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In the name of science?

The controversial trachea transplantations by the notorious surgeon Paolo Macchiarini created a storm in the scientific world. It initiated a debate on the intersection between research and healthcare and the importance of a distinct ethical compass for the patient’s safety.

At first the world was in awe about the groundbreaking news. Paolo Macchiarini, a well-renowned thoracic surgeon and guest professor at the Karolinska Institute (KI) in Stockholm, had implanted the world’s first artificial trachea. He had replaced missing or damaged windpipes with an artificial trachea made of a polymer scaffold “seeded” with the patient’s own stem cells, which were supposed to grow into living tissue.

Read more: Macchiarini on trial in Sweden

A 36-year old patient, an Eritrean man with tracheal cancer had undergone a successful transplantation and – at the time – seemed to be recovering and in good health, according to the reports that the surgeon himself gave. Two more patients underwent surgery and Paolo Macchiarini also tested the technique in Krasnodar, Russia. Macchiarini received international tributes and his transplantations of artificial trachea were perceived as pioneering. Finally there was a new possibility that had opened up that could solve the problem of the lack of donated organs. These could now be built in the laboratory and a new era of regenerative medicine could begin.

 

Paolo Macchiarini

 

A dramatic turn

Alas the development took a dramatic turn, with devastating consequences. The transplants had not been as successful as had been hoped for. The artificial tracheas did not integrate with the patients’ own tissue resulting in severe complications, and tragically to lethal consequences. Most of the patients who had been treated by Macchiarini passed away some time after their operations.

The focus of the media attention took on a more sinister character as also other revelations were made. Colleagues at KI alleged that Macchiarini’s papers made his transplants seem more successful than they were, omitting the serious complications. He was also criticized for persuading patients to undergo surgery, performing it without proper clinical trials in animals first and performing operations while knowing that the implants were not in a good condition.

The scandal was a fact. The world of science was now stunned at what had been going on at Sweden’s most esteemed institution and hospital. It has raised questions of morality and ethics, of institutional transparency and responsibility. The Macchiarini story also became a legal matter. Sometime later it emerged that the transplantations had not been performed in accordance with legislation, as they had been done without the proper permits. In April 2015 the Medical Products Agency filed a complaint with the police and the public prosecutor. The operations performed by Paolo Macchiarini were a breach of the Medicinal Products Act as no permit had been issued.

“The agency did neither receive an application for a permit for a clinical trial of a medicinal product, nor an application for a permit to manufacture it.”

Gunilla Andrew-Nielsen at the Medical Products Agency explained to NLS in 2016, “The agency did neither receive an application for a permit for a clinical trial of a medicinal product, nor an application for a permit to manufacture it. The transplantations of the synthetic tracheas are categorized as advanced therapy medicinal products. According to the agency’s apprehension of this particular case it is to be considered as either research and thus demands a permit for a clinical trial, or as use of a medicinal product according to the so called hospital exemption and thus demands a manufacturing permit. The legal framework for clinical trials is based on international regulations, these are well revised and well-established.”

In other words, to conduct research and try out new methods there can be no doubt about what is allowed. Here is a brief reminder of the fundamental principles: clinical trials must be performed in agreement with the latest versions of Good Clinical Practice (GCP) and the Declaration of Helsinki. Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. What is then considered to be a clinical trial? According to GCP it is “any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.”

The conduct of clinical trials is based on the Declaration of Helsinki. It was adopted by the World Medical Association in 1964 and is there to provide ethical principles for medical research performed in human subjects. In the Declaration it is stated that 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.” Clinical trials have to be carried out in such a manner that the risk for the person participating isn’t greater than the utility. 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.”

A clinical trial also has to be approved by the Swedish Medical Products Agency and by a regional Ethical Review Board. The Medical Products Agency monitors that the clinical trial is correctly planned, that the data regarding the medicine is well-founded and that all safety demands are met. The regional Ethical Review Board supervises all types of clinical trials and assesses if there is an acceptable relation between risk and benefit for the individual, as well as if the information provided to the clinical study participants is correct and comprehensible.

Protecting patient safety

When it comes to the ethical aspects these have also been regulated for some time now. Since January 1, 2004, a law has been in force in Sweden that deals with vetting the ethics of research that involves humans. The Act concerning the Ethical Review of Research law encompasses research involving living persons, but it also covers such areas as research on the deceased, biological material from people and research that involves dealing with sensitive information about people or personal information concerning offences against the law. The law should also be applied to research that involves a physical intervention.

