Research Ethics

Puberty-Blocking Drugs: The Difficulties of Conducting Ethical Research

The ethics of research trials for young people with gender dysphoria are complicated.
Billion Photos/Shutterstock

Dominic Wilkinson, University of Oxford and Julian Savulescu, University of Oxford

A recent Newsnight programme reported that a major UK puberty-blocking trial is under investigation. Doctors at a London clinic provided drugs to block the development of puberty in young adolescents with gender dysphoria, a condition where the person experiences discomfort or distress because of a mismatch between their biological sex and gender identity.

The trial began in 2011. A year after starting the drugs, the young people were apparently more likely to report thoughts of wanting to harm themselves. The worry is that perhaps the treatment they received was causing them to have these thoughts of self-harm and suicide.

One of the criticisms of the study, put forward on Newsnight, is the design. The study involved giving the drugs to a group of adolescents and monitoring the effects. However, there was no control group, that is, adolescents who did not receive the drugs. This makes it hard to be sure whether the rates of self-harming thoughts are related to the drugs, would have happened anyway, or perhaps were lower than they would have been without treatment. Continue reading

Four Lessons from the Covert Separation and Study of Triplets

Written by Julian Savulescu

Today, the Journal of the American Medical Association published an article entitled “Three Identical Strangers and The Twinning Reaction— Clarifying History and Lessons for Today From Peter Neubauer’s Twins Study” written by Leon Hoffman and Lois Oppenheim.  It provides background to a documentary, Three Identical Strangers, which gained a lot of attention earlier in the year into “the lives of Edward Galland, David Kellman, and Robert Shafran, triplet brothers who stumbled upon each other in their college years and enjoyed a brief period of celebrity before emotionally confronting the implications of their separation.” One triplet ultimately committed suicide.

The triplets were part of a covert research study by child psychiatrist Peter Neubauer who followed them up for many years to study gene-environment interactions in triplets separated at birth. The article alleges that Neuberger was wrongly blamed by the triplets and film makers for their separation at birth. The authors argue it was “Viola Bernard, then a prominent child psychiatrist from Columbia University and consultant to a now-defunct adoption agency” who was responsible for their separation because she “believed that children born of the same pregnancy and placed for adoption would fare better if they were raised by separate families.” The authors review some evidence from the child development literature at the time that supported the idea that twins or triplets would fare better if adopted, experiencing less sibling rivalry and having greater access to parental resources.

Importantly they argue that Bernard and Neubauer acted independently of each other. Moreover, the secrecy was required by laws at the time. “It was illegal at the time of the study to provide information about biological families to adoptive parents, a practice that did not begin to be modified until the late 1970s and 1980s.”

Hoffman and Oppenheim conclude:

“So the study was ethically defensible by the standards of its time—principles of informed consent and the development of institutional review boards lay in the future.10 However, these documentaries demonstrate how unsatisfactory that defense is to the study’s families who live with its legacy.

The films’ message for today’s child specialists and researchers is thus something other than their surface themes of outrage and restitution. They rather provide an unusually dramatic example of the potential for harm from human participant research, even if only observational.”

I would like to draw four other lessons from this episode.

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Medical Nihilism: When A Dose Of Scepticism Can Be Healthy

In his 2018 book, the philosopher of science, Jacob Stegenga defends the view “that we should have little confidence in the effectiveness of medical interventions.” (Stegenga 2018) On the face of it, he acknowledges, this position seems unreasonable: most of us can think of myriad ways in which modern medicine has improved – perhaps saved – our own lives and the lives of those close to us. The asthma attack I had as a baby, effectively treated at the time and subsequently managed through the use of seemingly magical medications which relax the muscles around the airways, opening them up and allowing air to pass freely again. Or the schoolfriend whose ruptured appendix could have resulted in a fatal infection, but for emergency surgery and the administration of antibiotics. Or the countless lives made less painful by the availability of cheap and safe painkillers. 

Medical sceptics tend to get a bad rep – anti-vaxxers who risk the lives of children by regurgitating debunked myths about the links between vaccines and autism, leading to dips in herd immunity and disease outbreaks; credulous folk who believe in the mystical powers of homeopathy and eschew conventional therapies in favour of potions that contain little more than water. This is not the sort of company one wishes to associate with. Continue reading

Reversibility, Colds, and Neurosurgery

By Jonny Pugh

This blog was originally published on the Journal of Medical Ethics Blog

 

Happy new year to readers of the blog!

