Without subjects research stops

Group image i people how have volunteered as research subjects.
Sanna and Rebecka Johansson, Monica Röhr Sjöqvist, Henrik Forsberg and Mattias Carlsten have all particitated in research. Photo: Lindsten & Nilsson

"I would like to thank all the test subjects, both healthy volunteers and patients, who have taken part in my experiments. I have been doing research on chronic pain in the musculoskeletal system since the early 1990s and I am extremely grateful to everyone who has participated in my studies,” says Eva Kosek, senior physician and professor in clinical pain research at the Department of Clinical Neuroscience at Karolinska Institutet.

Eva Kosek researches on how and why chronic pain arises, a question that has been a medical puzzle for many centuries. In addition to the suffering the pain has caused the patients, it has been a concern for doctors for a long time because it is often not possible to cure, and it is sometimes also difficult to offer effective relief from the constant pain. Unfortunately, this resulted in the patients, rather than their symptoms, often being seen as a problem, something that has not infrequently led to patients being treated badly and blamed for their own ailments.

Much of Eva Kosek’s research is about what happens when a person is diagnosed with fibromyalgia, a chronic pain condition with a widespread pain primarily in the muscles, and why some people suffer from chronic pain and others do not.

“The only real, well-documented, risk factor for developing chronic general pain is more localised pain over a long period. We believe that chronic pain wears the body’s own pain-inhibiting systems down and that some individuals have more vulnerable systems to begin with,” she says.

She has come to the conclusion that patients with fibromyalgia have several different disorders in their pain-regulating systems that interact and disturb the balance in the experience of pain. The systems that should alleviate the pain function much less well than in healthy people, leading to a heightened sensation of pain, that is to say, things that do not normally hurt do so if you have fibromyalgia.

Professor Eva Kosek. Photo: Stefan Zimmerman

Many of her studies involve subjecting people to something painful and then studying how their pain-regulation system responds. During her experiments, pressure on the thumbnail is often used as a pain stimulus and brain activity is studied using a technology called functional magnetic resonance imaging or fMRI. The reactions to pain are then compared to reactions to a painless pressure on the thumbnail. By comparing healthy volunteers with patients, she can see what separates them as regards how the brain processes pain and relate it to the perception of pain.

“We can see that people with fibromyalgia do not activate their pain-relieving systems in a normal way. In simple terms, we can say that they do not protect themselves against pain. We can also see that some parts of the brain that have to do with pain processing have become smaller and also communicate less well with other parts of the brain that are also involved in pain control. You could say that the pain-regulating system shuts down and shuts down more and more depending on how long you've been ill,” she explains.

The studies often involve several visits to undergo experiments where the researchers first calibrate the subject's individual pain levels and then perform fMRI examinations and pain tests. What test subjects are paid varies but is usually between 500 and 1,500 kronor. That people are prepared to contribute to her research by subjecting themselves to these experiments is crucial to her being able to move forward.

“You could certainly make excellent animal studies of pain mechanisms, but because pain is a subjective experience and you can’t communicate this with animals, it is next to impossible to do the research that we do on animals. The development of pharmaceuticals also shows that one cannot assume that results from animal studies will also hold in the case of humans since many substances that have shown a good analgesic effect in animals have then proven to be ineffective in humans,” she says.

But medical research on humans is something that must be done with great caution. Today research on people is regulated both legally and professionally in legislation and professional regulations that all emphasise the researchers’ duty to protect research participants’ life and health. But that has not always been the case. History tells us that doctors and researchers have repeatedly had a “the end justifies the means” attitude.

One well-known example is the 18th century British doctor Edward Jenner. He is probably the doctor who has saved most lives in history by discovering the smallpox vaccine. But his methods were anything but ethical by today’s standards. In 1796, he carried out a notorious experiment in which he deliberately infected a servant’s eight-year-old son with the fatal disease smallpox after having infected him with chickenpox two months earlier. The boy survived and the experiment is considered to be the first scientifically documented vaccination (from ‘vacca’, which means ‘cow’ in Latin) and now, 200 years later, the smallpox virus has been completely eradicated as a pathogen.