“The basics are that research can only be approved if it can be performed with respect for human value and the consideration of basic human rights and liberties. The law is there to protect the safety and integrity of the research subject,” explained Helena Hallgren Lönn, Chief Secretary of the Stockholm Ethical Review Board to NLS in 2016.

According to the legislation it is the head of the research, for example a university, county council or pharmaceutical company that vouches for the research that is to be made.

 

No application was made for the transplantations Macchiarini performed at the Karolinska University Hospital, KUH.

 

The kind of research that the law is applicable for can only be carried out if it has been approved for ethical review. Each scientist must apply for a permit to the Ethical Review Board when certain methods are to be used. According to Helena Hallgren Lönn, the most important criteria for the approval – or rejection – of an application is the respect for human rights.

“Human welfare is the priority and there always has to be a consideration of if there is a risk to a person’s integrity or safety.”

“The application can only be approved if the research can be carried out with respect for the value of human life. Human welfare is the priority and there always has to be a consideration of if there is a risk to a person’s integrity or safety. If the risks are outbalanced by the scientific value there could be a reason for approval but not if the same result can be achieved with other proceedings,” she said.

No application was made for the transplantations Macchiarini performed at the Karolinska University Hospital, KUH. The operations were a breach against the Act concerning the Ethical Review of Research concluded the Health and Social Care Inspectorate and have also initiated legal proceedings. If that application had in fact been sent in for the transplantations, it is still a doubtful issue whether or not it actually would have been approved. It is of course a theoretical question, but in Helena Hallgren Lönn’s view it is not that likely.

“That is an interesting question that is difficult to answer. An application to the Board needs to include accounts for animal testing. Seeing that there were none for the methods that were used in this case, I am uncertain if the application would have been approved. Given the circumstances, it seems unlikely,” she said.

Science or healthcare

Scientists, physicians and other professionals in the medical field have criticized the actions of KI and KUH and there is a desire for clarification. Following the operations run by Macchirini, a debate was raised about the fine line between healthcare and science. KI and the Karolinska University Hospital had in 2016 maintained that the advanced transplantations of artificial tracheas into three patients in Sweden were lifesaving healthcare. The Health and Social Care Inspectorate deemed them to be considered as research.

Bengt Gerdin, a professor emeritus of surgery at Uppsala University in Sweden, made an external investigation of the Macchiarini case and was able to study the whole process thoroughly. He is very critical of the claim that the transplantations were solely lifesaving healthcare.

“In this case, there were also several extra investigations done on biopsies or blood taken from the patient which only served research purposes. To me this is a clear case of a research project.”

“When it comes to this type of experimental surgery on patients there is an intention to gain knowledge applicable also for others than the actual patient. That means that the criteria for research is fulfilled. In this case, there were also several extra investigations done on biopsies or blood taken from the patient which only served research purposes. To me this is a clear case of a research project,” he said to NLS in 2016.

 

Bengt Gerdin

Bengt Gerdin, professor, Uppsala University. Photo: Linda Koffmar/Uppsala University

 

The grey area of science vs healthcare was now under the microscope. The Royal Swedish Academy of Sciences, in collaboration with the Swedish Society of Medicine, appointed a review panel to investigate the matter, with the task of proposing recommendations for clinicians and scientists working at the boundary between clinical research and medical care. The review was to be led by Professor Olle Lindvall at Lund University and has gone through the legal and ethical requirements, as well as highlighting the responsibility of scientists and physicians, and revise how patients can be provided with the best possible information and protection. The focus has been on developing practical guidelines concerning the requirements that need to be met for using untested treatments on seriously ill patients. Principles was also formulated for how treatment trials are to be reported in scientific journals.

“The boundaries between science and healthcare are thus subject to the definition of science.”

Helena Hallgren Lönn agreed that there is a difficulty in drawing the line between science and healthcare. “It is a problematic and interesting issue that we discuss on a daily basis at the Board. The Ethical Review Act states that research is carried out to acquire new knowledge on a scientific basis. That is a very wide definition of the concept of science. The praxis that the Central Ethical Review Board has set up includes some important factors; the project should be carried out by someone who is scientifically educated, who has a scientific question and method and intends to publish. Nevertheless, there has to be an individual assessment in each case. The boundaries between science and healthcare are thus subject to the definition of science,” she said to NLS in 2016.