I always approach the new year with some trepidation. This is not just due to the terrible weather, or even my resolution to take more exercise (unfortunately in the aforementioned terrible weather). Instead, I approach January with a sense of dread because it is always when I seem to come down with the common cold.

In my recent research, I have been interested in the nature and moral significance of reversibility, and the common cold is an interesting case study of this concept. In this blog, I will use this example to very briefly preview a couple of points that I make in a forthcoming open access article about reversibility in the context of psychiatric neurosurgery. You can read the open access paper here.

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The Fundamental Ethical Flaw in Jiankui He’s Alleged Gene Editing Experiment

By Julian Savulescu

Chinese researcher Jiankui He of Shenzhen claims to have gene edited two healthy embryos, resulting in the birth of baby girls born this month, Lulu and Nana. He edited a gene to make the babies resistant to HIV. One girl has both copies of the gene modified while the other has only one (making her still susceptible to HIV).

On July 29, 2017, He uploaded a copy of his lecture on YouTube, “Evaluating the safety of germline genome editing in mouse, monkey and human embryos“. He finishes the lecture (see 11:22) arguing that experimentation in humans should be “slow” and with “caution”, remarking that “a single case of failure might kill the entire field”, as in the case of the death of Jesse Gelsinger. He closes with a picture of Gelsinger.

Gelsinger died during a somatic (not germline) gene therapy trial nearly 20 years ago. Early gene therapy trials were conducted with an emphasis on participant consent. A somatic cell gene therapy was developed for ornithine transcarbamylase deficiency, a disorder of nitrogen metabolism. The condition comes in two forms: mild, with normal life expectancy and management by diet, and severe, which is lethal in the first year. Researchers, acting on the advice of ethicists, decided to conduct the first trials in adults with the mild form of the disease as they were capable of consenting. Gelsinger consented at age 18 and died due to a catastrophic immune reaction. He would have had a normal life expectancy in the absence of the intervention.

At the time, I wrote this paper. I argued the main failing of that experiment was failure to minimise expected harm. The design of the trial was flawed; it should have been conducted in infants with the severe form of the disease, as this would have resulted in less expected harm.

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Press Statement: Monstrous Gene Editing Experiment

Chinese researcher He Jiankui of Shenzhen claims to have gene edited two healthy embryos, resulting in the birth of baby girls born this month, Lulu and Nana. He edited a gene to make the babies resistant to HIV. One girl has both copies of the gene modified while the other has only one (making her still susceptible to HIV). 

If true, this experiment is monstrous. The embryos were healthy. No known diseases. Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life, including the development of cancer. There are many effective ways to prevent HIV in healthy individuals: for example, protected sex. And there are effective treatments if one does contract it.

This experiment exposes healthy normal children to risks of gene editing for no real necessary benefit.

It contravenes decades on ethical consensus and guidelines on the protection of human participants in research.

In many other places in the world, this would be illegal punishable by imprisonment.

Could gene editing ever be ethical? If the science progressed in the future and off target mutations reduced to acceptable and accurately measurable level, it might be reasonable to consider first-in-human trials (with appropriate safeguards and thorough ethics review) in one category of embryos: those with otherwise lethal catastrophic genetic mutations who are certain to die. Gene editing for this group might be life-saving; for these current babies, it is only life-risking.

These healthy babies are being used as genetic guinea pigs. This is genetic Russian Roulette.

Prof Julian Savulescu

Uehiro Chair in Practical Ethics

Director Oxford Uehiro Centre for Practical Ethics

University of Oxford

Gene-Editing Mosquitoes at The European Youth Event 2018

By Jonathan Pugh

 

The below is a slightly extended version of my two 5min presentations at the European Youth Event 2018, at the European Parliament in Strasbourg. I was asked to present on the following questions:

 

  1. What are the ethical issues surrounding gene-editing, particularly with respect to eradicating mosquitoes?

 

  1. Should the EU legislate on gene-editing mosquitoes?

 

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Why It’s Important to Test Drugs on Pregnant Women

By Mackenzie Graham

Crosspost from The Conversation. Click here to read the full article.

The development of accessible treatment options for pregnant women is a significant public health issue. Yet, very few medications are approved for use during pregnancy. Most drug labels have little data to inform prescribing decisions. This means that most medicines taken during pregnancy are used without data to guide safe and effective dosing.

The United States Food and Drug Administration recently published draft ethical guidelines for how and when to include pregnant women in drug development clinical trials. These guidelines call for “the judicious inclusion of pregnant women in clinical trials and careful attention to potential foetal risk”. The guidelines also distinguish between risks that are related to the research and those that are not, and the appropriate level of risk to which a foetus might be exposed. Continue reading

Can We Trust Research in Science and Medicine?

By Brian D. Earp  (@briandavidearp)

Readers of the Practical Ethics Blog might be interested in this series of short videos in which I discuss some of the major ongoing problems with research ethics and publication integrity in science and medicine. How much of the published literature is trustworthy? Why is peer review such a poor quality control mechanism? How can we judge whether someone is really an expert in a scientific area? What happens when empirical research gets polarized? Most of these are short – just a few minutes. Links below:

Why most published research probably is false

The politicization of science and the problem of expertise

Science’s publication bias problem – why negative results are important

Getting beyond accusations of being either “pro-science” or “anti-science”

Are we all scientific experts now? When to be skeptical about scientific claims, and when to defer to experts

Predatory open access publishers and why peer review is broken

The future of scientific peer review

Sloppy science going on at the CDC and WHO

Dogmas in science – how do they form?

Please note: this post will be cross-published with the Journal of Medical Ethics Blog.

The Moral of the Case of Charlie Gard: Give Dying Patients Experimental Treatment … Early

The tragic case of Charlie Gard has captured the imagination of social media, the Pope and President Trump. All of Charlie’s legal options appear to have been exhausted so, despite the tsunami of opinion, it looks like treatment will be withdrawn, barring some act of God or other authority.

I argued back in April  and then in May that it would be reasonable to give Charlie a trial of experimental treatment for a fixed period, say 6 months. The treatment was not going to make him worse and there was a non-zero possibility of some improvement. At the end of 6 months, his progress could have been reviewed and a decision then made to withdraw treatment if no significant progress had been made. I argued that we can’t be certain that his life is not worth living and we can’t be certain treatment will lead to zero improvement. I argued that the costs – 6 months of sedation and analgesia, with limited amounts of suffering associated with medical procedures, was arguably worth taking. That course was not taken.

Worst of All Possible Worlds

Charlie was born in September 2016. He was admitted to hospital in October. By January 2017, his mother had identified an experimental treatment (nucleoside replacement therapy) available in the US.

By April 2017, the Gards had crowd-sourced £1.2million to take Charlie to the US for experimental therapy. However, a judge ruled life is not in his best interests. He must die. Numerous appeals were lodged, and lost, all the way up to the European Court of Human Rights. Now the Pope and President Trump have weighed in.

It is now over 6 months since Connie Yates , Charlie’s mother, identified and petitioned for an experimental treatment. During the whole of that time, Charlie has been ventilated in intensive care, receiving no therapy offering any prospect of improvement. If treatment had been started back in January, immediately, we would now have evidence presentable to the family, courts, media and doctors of whether it was yielding any improvement, or not.

Unless the treatment itself would have serious side-effects, or was expensive, there is no downside to it being provided, especially when Charlie is being kept alive anyway. Since the parents had raised funds to provide it themselves, there is no justice or resource allocation issue.

Not providing the experimental treatment at the outset is the very worst situation for everyone:

  1. Charlie has been kept alive since January, suffering the alleged harms of intensive care, without receiving an intervention that might lead to an improvement.
  2. His parents have had to watch their child being kept alive, without receiving the treatment they hope will have some effect.
  3. Doctors have had to keep alive a child for 6 months whom they believe is suffering and should die with dignity.
  4. Courts and the family have been denied real time real life information about whether the intervention does have any effect. They have been forced to make non-evidence based decisions.

The reasonable course of action, given the time taken by the court process, would have been to immediately start nucleoside replacement therapy at the parents’ cost (if justice precludes stricken NHS funds being used for it), while petitions to court were made to withdraw active treatment. That would have meant we would have more information about what 6 months of therapy might be able to achieve, and Charlie would have been given his fair go. It would be a better position to be in for all concerned.

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