Pragmatic trials without informed consent?

April 8, 2019

Pär SegerdahlRandomized controlled trials (RCTs) are considered to be the gold standard for determining a causal effect of medical interventions. To achieve this aim, possible confounding factors must be avoided. This implies excluding many patients from participating in the trial, for example, patients with concomitant conditions. A negative consequence of these exclusions, however, is limited generalizability. Studying the artificially uniform participant group, you will be able to determine a causal effect, but you will know much less about real-life treatment outcomes in the population where the intervention actually will be used.

Further artificiality is created by the written informed consent procedure, which excludes even further patients from participating in the trial. Moreover, because they know they participate in a clinical trial, participants may change their behavior.

All this points to the importance of so-called pragmatic randomized controlled trials. In such trials, the effectiveness of two approved and routinely prescribed medicines are compared in normal clinical practice. This avoids most of the artificiality of RCTs and significantly improves generalizability and practical clinical relevance. Randomization is still required for scientific purposes, however, and written informed consent is an ethical obligation.

The demand for written informed consent is an obstacle to pragmatic trials. By creating, once again, artificial selection of patients, results continue to be less generalizable, which detracts from the whole point of conducting pragmatic trials. In a recent paper in the BMJ, twelve authors, among them, Stefan Eriksson at CRB, therefore argue that “EU clinical trial regulations should be revised to allow the waiver or modification of informed consent in low risk pragmatic trials.”

Some would consider this suggestion to be controversial. We need to keep in mind, however, the extremely low risks of studies that compare standardly prescribed medicines in normal clinical practice. We need to balance that low risk against the enormous social value of generalizable findings in evidence-based medicine.

Pär Segerdahl

Dal-Ré, R. et al. Low risk pragmatic trials do not always require participants’ informed consent. BMJ 2019;364:l1092

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Sometimes you do not want to be taken seriously

April 1, 2019

Pär SegerdahlWhat does taking something seriously mean? Seriously, I do not think there is a given answer. A common view, however, is that serious questions must have given answers: definitive either/or answers. Without either/or answers, truth seeking degenerates into irresponsible chattering. Embryo destruction is either murder or not murder (banging one’s fist on the table). Embryo research is either permissible or not permissible (banging one’s fist on the table).

Seriousness is polarized, one could say. If I were to take polarized seriousness seriously, which seems reasonable since nothing could be more serious than seriousness itself, I would have to ask: Is seriousness polarized or not? Either it is polarized or it is not polarized! I say this resolutely, banging my fist on the table. However, the question itself is polarized. My resolution and categorical banging suddenly appear comically embarrassing. My gestures seem to run ahead of me, answering the question I thought I asked seriously by making them. What happened? Did I reach the limit of seriousness, beyond which I no longer can ask serious questions about seriousness without ending up in self-contradiction?

Perhaps I just reached the limit of small seriousness, where great seriousness can begin. Contradicting myself need not be as bad as it sounds. Perhaps I did not even know I existed until I contradicted myself. My polarized reasoning ran aground. The sunken rock was myself. Self-contradiction allowed self-discovery. For we are not dealing with two contradictory propositions, so that we must seriously investigate which of them is the true proposition and which of them is the false proposition. I was contradicted by how I myself banged my fist on the table and said, resolutely, “either-or.”

Let us be grateful for the self-contradiction. It can open our eyes to another seriousness: the seriousness of self-reflection, where we, as Confucius says, turn around and seek the cause of our failure within ourselves. Thank you, dear self-contradiction. You may be embarrassing, but just for that reason I know that I am alive and not just a propositional machine that easily can be replaced by an online chatbot!

Why do I bring up these remarkable things? Perhaps because it would be tragic if we misunderstood contemplative thinking as superfluous in an empirically founded age. Schopenhauer said something similar: “Pure empiricism is related to thinking as eating is to digestion and assimilation. When empiricism boasts that it alone has, through its discoveries, advanced human knowledge, it is as if the mouth should boast that it alone keeps the body alive.”

Trying seriously to write a blogpost about seriousness, however, is risky. For blogposts are easily circulated as mere opinions. If you were to render the content of this post, you would almost certainly be forced to polarize it as a delimited position that is either true or false. If we followed Schopenhauer’s advice, however, we would give ourselves plenty of time to quietly digest, through thinking, the strange things said in the post. Such peaceful and quiet digestion of thoughts is beyond the capacity of chatterboxes and chatbots.