Niels Lynöe. Photo: Stefan Zimmerman

“A modern ethics review board would never have approved the experiment. Since everything turned out well and the boy didn’t become sick, we are in retrospect more willing to ignore ethical excesses,” says Niels Lynöe, Senior Professor of Medical Ethics at the Centre for Healthcare Ethics at Karolinska Institutet, but immediately adds:

“But the Ethical Reviews law says that we must not expose anyone to risk. It is thus the risk-taking that is regulated and then it of course does not matter if things turn out well.”

Ethics is not an absolute concept and what is considered ethically justifiable has varied over the years. The Hippocratic oath, which was written about 2,500 years ago, says that doctors must act for the benefit of the sick and avert what can injure them or cause them pain.

“In the balance between benefit and harm, there should be a surplus of what is good. This reasoning is almost always included in medical-ethical principles. So in that sense we can say that the basic principles are eternal,” Niels Lynöe continues.

But in other respects today’s research ethics’ regulatory framework is a modern invention. It has developed by stages over the last 100 years, often as a direct response to various research scandals.

A country that was one of the pioneers as regards research ethics is Germany. A regional regulatory framework for research ethics was adopted in Prussia as long ago as 1900 and in 1931 a national regulatory framework was introduced across the whole country. The decision had been preceded by a number of international and domestic scandals in medicine, where the trigger was the death of 77 babies in Lübeck after being vaccinated against tuberculosis.

But German doctors and researchers, who had previously worked within the strict research ethics regulatory framework subsequently, during the Nazi era, instead conducted particularly unethical research in Hitler’s concentration camps. A great many experiments were conducted that often had a fatal outcome for the test subjects. Most of the studies had military aims such as seeing how long a person could survive in freezing cold sea water or at what maximum altitude a fighter pilot could abandon the plane by parachute without dying in the thin air. Many studies also concerned vaccines for various infectious and fatal diseases, where some prisoners were vaccinated and a larger group was then infected with the disease to see if more people survived in the vaccinated group.

After the war, the German doctors and researchers who had survived went on trial in Nuremberg in 1946-47 and the court convicted 16 of the 23 who were accused of war crimes and crimes against humanity and sentenced seven to death by hanging and gave the other nine long prison sentences. During the course of the trial, the lawyers came to realise that there was no internationally recognised ethical regulatory framework for medical research on humans. That is why they in 1947 created the Nuremberg Code, which lists ten ethical principles. The code among other things lays down that voluntary consent to participate in studies is an absolute necessity, without exception. To be able to give their consent, a person must be legally capable of taking decisions, making research on children or the mentally handicapped impossible. The code also stated that the subject must be fully informed about the nature, purpose, risks and effects on health. Informed consent had thereby been defined.

According to the Nuremberg Code, informed consent was an absolute necessity, but not sufficient, and so it also required that the purpose of the study and the risk be proportionate to the potential humanitarian benefits of the experiment.

It is reasonable to assume that the Nuremberg Code and the unethical Nazi research that came out at the trials would have an impact on research in other countries. But that was not to be. The same year that the Nuremberg Code came into being, the caries-inducing experiments that involved mental patients being given large quantities of sweets to see if sugar increases the risk of developing dental caries were for example begun at the Vipeholms asylum for “the uneducable feeble-minded” just outside Lund in the southern Swedish province of Skåne. It did. For a year and a half, 220 inmates were given extremely sweet and sticky sweets several times a day without once being allowed to brush their teeth. On average the subjects developed ten new incidences of caries and for 50 of them their teeth were completely ruined.

It is difficult now to understand how this experiment could be initiated in the wake of the Nuremberg trials and everything that emerged there. But many saw the Nazi research that came to light at the Nuremberg trials as something other than normal research. There is also much to suggest that doctors and researchers outside the country considered the Nuremberg Code to largely apply only to Germans. It never really gained the importance it was intended to have. Examples of medical research that directly violate the Nuremberg Code can be found in many countries at this time, not least research on orphans and the mentally ill.

