensed medical product deployed under emergency use authorization (EUA) remains an experimental product under clinical research development. 2) EUA authorized by national authorities basically grants a short-term right to administer the research product to human subjects without written informed consent. 3) The Geneva Convention, the Helsinki declaration, and the entire structure which supports ethical human subjects research requires that research subjects be fully informed of risks and must consent to participation without coercion. Has that bright line been crossed? If so, what actions are to be taken? I look forward to learning from your thoughts and conclusions.

This was shared from
https://trialsitenews.com/bioethics-of-experimental-covid-vaccine-deployment-under-eua-its-time-we-stop-and-look-at-whats-going-down/

Here is the content of the links quoted within the above article

Did Pfizer Fail to Perform industry Standard Animal Testing Prior to Initiation of mRNA Clinical Trials?
Shared from https://trialsitenews.com/did-pfizer-fail-to-perform-industry-standard-animal-testing-prior-to-initiation-of-mrna-clinical-trials/

TrialSite has learned of material information regarding mRNA vaccine safety revealed by a freedom of information act (FOIA) request filed by a group of Canadian physicians. These doctors have become concerned about COVID-19 mRNA vaccine safety. This new safety information involves the Pfizer mRNA-based vaccine known as BNT162b2 or “Comirnaty.” The FOIA documents reveal animal study results demonstrating that the Pfizer mRNA-based vaccine does not remain at the injection site, but rather appears to spread widely after injection. According to the documents, pre-clinical studies show that the active part of the vaccine (mRNA-lipid nanoparticles), which produce the spike protein, spreads throughout the body and is then concentrated in various organs, including the ovaries and spleen. The FOIA-produced data sets are incomplete, so the full meaning of these data cannot be determined at this time. TrialSite has also learned via regulatory documents that apparently (at least in their European Medicines Agency submission), Pfizer did not follow industry-standard quality management practices during preclinical toxicology studies during vaccines, as key studies did not meet good laboratory practice (GLP). The full panel of industry-standard reproductive toxicity and genotoxicity studies were apparently also not performed. But does this matter in light of the risk-benefit analysis associated with regulatory emergency use authorization (EUA)?

Recently, there has been speculation regarding potential safety signals associated with COVID-19 mRNA vaccines. Many different unusual, prolonged, or delayed reactions have been reported, and often these are more pronounced after the second shot. Women have reported changes in menstruation after taking mRNA vaccines. Problems with blood clotting (coagulation) – which are also common during COVID-19 disease – are also reported.

Among the most critical tests, which must be performed prior to testing any drug or vaccines in a human being, is whether it can cause mutations in the DNA (genotoxicity), or whether it could cause problems with cells or tissues of the reproductive tract – including ovaries (reproductive toxicity). In the case of the Pfizer COVID mRNA vaccine, these newly revealed documents raise additional questions about both the genotoxicity and reproductive toxicity risks of this product. Standard studies designed to assess these risks were not performed in compliance with accepted empirical research standards. Furthermore, in key studies designed to test whether the vaccine remains near the injection site or travels throughout the body, Pfizer did not even use the commercial vaccine (BNT162b2) but instead relied on a “surrogate” mRNA producing the luciferase protein.

These new disclosures seem to indicate that the U.S. and other governments are conducting a massive vaccination program with an incompletely characterized experimental vaccine. It is certainly understandable why the vaccine was rushed into use as an experimental product under emergency use authority, but these new findings suggest that routine quality testing issues were overlooked in the rush to authorize use. People are now receiving injections with an mRNA gene therapy-based vaccine, which produces the SARS-CoV-2 spike protein in their cells, and the vaccine may be also delivering the mRNA and producing spike protein in unintended organs and tissues (which may include ovaries). Unfortunately, there is no way to know if this is related to vaccine safety signals or reports of menstrual irregularities; the required studies were either not done or not done properly.

How mRNA Vaccines are Believed to Work

The current mRNA vaccines are theorized to act locally in draining lymphoid tissue. Formulated lipid nanoparticles that contain mRNA able to produce the spike protein are syringe injected into a muscle such as the deltoid (shoulder muscle). Once the injection occurs, the muscle cells near the injection site are impacted by the mRNA-based vaccine (e.g. the lipid nanoparticles), while much of the dose moves into the intracellular fluid surrounding the muscle cells and consequently drains to lymph nodes (see for example here).

According to this theory, a properly functioning mRNA-based vaccine is delivered into and drives production of the SARS-CoV-2 Spike protein in muscle and lymph node cells. The cells then produce the Spike protein, which is then moved to the surface of these cells where it becomes attached. The foreign virus Spike protein then triggers the immune system to recognize and attack any cell in the body that is either infected by SARS-CoV-2 or has Spike protein on its surface. The vaccine was designed so that the Spike protein is affixed via a transmembrane anchor region, so that it cannot circulate around the body via the bloodstream (see here). The same general scenario applies to all mRNA-based vaccines as well as recombinant adenoviral vectored vaccines (such as the J&J vaccine) designed to use gene-therapy technology to express Spike protein in cells and tissues. This general strategy is designed to reduce the risk that any residual vaccine dose that does somehow end up in the bloodstream (or organs and tissues) ends up not being a safety risk due to unintended biologic effects. Spike protein will remain affixed to cell surfaces, and therefore is not released into the blood where circulating Spike might cause problems by binding to its natural target, ACE-2 receptors. However, any cell that has Spike protein (or protein fragments) anchored on its membrane or displayed on MHC antigen-presenting molecules becomes a target for vaccine-activated immune cells and antibodies, which would then attack, damage or kill those cells in the same way that SARS-CoV-2 virus-infected cells would be attacked. In other words, if very active mRNA delivery particles or recombinant adenoviral-vectored vaccines spread throughout the body, the resulting production of the vaccine antigen (Spike, in this case) will both stimulate immunity and also cause those same cells to be attacked by the immune system. If this actually happens, the resulting “vaccine reactogenicity” could resemble clinical symptoms seen with autoimmune syndromes.