Do not misunderstand my joking style. It is meant seriously to avoid being taken seriously. The Chinese thinker, Chuang Tzu, did not want to be perceived as a pedant, so he said to his audience, “I’m going to try speaking some reckless words to you and I want you to listen to them recklessly.”

Chuang Tzu was a great thinker who did not want to be taken seriously as a small one.

Pär Segerdahl

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Reality surpasses our concepts

March 20, 2019

Pär SegerdahlAfter thinking for some time about donation of human eggs and embryos to stem cell research, I want to express myself as in the headline. Reality surpasses our concepts of it. This is not as strange as it sounds. For, if our concepts already reflected reality, then no one would need to do research, or to think. Just talking would be sufficient. An endless flood of words could replace all sincere aspirations to understand life and the world.

So what is it about donation to research that makes me want to express myself as in the headline? Everyone knows that blood donation is a gift to patients. This makes blood donation humanly understandable. People want to help fellow human beings in need, even strangers. But what about donation of eggs and embryos to stem cell research? Conceptually, the donation does not go to patients in need, but to researchers. This makes it difficult to understand donation to research. Are we to assume that people feel sorry for researchers and that they therefore want to support them by donating to them? Why do donors support research?

Not only does the concept of “donation to research” make donation difficult to understand from a human point of view. The concept also causes donation to appear suspiciously exploitative. The recipient of the donation is more powerful than the donor is. Moreover, if research results are commercialized, the recipient can make a profit on the work that the donation enables, without the donor receiving any share of it. So not only does literal faith in the concept of “donation to research” make a free will to donate difficult to understand. The donation also looks suspicious. Some argue that we should prevent an increasingly capitalized life science sector from exploiting self-sacrificing donors in this way.

Nevertheless, there are people who freely donate to research. Why? I guess it often is because they use research merely as an intermediary, to be able to give to patients. The patient is equally important in donation to research as in blood donation, although the concept does not reflect this relationship. Let me give an unexpected example of intermediaries.

About one kilogram of bacteria lives in our intestinal tract. Without these bacteria, our bodies would not be able to absorb many of the nutrients in the food we eat. When we swallow the food, these bacteria are in a sense the first diners, and our bodies have to wait patiently until they have finished eating. Even if we know this, we rarely think that we are swallowing food in order to allow bacteria in the stomach to eat first. We eat without being aware of the work that these “intermediaries” in the stomach have to do, in order for the nutrients to become available to the body.

The concept of “eating” does not reflect this relationship between bacteria and us. This is not a shortcoming of the concept. On the contrary, it would be very unpleasant if the concept reflected the bacteria’s work in our guts. Who would then want to say, “Let us sit down and eat”? However, problems arise if we have too much literal faith in concepts. Our vocabulary will then begin to impose limitations on us. Our own language will shrink our otherwise open minds to mental caves, where the words cast shadows on the walls.

Researchers, then, can be seen as intermediaries between donors and patients. I hope I do not upset sensitive minds if I suggest that researchers are the bacteria that we need to make donated material available to future patients’ bodies. That is why people donate to research. They sense, more or less intuitively, that research functions as an intermediary. “Donation to research” is at heart a gift to patients.

It is even more complicated, however, for research alone cannot act as intermediary. The task is too great. For the donation to become a gift to patients, a capitalized life science sector is needed, and a healthcare system, and much else. Moreover, just as the beneficiary function of bacteria in our stomachs requires a diet that regulates the balance between bacteria, this system of intermediaries, extending from donor to patient, needs regulation and monitoring, so that all the actors work harmoniously together. We cannot allow quacks to sell dangerous or inefficient drugs to the sick, and we cannot allow researchers to access donated material in any way they see fit.

Donation to research is a striking example of how reality surpasses our concepts. When we succeed in overcoming our literal faith in concepts – when we discover the way out of the cave and see the light – then donation to research finally becomes humanly understandable. The donor uses research to be able to give to patients. Moreover, donation to research ceases to appear as a suspicious transaction between unequal parties, since the donor uses the relatively powerful direct recipient to give to a more understandable recipient: the patient. Trying to counteract exploitation by paying the donor large sums, or by giving the donor a share of the profit, would tie the donor to the wrong recipient: the one emphasized in the concept.