Many doctors also disliked the fact that the rules had been written by lawyers; it was perceived as an intrusion on their professional area and the legal wording also left very little scope for doctors’ and scientists’ own judgement. The international medical organisation World Medical Association, WMA, therefore adopted a new ethical code at its General Assembly in Helsinki in 1964 – the Declaration of Helsinki. The new regulatory framework, however, was significantly weaker in its wording about patients’ rights. But in spite of this or perhaps because of it, doctors around the world began to pay attention to it. A few years ago the Declaration of Helsinki celebrated its 50th anniversary. The document has been revised seven times over that period and now comprises a total of 37 paragraphs. When doctors and researchers in Sweden ask for test subjects’ trust when participating in a research study, it is the Declaration of Helsinki that is their lodestar. Although research ethics issues are regulated in several Swedish laws, which of course have varying legal weight, they have all been built up in accordance with the Declaration of Helsinki to a greater or lesser extent.

In short, the regulatory framework means that doctors and researchers must protect not only research participants’ life and health but also their dignity, integrity, right to self-determination, privacy and personal data. Any person who is capable of giving his or her informed consent to voluntarily participation must have done so to be included in the research. Test subjects have the right to stop participating in the study without the risk of this affecting future care or their relationship with their doctor.

Ethics Professor Niels Lynöe says that Swedish patients who volunteer for medical tests have good protection in today’s regulatory framework.

“Yes, I'd say so. The principle is that the interests of research must never take precedence over patient safety or the individual’s interests. The Ethical Review Board and the Medical Products Agency, which also ensures that the drugs being tested are safe, are among other things the guarantors for this. I do not believe protection can be much stronger. Many patients who are asked to participate in a study today also agree to do so. It's because they have very great trust in the healthcare system. Many also see the benefits of participating in clinical trials and experiments. You will meet the same doctor all the time. You can call a research nurse at any time if you have questions or if there is a problem. I think most patients today consider it a great benefit to participate in clinical research,” he says.

But despite the research ethics framework, the mark continues to be overstepped in the name of science by researchers who become blinded by their own ideas. Few people have been able to avoid the research scandal caused by the surgeon and former guest professor at Karolinska Institutet Paolo Macchiarini and his synthetic trachea transplants on severely ill patients, among other places at Karolinska University Hospital here in Sweden.

The scientific basis for applying the experimental method on humans was insufficient. Ethical licences were never applied for, but the operations were nonetheless carried out because in the opinion of those responsible at the time it was a matter of care in a life-threatening situation and not research. The three patients who underwent surgery at Karolinska University Hospital are now deceased. Several of the scientific articles have later been found to contain elements of scientific misconduct and parts of the case are still under investigation.

In March this year another example came to light where researchers at an eye clinic in the United States used a previously untested stem cell method on patients suffering from age-related macular degeneration – alterations in the macula. The clinic was registered for a clinical study of the method, but the study had been cancelled, a fact the researchers concealed when they injected stem cells into the eyes of patients, who believed that they were taking part in a study. The experimental treatment was given in both eyes at the same time, which is considered highly unusual and unsafe. After a while, the patients suffered retinal detachment and effectively became blind or severely visually impaired.

The examples illustrate that the regulatory framework governing research ethics can only give patients protection if it is followed.

Johanna Ungerstedt. Photo: Salomon Rogberg

Johanna Ungerstedt is an associate professor and specialist doctor at the haematology unit at Karolinska Institutet. She researches on a precursor to leukaemia, blood cancer, called myelodysplastic syndrome and another blood disease called systemic mastocytosis. She and her research group are conducting several types of research study.

“We are trying to find out why you get these diseases. In systemic mastocytosis, we know that almost all patients have the same mutation, but some get a benign form of the disease while others develop an aggressive tumour disease that shortens their lives. What determines if you get one or the other form is unclear,” she says.

Much of the research involves test-tube experiments on cells from the patients’ bone marrow, something she asks them for when they are there for the bone marrow examinations they need to undergo. For the patients, participating in the study no additional tests or risks are therefore involved but merely give Johanna Ungerstedt and her colleagues permission to take a few extra millilitres of bone marrow or blood.

“When we take samples we tell the patients that we need to analyse fresh cells in the study. The patients are asked to give their consent and at the same time are told that they can withdraw it at any time. But almost all patients agree because they want to contribute. It is not often someone refuses to give cells for research purposes,” Johanna Ungerstedt says.