EMA Pfizer/BioNTech Vaccine Distribution Studies

As standard practice, the European Medicines Agency (EMA) discloses their assessment of investigational new drug (IND) submissions. In the case of the Pfizer-BioNTech “Comirnaty” vaccine, the EMA assessment can be found on the Web here. This document includes a summary of EMAs evaluation of the non-clinical vaccine distribution studies reported to EMA by Pfizer-BioNTech. These studies were carried out using two methods: 1) use of mRNA producing the luciferase protein and 2) use of radioactive label to mark the mRNA (a more sensitive approach). These studies reveal that the majority of radioactivity initially remains near the injection site. However, within hours, a subset of the stabilized mRNA-containing particles become widely distributed throughout the bodies of test animals.

Upon inspection of the EMA summary document, TrialSite found evidence suggesting that the issue of biodistribution and pharmacokinetics of the “Comirnaty” BNT162b2 vaccine was not thoroughly examined in accordance with industry norms prior to the EMA review of the BNT162b2 IND/CTD. The reviewers share an explicit admission that “No traditional pharmacokinetic or biodistribution studies have been performed with the vaccine candidate BNT162b2.” Rapporteur (Filip Josephson) and Co-Rapporteur (Jean-Michael Race) suggest, however, that Pfizer used “a qualified LC-MS/MS method to support quantitation of the two novel LNP excipients” and suggest that “the bioanalysis methods appear to be adequately characterized and validated for use in the GLP studies.” However, the studies that were performed and submitted were non-GLP. Additionally, the EMA document states “Biodistribution: Several literature reports indicate that LNP-formulated RNAs can distribute rather nonspecifically to several organs such as spleen, heart, kidney, lung and brain. In line with this, results from the newly transmitted study 185350, indicate a broader biodistribution pattern.” This EMA observation corresponds with what appears to be a growing number of adverse events and aligns with data TrialSite observed via the FOIA showing concentrations of LNP-formulated RNAs in the spleen, for example.

To obtain independent reviews of these EMA regulatory documents, TrialSite contacted both Dr. Robert W. Malone, MD, MS, and another expert that wished to remain anonymous, and provided them copies of the EMA analysis and the FOIA documents. Dr. Malone was the original inventor of the mRNA vaccine technology back in the late 1980s. He currently advises several companies in regulatory affairs and clinical development. One of TrialSite’s other sources is a senior regulatory specialist who currently serves as the President of a prestigious European association. When asked to review and comment on the EMA assessment, Dr. Malone noted that normal pharmacokinetic and pharmaco-toxicology studies had not been performed before EUA authorization for the product. “I was particularly surprised that the dossier of regulatory documents indicates allowance for use in humans based on non-GLP PK and Tox studies relying on formulations which are significantly different from the final vaccine.“ After completing a review, TrialSite’s other source noted the following:

“A quick review the Toxicology Section (2.3.3) of The European Medicines Agency (EMA) Assessment Report on Comirnaty (COVID-19 mRNA vaccine) issued on 19 February 2021, raisesconcerns about data applicability of preclinical study findings to clinical use:
To determine the biodistribution of the LNP-formulated modified mRNA (modRNA), the applicant did study distribution of the modRNA in two different non-GLP studies, in mice and rats, and determined the biodistribution of a surrogate luciferase modRNA.
Thus, one might question the validity and applicability of non-GLP studies conducted using a variant of the subject mRNA vaccine.
In addition, no genotoxicity data were provided to EMA.”

Based on the FOIA documents, the biodistribution results (which are not disclosed in the public EMA summary document) suggest that the delivery technology results in mRNA delivery and significant concentration of the delivery lipids in ovaries, spleen, and other tissues and organs.

Urgent Emergency?

The discovery and review of the biodistribution and pharmacokinetics data obtained by the FOIA request underscores the reservations disclosed in the public EMA assessment. Although not performed to industry GLP standards, these results seem to indicate that lipid/mRNA nanoparticles, which code for the Spike protein, circulate throughout the body and then collect in a variety of organs and tissues, including the spleen and ovaries. This means that the vaccine is not remaining localized near the injection site and draining lymph nodes, but rather is also circulating in both blood and lymph and is subsequently concentrating in important organs. If this results in Spike protein being produced in unintended places including the brain, ovaries, and spleen, it may also be causing the immune system to attack these organs and tissues.

What’s the Risk?

According to official government accounts, minimal risk is associated with this vaccine when compared to the risks of COVID-19 infection. That’s why the U.S. FDA approved the Emergency Use Authorization (EUA) based on a risk-benefit analysis. TrialSite, a vaccine proponent, only raises the issue to ensure full disclosure of any material safety implications to our readership, including clinicians, clinical research safety committees, and public health professionals.