Helena Hallgren Lönn also pointed out to NLS in 2016 that the Macchiarini case has opened up for an important debate. “Many have contacted the Board with questions about what the regulations are. People are keen to acquire the necessary permissions and to do what is right,” she said.

An ethical dilemma

In the revealing Swedish Television (SVT) documentary in the beginning of 2016, the questioned was raised of how sick the Icelandic patient was. Was it really motivated to operate on him with Paolo Macchiarini’s untested method? The answer was in 2016 yes, according to Karolinska University Hospital (KUH).

“Our judgement is that it was motivated,” stated Gunnar Öhlén, Chief Medical Officer at KUH in 2016, who explained further that the decision to operate was preceded by a multidisciplinary conference with representatives from various specializations, including a committed physician from Iceland. The assessment was clear, argued Öhlén, “The patient would have died if nothing had been done and there was no established treatment that could cure the patient.”

“On the part of Karolinska University Hospital nothing has emerged that changes our fundamental attitude regarding the three operations that were carried out here. They were conducted because there were no alternative treatments that could save the three patients’ lives.”

Even after what was shown in the documentary, KUH stood by the position that the operations had been necessary.

“On the part of Karolinska University Hospital nothing has emerged that changes our fundamental attitude regarding the three operations that were carried out here. They were conducted because there were no alternative treatments that could save the three patients’ lives,” said Gunnar Öhlén in a press release on January 28 2016, after the last part of the SVT documentary had been shown.

“Here, there was still time for consideration, something that should always be prioritized in healthcare, and a critical second opinion from someone outside the inner group, particularly as the proposed action involved so many unproven steps. Finally, extreme caution should have been taken to ascertain that the information given to the patient was objective in all respects.”

Bengt Gerdin strongly questions the ethical justification of the procedures that Macchiarini was able to perform. “I am essentially a clinician. I am well aware that there are certain situations where a surgeon has to face that a patient on the operating table will die unless a very unconventional approach is considered. This occurs utterly seldom, and this was not the scenario in the case with the Icelandic patient. Here, there was still time for consideration, something that should always be prioritized in healthcare, and a critical second opinion from someone outside the inner group, particularly as the proposed action involved so many unproven steps. Finally, extreme caution should have been taken to ascertain that the information given to the patient was objective in all respects,” he said to NLS in 2016.

The main concern in research should always be the person’s integrity and safety, he stressed. Something that he believes has been considered secondary in this case.

“Should the procedure have been properly evaluated by the regional ethical review board, this board would have guaranteed the patient’s integrity and safety. Actually, this would have made the ethical situation easier for the involved doctors, as the board would have taken the ethical responsibility, and doctors could have focused on the core medical problem instead. In this case, however, the responsible doctor, Paolo Macchiarini, actually more or less seduced the patient to undergo surgery.”

“The ethical rules that have been set up for research on humans, which includes all types of clinical trials, are aimed at protecting the patient in all respects. Here, the surgical procedure was not considered to be research, and no external unbiased body was set to protect the patient’s integrity, which was severely endangered. This is the most important issue. Should the procedure have been properly evaluated by the regional ethical review board, this board would have guaranteed the patient’s integrity and safety. Actually, this would have made the ethical situation easier for the involved doctors, as the board would have taken the ethical responsibility, and doctors could have focused on the core medical problem instead. In this case, however, the responsible doctor, Paolo Macchiarini, actually more or less seduced the patient to undergo surgery,” he said to NLS in 2016.

How is it possible then that an institution like KI could allow several trials to be carried out on humans, based on untested methods that were highly dubious from an ethical perspective and without the essential permits?   

“Karolinska University Hospital should never have let Paolo Macchiarini through to the operating table. As regards the Karolinska Institute they should have been clearer about the basic rules from the beginning. When Macchiarini was employed this was done to strengthen research in regenerative medicine, and also to recruit new patients to apply this research on. The problem was that there was no preparation to address the unavoidable highly problematic ethical issues which everybody must have realized would arise along the way. Macchiarini has this charismatic personality and held a strong position within his field. This may be an explanation why nobody said “Stop, let us think first”. In any case, I would say that KI has been completely naïve when allowing this to happen,” said Bengt Gerdin to NLS in 2016.

“Macchiarini has this charismatic personality and held a strong position within his field. This may be an explanation why nobody said “Stop, let us think first”. In any case, I would say that KI has been completely naïve when allowing this to happen.”