As mentioned, the donor uses not only research to reach the patient, but a whole system of intermediaries, such as industry, healthcare and governmental control. This system of beneficial societal bacteria is therefore, to some extent, subordinate to the donor’s will to help patients. Or rather, the subordination is an aspect of the relationship, as is bacteria’s subordination to human eating. If we want to, we can always see the opposite aspect as well. Who really eats first and who last? Who really uses whom? The questions lack definitive answers, for the aspects change into one another.

With this post, I wanted to suggest the possibility of a bigger seeing, which we can learn to use wisely in our thinking when we discover how conceptually purified standpoints easily shrink our minds to mental caves.

Pär Segerdahl

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On “truly” understanding the risk

March 12, 2019

Pär SegerdahlIt is a well-known psychological fact that people have great difficulties to understand probabilistic risks. What does it actually mean that the risk of developing breast cancer the next ten years is fifteen percent? In addition to the difficulties of understanding probabilities, mathematical expressions can cause a false appearance of exactitude and objectivity. It is often about uncertain evaluations, but expressed in seemingly definitive figures.

At our Monday seminar, Ulrik Kihlbom discussed another difficulty with understanding risk information. It can be difficult to understand not only the probabilities, but also what it is you risk experiencing. Sometimes, people face enormously complex choices, where the risks are high, but also the benefits. Perhaps you suffer from a serious disease from which you will die. However, there is a treatment, and it may work. It is just that the treatment has such severe side effects that you may die even from the treatment.

Ulrik Kihlbom interviewed physicians treating patients with leukemia. The doctors stated that patients often do not understand the risks of the treatment they are offered. The difficulty is not so much about understanding the risk of dying from the treatment. The patients understand that risk. However, the doctors said, no one who has not actually seen the side effects understand that the treatment can make you so incredibly ill.

Yet, it seems like quite comprehensible side effects: fatigue, serious infections, nausea and vomiting, stomach cramp, diarrhea, skin irritation, pain, and weight loss. Why would patients find it difficult to understand these risks?

Could it be that doctors have too high demands on “real” understanding? Must the patient, in order to “truly” understand the side effects, already have experienced the treatment? According to the doctors, experienced patients are at least easier to inform about the side effects. At the same time, the requirement that one must have had the experiences to really understand them seems too strong.

Rather, says Ulrik Kihlbom, doctors probably notice from the patients’ attitude that some of them underestimate what it is like to experience the side effects. Such attitudes can be sensed. The patients understand verbally that they are at risk of these side effects, but emotionally they do not really understand what the side effects are like, especially when they come together for a long time.

This resembles a general human difficulty. We often neglect how we ourselves are affected by our experiences. We project our present, unaffected self, and think: “I’m strong, I can handle those side effects.” However, when we actually experience the side effects, we are no longer strong! The self is not a constant, but changes with our experiences.

Here, then, it is not the probabilities that cause the difficulties, but the words. We understand the side effects verbally and can easily reproduce them. However, even words can cause a false appearance of objectivity: as if the experiences the words denote would not really reach us at our core. We separate ourselves from what we verbally understand we may experience, as if we could live our lives without being affected… without actually living them.

Ulrik Kihlbom has found a striking example of yet another aspect of the difficulty of understanding risk information. Not only probabilities but also common words such as “nausea” can create characteristic misunderstandings of risk information.

Pär Segerdahl

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Genetic risk entails genetic responsibility

March 5, 2019

Pär SegerdahlIntellectual optimists have seen genetic risk information as a human victory over nature. The information gives us power over our future health. What previously would have been our fate, genetics now transforms into matters of personal choice.

Reality, however, is not as rosy as in this dream of intellectual power over life. Where there is risk there is responsibility, Silke Schicktanz writes in an article on genetic risk and responsibility. This is probably how people experience genetic risk information when they face it. Genetic risk gives us new forms of responsibility, rather than liberates us from nature.

Silke Schicktanz describes how responsibility emerges in situations where genetic risk is investigated, communicated and managed. The analysis exceeds what I can reproduce in a short blog post. However, I can give the reader a sense of how genetic risk information entails a broad spectrum of responsibilities. Sometimes in the individual who receives the information. Sometimes in the professional who provides the information. Sometimes in the family affected by the information. The examples are versions of the cases discussed in the article:

Suppose you have become strangely forgetful. You do a genetic test to determine if you have a gene associated with Alzheimer’s disease. You have the gene! The test result immediately makes you responsible for yourself. What can you do to delay or alleviate the disease? What practical measures can be taken at home to help you live with the disease? You can also feel responsibility for your family. Have you transferred the gene to your children and grandchildren? Should you urge them to test themselves? What can they do to protect themselves? The professional who administered the test also becomes responsible. Should she tell you that the validity of the test is low? Maybe you should not have been burdened with such a worrying test result, when the validity so low?