While, according to the CDC’s VAERS database, over 4,000 deaths have been entered in association with all the vaccines, the US government argues that none of these deaths are formally linked to the jabs. About 291 million people have been vaccinated to date, hence overall reported adverse event risk is low. While it is true that many people are completely unscathed, the discovery of these documents and associated information may alter the risk-benefit assessment underlying the EUA decision.

TrialSite is aware that one must be particularly cautious about publishing or communicating speculations that might raise skepticism about vaccine use. Should researchers handle findings differently when there is a chance they might frighten the public? Perhaps small, inconclusive, worrying studies should not be published because they could do more harm than good. Dr. Paul Offit, Director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, states: “Knowing that you’re going to scare people, I think you have to have far more data.”

One could argue that even an inconclusive paper can be important, as it can spur the larger, more definitive studies that are needed. It should be “put out there for the scientific community, to look at it, see it, know about it, refine study design and go and look again,” says Gregory Poland, a renowned Mayo Clinic vaccinologist and the Editor-in-Chief of Vaccine. It is crucial, though, for researchers to carefully explain such results in their papers and regulatory filings to prevent misinterpretation or misunderstandings.

Other Relevant New Data

A recent study led by researchers at Brigham and Women’s Hospital and the Harvard Medical School measured longitudinal plasma samples collected from 13 recipients of the Moderna vaccine. The manuscript has been accepted for publication by “Clinical Infectious Diseases” and the pre-print is available here. Out of these individuals, 11 revealed detectable levels of SARS-CoV-2 protein as early as day one right after first vaccine injection. The authors considered that to be normal clearance.

Clearance of detectable SARS-CoV-2 protein correlated with production of IgG and IgA. Measured mean S1 peak levels were 68 pg/mL ±21 pg/mL, and mean spike peak level was 62 pg/mL ± 13 pg/mL. Assuming an average adult blood volume of approximately 5 liters, this corresponds to peak levels of approximately 0.3 micrograms of circulating free antigen for a vaccine designed to only express membrane-anchored antigen. For comparison purposes, most influenza vaccines administer a total of about 15 micrograms of HA antigen per influenza strain. Total levels of antigen expressed by the experimental SARS-CoV-2 mRNA vaccines currently administered to patients are not known.

Root Cause Analysis Suggested

A root cause assessment is suggested to better understand if any of this information adjusts or modifies the EUA risk-benefit analysis. TrialSite suggests that regulators and pharma manufacturers at least review and assess the risk that foreign mRNA-based spike protein delivery and expression in tissues and organs distal to the actual injection site may be contributing to the unusual reactogenicity and adverse event profile associated with these products. The uptake in vaccination rates has slowed in the United States in part due to vaccine hesitancy. However, such a phenomenon can be overcome with acknowledgement, transparency, and continuous commitment to risk mitigation.

COVID-19 and misinformation
From https://www.embopress.org/doi/full/10.15252/embr.202051420

Is censorship of social media a remedy to the spread of medical misinformation?

Emilia Niemiec Author InformationEMBO Rep (2020)21:e51420https://doi.org/10.15252/embr.202051420

In February this year, when the new coronavirus began to spread outside China, the Director General of the World Health Organization (WHO), Tedros Adhanom Ghebreyesus, announced: “we’re not just fighting an epidemic; we’re fighting an infodemic” (https://www.who.int/dg/speeches/detail/munich-security-conference). The term, coined in 2003 in the context of the first SARS epidemic, refers to a rapid proliferation of information that is often false or uncertain (https://www.merriam-webster.com/words-at-play/words-were-watching-infodemic-meaning). Academic researchers, international organizations such as the United Nations and the European Union, individual governments and the media have acknowledged and discussed the prevalence of the alleged COVID-19 infodemic and the importance of fighting it. Information campaigns have been launched to provide wider audiences with reliable information about COVID-19. Main social media platforms have also actively fought against false information by filtering out or flagging content considered as misinformation. In this essay, I will discuss the censorship on social media platforms related to COVID-19 and the problems it raises along with an alternative approach to counteract the spread of medical and scientific misinformation.

Censorship on social media platforms

Censorship on major social media platforms, such as Facebook, Twitter and YouTube, is not a new phenomenon. These companies regularly remove content that they consider as objectionable based on continually updated categories outlined in their policies. Examples of “objectionable content” include “hate speech”, “glorification of violence” or “harmful and dangerous content”. These categories are not only often broader than the exceptions to the freedom of speech entrenched in legislations of democratic countries, but also implicitly vague and leave plenty of room to interpretation. Indeed, an analysis of content banned on social networks suggests that the moderation is often politically biased (Stjernfelt & Lauritzen, 2020). Some very recent examples of moderation with apparent political ramifications include Twitter’s labelling of US President Donald J. Trump’s tweets as violating Twitter’s policy about glorifying violence or abusive behaviour, or adding a warning suggesting that a post was factually inaccurate (https://twitter.com/realdonaldtrump/status/1275409656488382465; https://twitter.com/realDonaldTrump/status/1266231100780744704; https://twitter.com/realDonaldTrump/status/1265255835124539392).