Bengt Gerdin further stated that another part of the problem is of an organizational nature. “One has to remember that KI is not one tight institution but consists of many small departments with very autonomous research groups. The high level of decentralization makes it difficult to achieve a strong leadership and have full control of what happens in every back yard. Also, another part of the problem was that the view of KI’s leadership was that the suspicion of misconduct or other unethical behavior was the result of an overblown complaint that had its origin in a conflict, or even a crash, between two research groups. The management at KI seemed to be unable to see the gravity of the situation and that this was in fact a serious case of scientific misconduct,” he said in 2016.

Risk-takers for the greater good?

When the results from Macchiarini’s transplantations were announced they were described as revolutionary medical progress with the potential of saving thousands of lives. However, it didn’t take that long before the stellar surgeon went from being perceived as an acclaimed genius to a fraud. How is Macchiarini and his attempts to be seen? Is he playing God? Or is he taking absolute risks in the role of a surgeon at the forefront of research, with the hope of solving one of medicine’s most difficult problems? There have been daring pioneers before in the history of surgery, performing groundbreaking transplantations – sometimes with lethal outcomes as a result. Is it also important to discuss the possibilities of making progress and innovative attempts within science, with risk-takers in the equation? NLS asked Bengt Gerdin in 2016.

“Of course there has to be pioneers and innovators who push medical science forward. This is not about putting the brakes on progress, it’s about creating ethical ground rules, not least for the currently exploding field of stem cell research and the application of this in humans. In the case of Macchiarini the core issue was a matter of introducing unproven foreign material that had not been tested in humans before,” he said.

“This is not about putting the brakes on progress, it’s about creating ethical ground rules, not least for the currently exploding field of stem cell research and the application of this in humans.”

How should the best conditions for clinical research be structured, so that they are not too restrictive but at the same time make sure that the patient’s safety is not in danger?

Bengt Gerdin emphasized in 2016 the absolute need for independent investigations. “There is no doubt that such should be mandatory. There has to be a structure that implies independent supervision from someone, other than the stakeholder, to secure the patient’s integrity. We must never forget that the patients who are candidates to completely new treatment modalities suffer severe diseases and are very very vulnerable.”

Investigations started

In the middle of February 2016 KI announced that the organization’s own investigation into scientific misconduct by Paolo Macchiarini will be re-opened, due to the new information that had been presented during the preceding days that “gives a different picture of the time after the operation of the first patient on whose case some of Macchiarini’s articles are based.” The images shown in the SVT documentary gave “a whole new picture of the process after the surgery on the patient,” stated Jan Carlstedt-Duke, Professor and Adviser to the Vice-Chancellor at KI in 2016. The investigation was aimed at answering some key questions and would map the decision-making process and documentation in connection to the transplantations, if the choice of measures were correct based on the situation when the decisions were made and what role different decision-makers have played. The investigation team would also seek to clarify what ethical judgements were made before the transplantations and during the course of the disease. The task also involved giving recommendations for improvements, stated KUH in 2016.

An investigation was also carried out at KI to scrutinize the institution’s handling of the Macchiarini case. The documentary, and the reporting from the media, triggered a process of transformation and clean-up at KI. Anders Hamsten announced that he was to step down as Vice-Chancellor of KI. The Board of the Karolinska Institute was renewed and KI also announced that the role of the KI Ethics Council would be reviewed.

 

Anders Hamsten

Anders Hamsten stepped down as Vice-Chancellor of KI in 2016

 

As regards Paolo Macchiarini’s commitments at the Kuban State University in Russia, KI stated that this was a side-line job that had previously been approved. However the details of these commitments had been unknown to KI, which they now reviewed to see if the institute had in any way failed in the control of Macchiarini’s side-line job.

“We do not allow side-line occupations that are detrimental to the confidence in KI and the manner in which Macchiarini’s activities in Russia are described in the documentary, that sort of side-line occupation would not likely have been approved,” stated KI in a comment.

On March 23 2016  the Staff Disciplinary Board at the Karolinska Institute decided to relieve Paolo Macchiarini of his duties as a researcher at KI. His dismissal was based on numerous reasons according to KI, including his activities at Kuban State Medical University in Krasnodar that “are in breach of KI’s fundamental values and have damaged KI’s reputation.”

Paolo Macchiarini has also failed to truthfully and fully report his extra-occupational activities, he supplied false or misleading information in the CV he submitted to KI and has demonstrated scientific negligence, according to KI’s investigation in 2015. “It’s impossible for KI to have any kind of collaboration with Paolo Macchiarini any longer,” said HR manager Mats Engelbrektson. “He has acted in a way that has had very tragic consequences for the people affected and their families. His conduct has seriously damaged confidence in KI and for research in general.”