Suppose you have rectum-colon cancer. The surgeon offers you to participate in a research study in which a genetic test of the tumor cells will allow individualized treatment. Here, the surgeon becomes responsible for explaining research in personalized medicine, which is not easy. There is also the responsibility of not presenting your participation in the study as an optimization of your treatment. You yourself may feel a responsibility to participate in research, as patients have done in the past. They contributed to the care you receive today. Now you can contribute to the use genetic information in future cancer care. Moreover, the surgeon may have a responsibility to counteract a possible misunderstanding of the genetic test. You can easily believe that the test says something about disease genes that you may have passed on, and that the information should be relevant to your children. However, the test concerns mutations in the cancer cells. The test provides information only about the tumor.

Suppose you have an unusual neurological disorder. A geneticist informs you that you have a gene sequence that may be the cause of the disease. Here we can easily imagine that you feel responsibility for your family and children. Your 14-year-old son has started to show symptoms, but your 16-year-old daughter is healthy. Should she do a genetic test? You discuss the matter with your ex-partner. You explain how you found the genetic information helpful: you worry less, you have started going on regular check-ups and you have taken preventive measures. Together, you decide to tell your daughter about your test results, so that she can decide for herself if she wants to test herself.

These three examples are sufficient to illustrate how genetic risk entails genetic responsibility. How wonderful it would have been if the information simply allowed us to triumph over nature, without this burdensome genetic responsibility! A pessimist could object that the responsibility becomes overpowering instead of empowering. We must surrender to the course of nature; we cannot control everything but must accept our fate.

Neither optimists nor pessimists tend to be realistic. The article by Silke Schicktanz can help us look more realistically at the responsibilities entailed by genetic risk information.

Pär Segerdahl

Schicktanz, S. 2018. Genetic risk and responsibility: reflections on a complex relationship. Journal of Risk Research 21(2): 236-258

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Thesis on reproductive ethics

February 25, 2019

Pär SegerdahlOn Thursday, February 28, Amal Matar defends her thesis in the field of reproductive ethics.

As genetic tests become cheaper and more reliable, the potential use of genetic tests also expands. One use could be offering preconception genetic screening to entire populations. Prospective parents could find out if they are carriers of the same recessive autosomal genetic condition, and could plan future pregnancies. Carriers of such genetic conditions can be healthy, but if both parents have the same predisposition, the risk is 25 percent that their child will have the disease.

Preconception genetic screening is not implemented in Sweden. Would it be possible to do so in the future? What would the ethical and social implications be? Is it likely that preconception genetic screening will be implemented in Sweden? These are some of the questions that Amal Matar examines in her thesis.

Amal Matar’s interviews with Swedish healthcare professionals and policymaking experts indicate that preconception genetic screening will not be implemented in Sweden. The interviewees expressed the opinion that such screening would not satisfy any medical need, would threaten important values ​​in Swedish society and in the healthcare system, and require excessive resources.

Amal Matar defends her thesis in the Uppsala University Main Building (Biskopsgatan 3), room IV, on Thursday, February 28 at 13:00. You find an earlier interview with Amal Matar here. If you want to read the thesis, you find a link below.

Pär Segerdahl

Matar, Amal. 2019. Considering a Baby? Responsible Screening for the Future. Uppsala: Acta Universitatis Upsaliensis

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Neuroethics goes global

February 12, 2019

The complicated meaning, powerful assumptions, and boundless hopes about what can be revealed through neuroscience have made this discipline a national funding priority around the globe. A growing cohort of large-scale brain research initiatives aim to unravel the mysteries of the basis of feelings, thinking, and ultimately the mind. Questions formerly in the domain of the philosophical world have become part and parcel to neuroscience.

Just as science has so clearly become a global enterprise, ethics must keep pace. Cultural misunderstandings have nontrivial consequences for the scientific enterprise. Gaps in understanding negatively impact opportunities for collaboration and sharing, ultimately slowing scientific advancement. Too narrow of a view on science can limit our ability to reap the benefits of discoveries and, perhaps most damning for science, can result in a failure to anticipate and recognize the full consequences and risks of research.