… an analysis of content banned on social networks suggests that the moderation is often politically biased …

Social media platforms are private companies and as such, one could argue, they should be able to decide what content they tolerate or not. However, such a view overlooks salient aspects of the issue. First, censorship on Facebook, Twitter or YouTube appears to contradict the very idea of these communication networks, that is, of spaces where everyone can express their opinion. YouTube, for example, declares on its website that its “mission is to give everyone a voice” (https://www.youtube.com/about/). Twitter’s manager once described his company as “the free speech wing of the free speech party” (https://www.theguardian.com/media/2012/mar/22/twitter-tony-wang-free-speech). Mark Zuckerberg, the CEO of Facebook, has similarly been vocal about Facebook’s commitment to the freedom of speech (https://about.fb.com/news/2019/10/mark-zuckerberg-stands-for-voice-and-free-expression). Many users of social media might have believed in these ideals when joining the online communities. Or, at least, they did not expect biased censorship on the platforms. From this point of view, appeals to the freedom of speech made by the social networks seem unfair or deceptive.

Another important point to consider is the fact that a few big tech companies currently dominate social media services, which also serve as a source of news to many users. According to a 2020 survey by the Reuters Institute for the Study of Journalism, 36% of 24,000 respondents from 12 countries use Facebook for news weekly, while 21% of the surveyed use YouTube for the same purpose (https://reutersinstitute.politics.ox.ac.uk/sites/default/files/2020-06/DNR_2020_FINAL.pdf). If we add to this the fact that Google is the most popular search engine, it becomes clear that a few tech companies have huge power over what information Internet users can see and how their views are shaped.

Referring among others to the role of the “modern public square” ascribed to online platforms, President Trump recently issued an executive order which aims to limit the current legal protections of the big tech companies and prevent the censorship on their platforms (https://www.whitehouse.gov/presidential-actions/executive-order-preventing-online-censorship/). What will be the effect of the order and whether it is an adequate solution to the problem is yet to be seen. What is clear, however, is that the tech giants’ role in shaping public discourse has become apparent. The governments of various countries have either attempted to find a solution to this issue or to use the possibility of censorship by big tech companies for their own purposes (Stjernfelt & Lauritzen, 2020).

While it is difficult to overlook the politically motivated censorship on online platforms and its implications, the removal of misinformation related to medical topics such as COVID-19 may seem to belong to a different category—not political, but rather one of science, where information can be objectively judged based on scientific evidence. At a closer look, however, this does not seem to be the case.

… censorship on Facebook, Twitter or YouTube appears to contradict the very idea of these communication networks, that is, of spaces where everyone can express their opinion.

Censorship of information about COVID-19

In response to calls to combat misinformation about COVID-19, a group of companies, including among others Facebook, Twitter and YouTube, issued a joint statement in mid-March this year. They stated that they are “jointly combating fraud and misinformation about the virus, elevating authoritative content on [their] platforms” (https://about.fb.com/news/2020/10/coronavirus/#joint-statement). Their actions include the introduction of “educational pop-ups connecting people to information from the WHO” (Facebook), adding warning labels to content considered as false or misleading (Facebook, Twitter), removing content contradicting health authorities or the WHO (YouTube) and content that could directly contribute or lead to (physical) harm (Facebook and Twitter) (https://about.fb.com/news/2020/03/combating-covid-19-misinformation/, https://covid19.twitter.com, https://support.google.com/youtube/answer/9891785). One example is a video removed by YouTube, in which a researcher, John Ioannidis, discussed data related to COVID-19, questioned the need to continue the ongoing lockdown and raised concerns about the negative impact of the restrictions (https://medium.com/@michaelaalcorn/how-wrong-was-ioannidis-5940e49c9af6). Other cases of censorship on major social media platforms have been reported, for example removal of information about anti-quarantine protests on Facebook (https://www.reuters.com/article/us-health-coronavirus-usa-facebook/facebook-removes-anti-quarantine-protest-events-in-some-us-states-idUSKBN2222QK).

A major question regarding the policies of the communication platforms is who exactly defines and how which information is deemed to be false or harmful? And can we rely on these judgements? One of the authoritative sources that all three major social media platforms mention in their policies on COVID-19 is the WHO. It is an established and influential organization, yet it may make mistakes, including in the context of handling epidemics. For example, concerns have been raised about influences of pharmaceutical companies on the guidelines related to the flu pandemic in 2009 (Cohen & Carter, 2010).

A major question regarding the policies of the communication platforms is who exactly defines and how which information is deemed to be false or harmful?

YouTube and Twitter also refer to guidelines from local health authorities. Although these are usually developed by experts and may be legally binding, this does not imply that they are unerring. There has been disagreement among researchers in medical sciences about the necessity for lockdown measures (Melnick & Ioannidis, 2020). Furthermore, researchers and many healthcare professionals have indicated numerous and serious negative impacts of the policies introduced to combat the spread of COVID-19, and expressed doubts about the evidence supporting these measures (Ioannidis, 2020) (https://www.scribd.com/document/462319362/A-Doctor-a-Day-Letter-Signed).

This variety of opinions on how to handle the COVID-19 pandemic is related, among others, to the fact that it is a new disease and the knowledge about it is relatively limited and unsettled. Moreover, the implications of the pandemic and measures taken to counteract it exceed the remit of epidemiology or public health experts and fall into areas of economy, education, psychology and sociology. Meanwhile, experts who develop policies or express opinions about COVID-19 may not have a complete overview of the implications of pandemic-related policies.

Processes of reviewing research results, drawing conclusions, and preparing guidelines may be complex, prone to mistakes and not immune to political or commercial interests.