Regaining trust

With time this story will – as most stories do – fade in the lights of other ongoing global events. Nevertheless, KI had and has some important work to do in order to regain trust from the rest of the scientific world, as well as from the average citizen. Following the whole Macchiarini scandal, the interest of participating in clinical trials at KI decreased. Karolinska Trial Alliance reported more difficulties in recruiting patients for clinical trials, which according to KTA appears to be connected to the Macchiarini events. Bengt Gerdin said in 2016 that it is of vital importance that appropriate measures are taken to restore confidence.

“Trust is a key issue and is something very concrete. If there is no trust then you will neither get people to participate in clinical trials nor get investors to invest in research. There has to be some radical action with internal revisions to show that this is being taken seriously,” he said.

Footnote: Both the Karolinska Institute and the Karolinska University Hospital declined to answer any questions regarding the Macchiarini case for this article, published in Q2 2016.

 


Facts

A brief summary – from groundbreaking surgery to global scandal

2010: Paolo Macchiarini (PM) was recruited as a visiting professor at Karolinska Institutet (KI)

2011: PM performed the world’s first synthetic organ transplant at Karolinska University Hospital (KUH) involving fashioning a trachea out of plastic and then coating it with a patient’s own stem cells. After that, he performed two more operations at Karolinska and he has also operated on patients in Russia. PM published a report in the Lancet that described the outcome of the first patient’s surgery. According to the article, the patient did not have “any larger complications”.

2012: In the spring, the second patient died and just a few months later a third patient was operated on at KUH who shortly afterwards had to be operated again after serious complications. The trachea of the first patient, an Eritrean man living on Iceland, had now become worse and he was moved to Sweden during the summer of 2012. The patient died in January 2014.

2013: In October, PM was prohibited from performing surgeries at the thorax clinic at KUH after a meeting where PM had declared the outcome of the surgeries performed with his method. Four physicians at the hospital reported PM to Vice Chancellor Anders Hamsten for distorting results of the operations in six scientific articles. The Belgian scientist Pierre Delaere also reported PM’s Lancet article for scientific misconduct.

2014: In the fall, an external investigator, Professor Bengt Gerdin, was given the task of investigating the physicians’ report against PM. The ethical council of KI informed Anders Hamsten that they didn’t consider PM guilty of misconduct. The allegations of research misconduct from Delaere against PM were dismissed.

2015: In April, the Medical Products Agency filed a complaint with the police and the public prosecutor. The operations performed by PM were a breach of the Medical Products Act as no permit had been issued. In May, an investigation by Gerdin had concluded that PM was “guilty of scientific misconduct”. PM was cleared by Hamsten, even though he “acted carelessly”. It was also concluded that PM has not pursued research. KI and KUH maintained that the advanced transplantations of artificial tracheas on three patients in Sweden were life-saving healthcare.

2016, Q1: In January, Swedish Television showed three documentaries about PM, and shortly afterwards Hamsten said in an interview that PM cannot stay at his position and that KI will initiate an external investigation into the suspicions of scientific misconduct and the world-renowned surgeon’s time at KI. In March, PM was dismissed after KI’s disciplinary board found that he “engaged in conduct and research that is incompatible with a position of employment at KI.”

2016, Q2: In May, the four doctors who reported PM in 2014 submitted another report of suspected misconduct in research concerning an article that already forms part of the ongoing inquiry. In June, the public prosecutor officially served a write against PM informing him that he is suspected of gross negligence causing manslaughter and bodily injury.

2016, Q3: In July, expert Eva Ekblad notes in a statement that there are some uncertainties concerning the animal experiments that formed the basis for the article Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats, published in Nature Communications on 15 April 2014. In August-September, the external investigation is completed. In August, KI receives another report of suspected scientific misconduct, this time concerning a scientific poster used to present PM’s research at a scientific conference in 2012. In August, Kjell Asplund’s external investigation is presented. The investigation is fiercely critical of KUH as well as of KI and notes, amongst other things, that the operations constituted research and not healthcare, and that KI was proactive in the hiring of PM, who was initially employed at both institutions.