The challenge for her is instead to get fresh bone marrow from healthy volunteers to compare with patients’ bone marrow.

“When a patient comes in, we need to have healthy bone marrow the same day from a person of about the same age,” she says.

A bone marrow sample is taken by inserting a needle a good way into the hipbone and extracting bone marrow. The procedure takes about 10-15 minutes and is done with local anaesthesia at several levels down to the bone but still causes a lot of discomfort and pain.

So where do you find healthy people who at short notice think it's a good idea to have a needle inserted into their hipbone? Primarily among colleagues and students, it turns out.

“I have taken samples from most of my colleagues and also those in neighbouring clinics because it’s important to be available immediately. People who give samples are paid 1,000 kronor but that's not why they do it. Most people at our clinic do it because they think it’s fun to contribute to the research. They have also seen many patients giving bone marrow samples and want to know what it feels like. Many medical and nursing students agree because they want to subject themselves to the same thing that they will subject their patients to,” Johanna Ungerstedt continues.

She is very grateful for this unselfish desire to fully understand the patients’ situation.

“For us, it’s essential to have these healthy cells to compare with. Without them we would not be able to come to almost any conclusions. We need to have a healthy frame of reference at all times because otherwise we naturally don’t know if we’re dealing with something healthier or sicker. It's wonderful if we can kill cancer cells of course, but if the treatment kills the healthy cells just as effectively the drug’s no use to us,” she says.

Johanna Ungerstedt also conducts certain clinical treatment studies on patients where a new treatment can actually be important to the patient him- or herself, not only for knowledge of the diagnosis in the future.

Studies of cancer patients’ reasons for participating in clinical trials show that some may have a, sometimes, unrealistic expectation that they will be cured. But Johanna Ungerstedt says she tries to be very clear in her communication with patients about what the prerequisites for participation are.

“Clinical studies usually mean more tests and more frequent visits for the patient, and there is no guarantee that the new treatment being tested is better than the ‘standard treatment’. At worst, the new treatment might in fact be worse. So in the treatment studies patients sometimes choose not to participate, which is quite understandable,” she says.

According to Niels Lynöe, it can be difficult to tell potential participants about a study. What determines if the subjects want to take part or not is what risk assessment they make and it has been found that it is not always based on the facts that were presented. In the studies of the cancer patients, it turned out, for example, that it was the patients who had participated in studies previously who had least knowledge about the fact that they could decide not to continue at any time without needing to say why.

“The greater the trust patients have in healthcare the more delicate this task is. The patients who are slightly more critical are naturally better in that respect. When they say yes you know that they have found out what participating involves,” he says.

Another ethically difficult question is what compensation subjects should be given for participating in the research. That it's a tricky issue is shown by the fact that one effect of the disastrous experiment in London in 2006 with a research substance called TGN-1412 – where five young men suffered severe immunological allergic reactions where their heads swelled up and one of them was forced to amputate parts of both fingers and toes – was increased interest in participating in clinical experiments. The reason was that it at the same time came out that participants in the experiment were paid £2,000, more than 20,000 kronor.

“That says quite a lot about why people choose to take part. When does it change from being voluntary to an offer you can’t refuse?” Niels Lynöe asks.

In Sweden, people who participate in research studies are also paid and how much they get can vary from study to study, but it is generally less than in Great Britain or the United States for example. According to the Swedish Research Council’s guidelines, the size of the payment should be based on the discomfort and distress caused to the subject, not the fact that cash is available. The issue of payment is extra-sensitive when it comes to research on children.

“There is a principle that most ethics review boards follow which allows a cinema ticket or similar to be offered but no more,” says Niels Lynöe.

But for adults there are no such limits because it must also be possible to compensate subjects for loss of income while taking part in experiments that can take several days.

A completely different type of study, that seldom involves discomfort and distress, is register studies. Here it is not a matter of clinical experiments but records data concerning patients with a certain disease which, after being anonymised, is compiled and used for various analyses of the effectiveness of different treatments. Analysis of the records data can also be supplemented with questionnaires if the researchers are also interested in information that is not registered in the records, for example dietary habits or other behavioural aspects. Register research has increased in importance and has grown fairly significantly as the need for long-term follow-ups, among other things of the effects of pharmaceuticals, has increased.