Additionally, there are the “usual” problems related to evaluation and translation of evidence into medical or public health practice. They include questions about the validity of a given study, limitations of methods, reproducibility of results and so on. Processes of reviewing research results, drawing conclusions and preparing guidelines may be complex, prone to mistakes and not immune to political or commercial interests. Retracted articles on COVID-19, including publications in The Lancet and the New England Journal of Medicine (https://retractionwatch.com/retracted-coronavirus-covid-19-papers/), suggest that research on COVID-19 is not an exception to problems related to the ethics of research.

Constructive critique, questioning of evidence and opinions of scientists and policy-makers are thus necessary to identify and correct potential errors and to prevent them from being propagated. By following their policies on COVID-19, social media platforms filter out content which contradicts specific views that are not necessarily correct or unanimously accepted, with respect to the underlying scientific evidence or represented values and political views. If critique of these views is eliminated or restricted, the possibility to correct errors, contribute to the understanding of the topic and inform public debate is limited. Additionally, since the censorship is not based solely on science—as scientific evidence is currently limited and medical experts still disagree on various topics—other factors influence decisions to remove content. Questions about the commitment to the freedom of speech of the social media providers and risk of manipulation of public opinion are therefore relevant also in case of information about COVID-19.

The remedy to medical misinformation

If censorship of scientific information does not seem to be an adequate solution to the problem of false medical news on social media, what then is a fitting remedy to the “infodemic”? In order to adequately address this question, it seems that a few related and more fundamental issues should be addressed. What exactly is the COVID-19 infodemic? Based on what criteria is it declared and what are the implications of such a declaration? How do the different actors define “misinformation”? What are the actual and potential harms of the spread of false medical information? These questions should be answered in order to determine what exactly the problem is that we are trying to solve.

General understanding of how social media function may help users make informed decisions about the use of Facebook, YouTube, Twitter and similar services …

Notwithstanding, we may reflect on general approaches to prevent the potential harms related to misinformation. Education and raising awareness among publics, including during formal school education, may be one crucial strategy in immunizing society against misinformation. In this context, two areas of knowledge appear particularly relevant for Internet users: related to social media, in particular, the mechanisms they use, their business models, as well as benefits and risks related to the use of their services; and general knowledge related to science reporting, scientific research and its limitations.

General understanding of how social media function may help users make informed decisions about the use of Facebook, YouTube, Twitter and similar services, in accordance with one’s goals and values. In particular, the fact that social media platforms are provided and operated by private companies, which are interested primarily in making profit, and the implications of this fact may be worth to consider. The business model of social media companies is based on revenue from ads tailored to the users: the more users and the more time they spend on their websites, the higher the profit. Consequently, these companies use knowledge from psychology and huge amounts of personal data to design ever more efficient mechanisms to motivate users to spend more time on their websites. Sean Parker, a former president of Facebook, put it this way: “…we need to sort of give you a little dopamine hit every once in a while, because someone liked or commented on a photo or a post or whatever. And that’s going to get you to contribute more content, and that’s going to get you… more likes and comments. It’s a social-validation feedback loop … exactly the kind of thing that a hacker like myself would come up with, because you’re exploiting a vulnerability in human psychology.” (https://www.axios.com/sean-parker-facebook-was-designed-to-exploit-human-vulnerability-1513306782-6d18fa32-5438-4e60-af71-13d126b58e41.html).

The human psychology used by social media sites—for example the need of social approval, reciprocity and novelty seeking—may also play a role in the spread of misinformation. For example, a study of news shared on Twitter suggests that not only false stories are more likely to be shared than true news, but also that false news is usually more novel than the true one (Vosoughi et al, 2018). Realization of the psychological mechanisms that often drive the use of social media and sharing information as well as of the benefits gained by the companies from the use of their platforms may help avoid being manipulated and prompt more reflection over why we share or interact with a given content.

Furthermore, better awareness of the variable quality of science reporting as well as the limitations of scientific research may be helpful to discern whether one should share a given science news story or medical advice. General public usually receives science news from media, notably newspapers and blogs where reporting may be, intentionally or not, biased or erroneous. Moreover, even if science reporting is of highest quality or one reads directly scientific articles, one should keep in mind that there is still a risk of mistakes or bias. Research is being conducted by people who are not free from mistakes, career or commercial interests, political and moral views, and other influences which may impact their conclusions. Although the peer-review system and the requirement to report conflicts of interest in published articles address some of these issues, these mechanisms are not entirely efficient.

Understanding of these two issues may elicit a more critical attitude to scientific news, prompt more consideration of potential benefits and harms of sharing a given content—as well as the use of social media in general—so that it is not based on compulsive reactions but is thoughtful and aligned with one’s goals and values. Prudence in using the Internet, including critical attitude towards information, should be inculcated as early as possible by parents and teachers, since the young may be more prone to fall prey to the strategies employed by the online communication platforms. What is related to this, efforts should be taken to introduce classes tackling these topics in school and university curricula as well as to develop research to increase understanding of the problems related to the use of social media, including the issue of misinformation, and its impact on society.

Prudence in using the Internet, including critical attitude towards information, should be inculcated as early as possible …

Although the censorship on social media may seem an efficient and immediate solution to the problem of medical and scientific misinformation, it paradoxically introduces a risk of propagation of errors and manipulation. This is related to the fact that the exclusive authority to define what is “scientifically proven” or “medically substantiated” is attributed to either the social media providers or certain institutions, despite the possibility of mistakes on their side or potential abuse of their position to foster political, commercial or other interests. Focusing on understanding and studying the problem of misinformation, education and promotion of a virtuous use of social media and information seem more laborious and may not bring immediate results, but, in the long run, may contribute to a society that is more immune to infodemics.