In September, Lars Leijonborg, chairman of the university board, resigns. The same month, Sten Heckscher’s investigation and internal review  is presented. It criticizes KI on several counts: insufficient regard to the rules; the recruitment of PM in 2010 and the decision to extend his contract in 2013 and 2015, which was taken in breach of proper procedure; partial responsibility for the transplantation procedures carried out at KUH; shortcomings in following-up on PM’s research at KI; failure to properly investigate his extra-mural activities and flawed handling of the misconduct case. The same day saw the presentation of KI’s internal review of Clintec, the institution of clinical science, intervention and technology, where PM was employed as a researcher. The external review of KI’s handling criticises KI on several points. On 9 September the expert group for misconduct at the Central Ethical Review Board (CEPN) submits its report finding PM and his co-authors guilty of scientific misconduct in research in the article Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats. On 19 September, KI’s acting vice-chancellor, Karin Dahlman-Wright, asks KUH, in view of the CEPN’s statement of 9 September, to urgently investigate potential shortcomings in animal-handling at the animal facility where PM conducted his research.

2016, Q4: In October the university board decides to endorse the direction as set out in the vice chancellor’s action plan, which is a consequence of Heckscher’s external investigation of KI’s handling of the PM case and KI’s internal review of Clintec. The action plan is based on three main areas: The internal culture and management at KI, quality issues including regulatory compliance, and organizational issues including the interface with KUH. The then director of R&D at KUH submits a report at the request of KI’s vice-chancellor on urgent investigation of potential shortcomings in animal-handling.

In December, KI makes a decision in a misconduct case that relates to PM and about which the expert group for misconduct in research at the CEPN has issued a statement. KI’s decision is that PM and three co-authors are considered guilty of misconduct in research in regard to the article in Nature Communications from 2014. For two of the more junior authors, there are mitigating circumstances. On 20 December, Urban Lendahl, professor of genetics at the Department of Cell and Molecular Biology at KI, chooses to step down as a member of the Nobel Assembly by reason of his behavior in the PM case. In December, KI’s acting vice-chancellor, Karin Dahlman-Wright, and the director of KUH, Melvin Samsom, decide to appoint an external investigator to investigate whether there have been shortcomings in the review of animal management, and if so, how it can be improved.

2017: In March, the last of the three patients to have been given an artificial trachea surgically implanted by PM at KUH dies at a hospital in the USA. The same month, the article entitled “Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats” is withdrawn by the authors, with reference to the technical failings that have emerged from reviews of the article.

In April, the government decides to appoint Ole Petter Ottersen as the new vice-chancellor at KI at the suggestion of the university board. In September an external investigation into PM’s animal experiments at the animal departments at KUH in Huddinge (2011–2016) revealed failings in the supervision of PM’s group, the way in which they conducted animal experiments and compliance with ethical authorizations.

In October, the Swedish Prosecution Authority decides to close down the preliminary investigations of PM relating to tracheal surgery and other operations performed at KUH where he had previously been employed as a surgeon. CEPN issues its statement concerning six articles of which PM was the principal author. All authors must make statements before the vice-chancellor of KI makes a decision in the case. In November, in a supervisory decision, the UKÄ directs sharp criticism at KI with respect to issues relating to PM’s activities at KI during the period 2013 to 2016. The UKÄ has reviewed a number of issues that fall under the authority’s supervisory responsibility.

2018: In January KI’s vice-chancellor reaches the decision to find Paolo Macchiarini, Philipp Jungebluth, Bernhard Holzgraefe and Håkan Kalzén guilty of scientific misconduct. The case relates to the article “Autologous peripheral blood mononuclear cells as treatment in refractory acute respiratory distress syndrome”, published in 2015 in Respiration. In June, the President of KI made the decision to find seven researchers responsible for scientific misconduct in research. The case concerns six articles published in the scientific journals the Lancet, Biomaterials, the Journal of Biomedical Materials Research, and Thoracic Surgery Clinics. PM is one of the main authors of the articles. KI is requesting that the six articles be retracted without undue delay. In December, Director of Public Prosecutions Mikael Björk announces that the investigation into the surgical transplantation of synthetic tracheae in patients at KUH is to resume. The suspected criminal offence is gross negligent bodily harm.

2019: In June, some of the researchers found guilty of misconduct on 25 June 2018 hoped to lodge a legal appeal against the decision. The Supreme Administrative Court announces that it will not be granting leave to appeal.

2020: In September, the Director of Public Prosecution Mikael Björk announces that PM will be indicted for aggravated assault in connection with three surgeries at KUH.

2022: The PM trial will be heard in Solna District Court from 27 April to 23 May. In total, 13 days are scheduled for the hearing.