A variant of register studies is the Swedish Twin Registry, where twins born in Sweden are followed during their lives and are interviewed at regular intervals.

Patrik Magnusson. Photo: Ann Svalander

“The Swedish Twin Registry has existed since the late 1950s and Karolinska Institutet has hosted the registry since the early 1960s,” says Patrik Magnusson, associate professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and responsible for the Swedish Twin Registry.

The registry contains about 100,000 pairs of twin with a fairly even split between monozygotic twins, like-sex dizygotic twins and unlike-sex dizygotic twins.

Studies of twins can primarily give answers to two different types of question.

The first is whether an observed association between an exposure (e.g. smoking) and an outcome (such as lung cancer) is due to both environmental exposure and the outcome is consequences of the same genes. One hypothesis during the twin registry’s early years was that it was not smoking that caused cancer but that both were due to shared genetics. A question to which the Twin Registry could answer no, it was not due to shared genetics. The results were part of the evidence that it was smoking that accounted for the risk of cancer.

The second type of question that the Twin Registry can answer concerns the role of heredity in a specific disease. The research is conducted by periodically sending out questionnaires to those twins who voluntarily registered their interest in participating. The medical questions normally do not have anything to do with the twins in the survey but are universal for all people. The Twin Registry is merely the tool that makes it possible to see the importance of genetics in the specific research question.

“The great beauty of this type of study design is that we can get somewhere regarding causality. So very many associations are reported today that may only be apparent connections,” he says.

The Swedish Twin Registry has over the years provided much new knowledge in a broad spectrum of research areas. For example, it has been shown that personality, risk of depression and obesity are very strongly linked to genetics. But also that genetics influence how many cups of coffee we drink a day and that children do not become more talented by practising on a musical instrument (the clear correlation between IQ and playing music previously seen in studies was instead mainly due to the fact that the talented children chose to play an instrument more often).

“You can also grade the different forms of cancer by how hereditary they are. This can then guide the cancer researchers as to whether it is worth looking for specific genes or environmental factors,” says Patrik Magnusson.

Renowned are also the studies of the importance of the environment in which one grows up, where monozygotic twins who had grown up in different homes were compared. Such studies are not made any longer because twins growing up in different places is so unusual but at the turn of the last century, it was more common.

“If a poor family then had twins they could not afford to care of both. One of the twins might then have been put up for adoption. The studies, however, show that it does not seem to matter very much if you grow up in the same home or different homes. The twins were often similar to each other to the same extent regardless of whether they had grown up together or apart. As long as it’s a reasonably good home, the family environment is not so important as we might think,” says Patrik Magnusson.

Previously the twins were recruited in adulthood, but nowadays they are contacted when they turn nine and it is their parents who must make the decision and also answer the first questionnaires.

“But it’s the children who are the participants. We have no identity data or personal identity numbers for the parents,” Patrik Magnusson goes on.

Then the researchers send out new questionnaires when the twins are 15, 18 and 24 years old, and then throughout their lives and then of course it is the twins themselves who answer them. Interest in being included in the registry has always been high but has fallen slightly in recent years.

“It’s a concern but we still have a pretty good response rate compared to many other studies. But it’s dropped from a high of 80 per cent and is now down to as low as 60 per cent,” he continues.

Every year approximately 1,500 pairs of twins are born so there is still quite a good influx of new subjects. Patrik Magnusson believes that the reduced interest is among other things due to the general overload in the question area in today’s society.

“We’ll soon hardly be able to visit a page on the Internet without directly being presented with a survey about how we experience it,” he says.

For the studies and the results to be representative, it is important to have a high response rate, so every participant is important, but not at any price.

“From an ethical point of view, it is important to describe what we are doing in a neutral manner and not exaggerate the importance of the individual twin’s participation in the registry. It’s the statistical evaluation that constitutes the outcome of the research, not what an individual participant answers,” he explains.

Nor are the twins who take part in questionnaire studies paid any money but are given cinema tickets fully in accordance with ethical guidelines.