Acknowledgement

I thank Dr. Heidi Howard for her comments on this essay.

Conflict of interest

The author declares no conflict of interest.

References

1. Cohen D, Carter P (2010) WHO and the pandemic flu “conspiracies”. BMJ 340: 1274–1279Crossref Web of Science®Google Scholar
2. Ioannidis JPA (2020) Coronavirus disease 2019: the harms of exaggerated information and non-evidence-based measures. Eur J Clin Invest 50: e13222Wiley Online Library CAS PubMed Web of Science®Google Scholar
3. Melnick ER, Ioannidis JPA (2020) Should governments continue lockdown to slow the spread of covid-19? BMJ 369: m1924Crossref PubMed Google Scholar
4. Stjernfelt F, Lauritzen AM (2020) Chapter 12 Facebook and Google as offices of censorship. In Your post has been removed: tech giants and freedom of speech, pp 139–172. Cham, Switzerland: Springer Nature Switzerland AGCrossref Google Scholar
5. Vosoughi S, Roy D, Aral S (2018) The spread of true and false news online. Science 359: 1146–1151Crossref CAS PubMed Web of Science®Google Scholar

WMA DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS

Shared from https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013

Preamble

1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.

The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs.

2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA encourages others who are involved in medical research involving human subjects to adopt these principles.

General Principles

3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”

4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.

5. Medical progress is based on research that ultimately must include studies involving human subjects.

6. The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality.

7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights.

8. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.

9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent.

10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.

11. Medical research should be conducted in a manner that minimises possible harm to the environment.

12. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional.

13. Groups that are underrepresented in medical research should be provided appropriate access to participation in research.

14. Physicians who combine medical research with medical care should involve their patients in research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.

15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.

Risks, Burdens and Benefits

16. In medical practice and in medical research, most interventions involve risks and burdens.

Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects.

17. All medical research involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and to other individuals or groups affected by the condition under investigation.

Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and documented by the researcher.

18. Physicians may not be involved in a research study involving human subjects unless they are confident that the risks have been adequately assessed and can be satisfactorily managed.

When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, physicians must assess whether to continue, modify or immediately stop the study.

Vulnerable Groups and Individuals

19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm.

All vulnerable groups and individuals should receive specifically considered protection.

20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research.

Scientific Requirements and Research Protocols

21. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

22. The design and performance of each research study involving human subjects must be clearly described and justified in a research protocol.

The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study.

In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.

Research Ethics Committees

23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration.

The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study’s findings and conclusions.

Privacy and Confidentiality

24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.

Informed Consent

25. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable of giving informed consent may be enrolled in a research study unless he or she freely agrees.

26. In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information.

After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed.

All medical research subjects should be given the option of being informed about the general outcome and results of the study.

27. When seeking informed consent for participation in a research study the physician must be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent must be sought by an appropriately qualified individual who is completely independent of this relationship.

28. For a potential research subject who is incapable of giving informed consent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the potential subject, the research cannot instead be performed with persons capable of providing informed consent, and the research entails only minimal risk and minimal burden.

29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorised representative. The potential subject’s dissent should be respected.

30. Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research group. In such circumstances the physician must seek informed consent from the legally authorised representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorised representative.

31. The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the patient-physician relationship.

32. For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee.

Use of Placebo

33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances:

Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or

Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention

and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.

Extreme care must be taken to avoid abuse of this option.

Post-Trial Provisions

34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.

Research Registration and Publication and Dissemination of Results

35. Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.

36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

Unproven Interventions in Clinical Practice

37. In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.

The Belmont Report

Office of the Secretary

Ethical Principles and Guidelines for the Protection of Human Subjects of Research

The National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research

Shared from https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

AGENCY: Department of Health, Education, and Welfare.

ACTION: Notice of Report for Public Comment.

SUMMARY: On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings.

The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution’s Belmont Conference Center supplemented by the monthly deliberations of the Commission that were held over a period of nearly four years. It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of Institutional Review Boards, and Federal employees. The two-volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78-0013 and No. (OS) 78-0014, for sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

Unlike most other reports of the Commission, the Belmont Report does not make specific recommendations for administrative action by the Secretary of Health, Education, and Welfare. Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department’s policy. The Department requests public comment on this recommendation.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Members of the Commission

Kenneth John Ryan, M.D., Chairman, Chief of Staff, Boston Hospital for Women.
Joseph V. Brady, Ph.D., Professor of Behavioral Biology, Johns Hopkins University.
Robert E. Cooke, M.D., President, Medical College of Pennsylvania.
Dorothy I. Height, President, National Council of Negro Women, Inc.
Albert R. Jonsen, Ph.D., Associate Professor of Bioethics, University of California at San Francisco.
Patricia King, J.D., Associate Professor of Law, Georgetown University Law Center.
Karen Lebacqz, Ph.D., Associate Professor of Christian Ethics, Pacific School of Religion.
*** David W. Louisell, J.D., Professor of Law, University of California at Berkeley.
Donald W. Seldin, M.D., Professor and Chairman, Department of Internal Medicine, University of Texas at Dallas.
***Eliot Stellar, Ph.D., Provost of the University and Professor of Physiological Psychology, University of Pennsylvania.
*** Robert H. Turtle, LL.B., Attorney, VomBaur, Coburn, Simmons & Turtle, Washington, D.C.

*** Deceased.

Ethical Principles & Guidelines for Research Involving Human Subjects

Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. Public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code became the prototype of many later codes[1] intended to assure that research involving human subjects would be carried out in an ethical manner.

The codes consist of rules, some general, others specific, that guide the investigators or the reviewers of research in their work. Such rules often are inadequate to cover complex situations; at times they come into conflict, and they are frequently difficult to interpret or apply. Broader ethical principles will provide a basis on which specific rules may be formulated, criticized and interpreted.

Three principles, or general prescriptive judgments, that are relevant to research involving human subjects are identified in this statement. Other principles may also be relevant. These three are comprehensive, however, and are stated at a level of generalization that should assist scientists, subjects, reviewers and interested citizens to understand the ethical issues inherent in research involving human subjects. These principles cannot always be applied so as to resolve beyond dispute particular ethical problems. The objective is to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects.

This statement consists of a distinction between research and practice, a discussion of the three basic ethical principles, and remarks about the application of these principles.

[RETURN TO TABLE OF CONTENTS]

Part A: Boundaries Between Practice & Research

A. Boundaries Between Practice and Research

It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research. The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called “experimental” when the terms “experimental” and “research” are not carefully defined.

For the most part, the term “practice” refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals [2]. By contrast, the term “research’ designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.

When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is “experimental,” in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project [3].

Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.

[RETURN TO TABLE OF CONTENTS]

Part B: Basic Ethical Principles

B. Basic Ethical Principles

The expression “basic ethical principles” refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect of persons, beneficence and justice.

1. Respect for Persons. — Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.

An autonomous person is an individual capable of deliberation about personal goals and of acting under the direction of such deliberation. To respect autonomy is to give weight to autonomous persons’ considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. To show lack of respect for an autonomous agent is to repudiate that person’s considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.

However, not every human being is capable of self-determination. The capacity for self-determination matures during an individual’s life, and some individuals lose this capacity wholly or in part because of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated.

Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence. The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations.

In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to “volunteer” or to “protect” them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself.

2. Beneficence. — Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. Such treatment falls under the principle of beneficence. The term “beneficence” is often understood to cover acts of kindness or charity that go beyond strict obligation. In this document, beneficence is understood in a stronger sense, as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms.

The Hippocratic maxim “do no harm” has long been a fundamental principle of medical ethics. Claude Bernard extended it to the realm of research, saying that one should not injure one person regardless of the benefits that might come to others. However, even avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm. Further, the Hippocratic Oath requires physicians to benefit their patients “according to their best judgment.” Learning what will in fact benefit may require exposing persons to risk. The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks.

The obligations of beneficence affect both individual investigators and society at large, because they extend both to particular research projects and to the entire enterprise of research. In the case of particular projects, investigators and members of their institutions are obliged to give forethought to the maximization of benefits and the reduction of risk that might occur from the research investigation. In the case of scientific research in general, members of the larger society are obliged to recognize the longer term benefits and risks that may result from the improvement of knowledge and from the development of novel medical, psychotherapeutic, and social procedures.

The principle of beneficence often occupies a well-defined justifying role in many areas of research involving human subjects. An example is found in research involving children. Effective ways of treating childhood diseases and fostering healthy development are benefits that serve to justify research involving children — even when individual research subjects are not direct beneficiaries. Research also makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer investigation turn out to be dangerous. But the role of the principle of beneficence is not always so unambiguous. A difficult ethical problem remains, for example, about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future. Here again, as with all hard cases, the different claims covered by the principle of beneficence may come into conflict and force difficult choices.

3. Justice. — Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of “fairness in distribution” or “what is deserved.” An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. However, this statement requires explication. Who is equal and who is unequal? What considerations justify departure from equal distribution? Almost all commentators allow that distinctions based on experience, age, deprivation, competence, merit and position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.

Questions of justice have long been associated with social practices such as punishment, taxation and political representation. Until recently these questions have not generally been associated with scientific research. However, they are foreshadowed even in the earliest reflections on the ethics of research involving human subjects. For example, during the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients. Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps was condemned as a particularly flagrant injustice. In this country, in the 1940’s, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population. These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became generally available.

Against this historical background, it can be seen how conceptions of justice are relevant to research involving human subjects. For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.

[RETURN TO TABLE OF CONTENTS]

Part C: Applications

C. Applications

Applications of the general principles to the conduct of research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research.

1. Informed Consent. — Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied.

Information. Most codes of research establish specific items for disclosure intended to assure that subjects are given sufficient information. These items generally include: the research procedure, their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Additional items have been proposed, including how subjects are selected, the person responsible for the research, etc.

However, a simple listing of items does not answer the question of what the standard should be for judging how much and what sort of information should be provided. One standard frequently invoked in medical practice, namely the information commonly provided by practitioners in the field or in the locale, is inadequate since research takes place precisely when a common understanding does not exist. Another standard, currently popular in malpractice law, requires the practitioner to reveal the information that reasonable persons would wish to know in order to make a decision regarding their care. This, too, seems insufficient since the research subject, being in essence a volunteer, may wish to know considerably more about risks gratuitously undertaken than do patients who deliver themselves into the hand of a clinician for needed care. It may be that a standard of “the reasonable volunteer” should be proposed: the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge. Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation.

A special problem of consent arises where informing subjects of some pertinent aspect of the research is likely to impair the validity of the research. In many cases, it is sufficient to indicate to subjects that they are being invited to participate in research of which some features will not be revealed until the research is concluded. In all cases of research involving incomplete disclosure, such research is justified only if it is clear that (1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them. Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and truthful answers should always be given to direct questions about the research. Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.

Comprehension. The manner and context in which information is conveyed is as important as the information itself. For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.

Because the subject’s ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject’s capacities. Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases. On occasion, it may be suitable to give some oral or written tests of comprehension.

Special provision may need to be made when comprehension is severely limited — for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent (e.g., infants and young children, mentally disable patients, the terminally ill and the comatose) should be considered on its own terms. Even for these persons, however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes and by the use of third parties to protect them from harm.

The third parties chosen should be those who are most likely to understand the incompetent subject’s situation and to act in that person’s best interest. The person authorized to act on behalf of the subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the subject from the research, if such action appears in the subject’s best interest.

Voluntariness. An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.

Unjustifiable pressures usually occur when persons in positions of authority or commanding influence — especially where possible sanctions are involved — urge a course of action for a subject. A continuum of such influencing factors exists, however, and it is impossible to state precisely where justifiable persuasion ends and undue influence begins. But undue influence would include actions such as manipulating a person’s choice through the controlling influence of a close relative and threatening to withdraw health services to which an individual would otherwise be entitled.

2. Assessment of Risks and Benefits. — The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility to gather systematic and comprehensive information about proposed research. For the investigator, it is a means to examine whether the proposed research is properly designed. For a review committee, it is a method for determining whether the risks that will be presented to subjects are justified. For prospective subjects, the assessment will assist the determination whether or not to participate.

The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons. The term “risk” refers to a possibility that harm may occur. However, when expressions such as “small risk” or “high risk” are used, they usually refer (often ambiguously) both to the chance (probability) of experiencing a harm and the severity (magnitude) of the envisioned harm.

The term “benefit” is used in the research context to refer to something of positive value related to health or welfare. Unlike, “risk,” “benefit” is not a term that expresses probabilities. Risk is properly contrasted to probability of benefits, and benefits are properly contrasted with harms rather than risks of harm. Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible harm and anticipated benefits. Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of psychological harm, physical harm, legal harm, social harm and economic harm and the corresponding benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked.

Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to the subject, if any, and the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. On the other hand, interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected. Beneficence thus requires that we protect against risk of harm to subjects and also that we be concerned about the loss of the substantial benefits that might be gained from research.

The Systematic Assessment of Risks and Benefits. It is commonly said that benefits and risks must be “balanced” and shown to be “in a favorable ratio.” The metaphorical character of these terms draws attention to the difficulty of making precise judgments. Only on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, nonarbitrary analysis of risks and benefits should be emulated insofar as possible. This ideal requires those making decisions about the justifiability of research to be thorough in the accumulation and assessment of information about all aspects of the research, and to consider alternatives systematically. This procedure renders the assessment of research more rigorous and precise, while making communication between review board members and investigators less subject to misinterpretation, misinformation and conflicting judgments. Thus, there should first be a determination of the validity of the presuppositions of the research; then the nature, probability and magnitude of risk should be distinguished with as much clarity as possible. The method of ascertaining risks should be explicit, especially where there is no alternative to the use of such vague categories as small or slight risk. It should also be determined whether an investigator’s estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies.

Finally, assessment of the justifiability of research should reflect at least the following considerations: (i) Brutal or inhumane treatment of human subjects is never morally justified. (ii) Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures. (iii) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject — or, in some rare cases, to the manifest voluntariness of the participation). (iv) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits. (v) Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process.

3. Selection of Subjects. — Just as the principle of respect for persons finds expression in the requirements for consent, and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects.

Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only “undesirable” persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions.

Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of research. Thus injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects.

Some populations, especially institutionalized ones, are already burdened in many ways by their infirmities and environments. When research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved. Also, even though public funds for research may often flow in the same directions as public funds for health care, it seems unfair that populations dependent on public health care constitute a pool of preferred research subjects if more advantaged populations are likely to be the recipients of the benefits.

One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.

[RETURN TO TABLE OF CONTENTS]

[1] Since 1945, various codes for the proper and responsible conduct of human experimentation in medical research have been adopted by different organizations. The best known of these codes are the Nuremberg Code of 1947, the Helsinki Declaration of 1964 (revised in 1975), and the 1971 Guidelines (codified into Federal Regulations in 1974) issued by the U.S. Department of Health, Education, and Welfare Codes for the conduct of social and behavioral research have also been adopted, the best known being that of the American Psychological Association, published in 1973.

[2] Although practice usually involves interventions designed solely to enhance the well-being of a particular individual, interventions are sometimes applied to one individual for the enhancement of the well-being of another (e.g., blood donation, skin grafts, organ transplants) or an intervention may have the dual purpose of enhancing the well-being of a particular individual, and, at the same time, providing some benefit to others (e.g., vaccination, which protects both the person who is vaccinated and society generally). The fact that some forms of practice have elements other than immediate benefit to the individual receiving an intervention, however, should not confuse the general distinction between research and practice. Even when a procedure applied in practice may benefit some other person, it remains an intervention designed to enhance the well-being of a particular individual or groups of individuals; thus, it is practice and need not be reviewed as research.

[3] Because the problems related to social experimentation may differ substantially from those of biomedical and behavioural research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.

Visits :9924

Please Share