To date, neuroethics discussions have been dominated by Western influences. However, the rapid neuroscientific development in East Asia in particular and the not-so-gradual relocation of a number of cutting-edge research projects from the West to East Asia, has made it clear that exploration and understanding of the ethics and cultural values informing research will be critical in engaging science as a collaborative global enterprise.

The Neuroethics Workgroup of the International Brain Initiative is comprised of members of each of the existing and emerging large-scale brain research initiatives. Leveraging the fellowship of the IBI and using an intentional culturally aware approach to guide its work, the Neuroethics Workgroup completes rapid deliverables in the near (within one year) and short-term (within two years).

With the inaugural 2017 summit, leading scientists, ethicists, and humanist co-created a universal list of neuroethics questions, Neuroethics Questions for Neuroscientists (NeQN) that should be addressed by scientists in each brain project. These NeQN were published in Neuron in 2018 and can be found here.

The neuroethics questions themselves were not necessarily unfamiliar neuroethics questions; however, these NEQN were designed to be adapted and informed by the cultural values and frameworks of each country.

The 2018 meeting served as a workshop, where each of the brain projects discussed why and how they will integrate neuroethics into their brain projects with particular recognition of the five questions from the 2018 Neuroethics Questions for Neuroscientists (NeQN) featured in Neuron. The product is the first neuroethics special issue in a high impact neuroscience journal.

Each perspective offers topics and context for their engagement with and practice of neuroethics. The issue features the seven existing and emerging large-scale brain research projects organized in alphabetical order.

The Australian Brain Alliance describes how neuroethics has been integrated into their research ethos as featured in their public outreach and advocacy efforts as well as their explorations in the public domains such as neurolaw and industry. A key component for the Australian project is diversity and inclusion, and there is a particular interest in engaging brain health with vulnerable Indigenous populations in Australia.

The Canadian Brain Research Strategy paper illustrates the rich historical efforts in pioneering neuroethics and future plans of a national collaboration to carefully consider public discourse and patient engagement as they pursue deeper knowledge of the how the brain learns, remembers, and adapts. A fundamental recognition of the neuroethics backbone of the Canadian project is that “The powerful ability of the brain to change or rewire itself in response to experience is the foundation of human identity.”

The China Brain Project discusses potential models for important public outreach campaigns and the balance of considering traditional Chinese culture and philosophy, particularly in the areas of brain death, conceptualizations of personhood and individual rights, and stigma for mental illness. The authors describe commitments for integrating neuroethics as the China Brain Project is being designed.

The EU Human Brain Project outlines its bold leadership and addresses the conceptual and philosophical issues of neuroethics and the implementation of philosophical insights as an iterative process for neuroscience research. A project with an extremely sophisticated neuroethics infrastructure, this paper provides examples of managing issues related to the moral status of engineered entities, how interventions could impact autonomy and agency, and dual use.

The Japan Brain/MINDS paper describes plans to reinvigorate historical efforts in neuroethics leadership as it expands the scope of its research and launches Japan Brain/MINDS Beyond. In particular, the project will integrate neuroethics to address issues related to privacy and data collection as well as in considering stigma and biological models of psychiatric disease.

The Korea Brain Initiative paper nicely demonstrates how advocacy for neuroscience and neuroethics at the government and policy levels go hand in hand. As Korea aims to advance its neuroscience community, the Korean government has seen neuroethics as integral to neuroscientists’ development. The Korea Brain Initiative is exploring ethical issues related to “intelligent” brain technologies, brain banking, cognitive enhancement, and neural privacy in the milieu of traditional and contemporary cultural traditions in Korea.

The US BRAIN Initiative outlines its efforts in building an infrastructure for neuroethics in research and policy and for funding research as it plans its roadmap for the next phase of BRAIN to 2025. Example of ethical issues that arise from the project’s goals of understanding neural circuitry include the moral relevance and status of ex vivo brain tissue and organoids as well as unique ethical concerns around informed consent in brain recording and stimulation in humans.

Each project illustrates that neuroethics is important regardless of the scope and methodologies inherent in its research goals and demonstrates the utility of the NeQNs for today’s and future scientists within and beyond the large-scale neuroscience research projects.

Karen Rommelfanger

PhD, Director, Neuroethics Program Emory Center for Ethics, Co-chair International Brain Initiative Neuroethics Workgroup

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