Patrik Magnusson’s own research is very much about biological questions and over roughly the past ten years all living twins in the registry have been asked if they would also like to contribute their DNA. So far, Patrik Magnusson has received approximately 33,000 DNA samples. The samples have already generated much research and he is convinced that they will continue to be an efficient way to obtain a great deal of new knowledge.

“When the twins provided their DNA at the age of nine turn 20, perhaps we want to examine the genetic link to ADHD and allergies, when they are 30 links with psychiatric conditions, when they are 40 to stomach problems, at 50 to obesity, and at 60 to cancer and cardiovascular diseases. It’s very efficient compared to collecting DNA for every new question,” he says.

Back to Eva Kosek and her pain research in fibromyalgia patients. For her, collaboration with patients has not only concerning their agreeing to participate in her research. One might say that she really has the patients to thank for many ideas for her research. She says that many patients whom she met at the beginning had questions about things they had experienced and observed. And when enough people had related the same experiences, she put two and two together.

“Among other things, they said that draughts caused them great discomfort, they said it hurt when cold gusts of air blew on them. I thought perhaps not only are their muscles tender but they may have a generally heightened sensitivity to pain. So we began to run tests with cold and heat and were able to show that these people have a generally increased pain sensitivity, which suggests that the nervous system is affected. What actually put me on what turned out to be the right track was that I listened to the patients,” she says.

Something that patients with fibromyalgia are very probably extremely grateful for. Now there is an explanation model as to why they have so much pain, something that did not exist only a few decades ago. Eva Kosek remembers clearly the general attitude in the early 1990s.

“When I began fibromyalgia research some of my colleagues asked me why I was researching on a disease that did not exist,” she says.

Her anecdote shows that medical research on humans is a collaboration that when it works optimally benefits everyone involved. Thanks to Eva Kosek’s and others’ research, we are much closer to understanding the mechanisms underlying the disease and thereby also have knowledge about how fibromyalgia is to be treated, even if the treatments do not help every sufferer and there is still no cure.

Important rules for participating in research

The ethical regulatory framework governing medical research in Sweden is extensive and is divided into various laws, regulations and ethical guidelines. Here follows a summary of the most important points.

The researcher’s obligations

  • The study must be approved by an ethical committee.
  • Researchers must protect participants’ life, health, dignity, integrity, right to self-determination, privacy and personal data.
  • The responsibility is always the researcher’s, never the research participants’, even if they have given their consent.
  • Medical research that involves humans may only be conducted if the importance of the research outweighs the risks and the inconvenience caused to the participants.

Informed consent

Every research participant must be given sufficient information about the purpose, methods, funding, possible conflicts of interest, the researcher’s departmental affiliation, expected benefits from and potential risks of the study, the discomfort the study may involve, arrangements for interventions after the study and every other relevant aspect of the study. The participants themselves can then consent to participate, preferably in writing.

Can stop at any time

Consent may be rescinded by the participant at any time and without any explanation without damaging the patient-physician relationship or impacting later treatment detrimentally.

Placebo an exception

A new treatment’s benefits, risks, inconvenience and effectiveness must normally be tested against the best available proven treatment(s). Placebos may only be used in exceptional cases.

Patient participation makes research better

Eva Larsson. Photo: Privat

Midwife and care teacher Eva Larsson has had rheumatoid arthritis since the mid-1980s. Her experience as a patient will help her in her role as research partner.

What does a research partner do?

“As a research partner, you are part of a research group and comment on the project. Your job is to bring the patient’s perspective to different issues.”

Why is it important to involve patients in research?

“Patient participation in research contributes to better projects. As a research partner, it’s my job to represent patients. For example, it’s important to know how patients can react to survey questions.”

What‘s the most important thing you’ve contributed?

“Among other things, I’ve helped formulate the survey questions in a major research project. I have also contributed to including questions about such things as climate care – rehabilitation in warmer countries – and on sleep apnoea.”

Would you like to contribute to research?

Studies at Karolinska Institutet

Volunteers registry

Text: Fredrik Hedlund, first published in the magazine "Medicinsk Vetenskap" no 2, 2017.

Content reviewer: