The ethics of enrolling terminally ill patients in clinical trials

[wizzed101]

As far as I know, this is an ongoing practice. This article, however, makes me wonder.

http://www.bbc.com/news/magazine-37311038

Paolo Macchiarini: A surgeon’s downfall

In July 2011, the world was told about a sensational medical breakthrough that had taken place in Stockholm, Sweden. The Italian surgeon Paolo Macchiarini had performed the world's first synthetic organ transplant, replacing a patient's trachea, or windpipe, with a plastic tube.

The operation promised to reshape organ transplantation. No longer would patients have to wait for a donor organ, only to run the risk of biological rejection. Plastic tracheas - and possibly other organs - would be produced quickly, safely, and made-to-measure for each patient.

It was a story that befitted the reputation of Dr Macchiarini's workplace, the prestigious Karolinska Institute, whose professors decide each year who will receive the Nobel Prize in Medicine.

But five years on, Macchiarini's headline-making work has brought KI and its sister organisation, the Karolinska University Hospital, no glory. Of the nine patients that received the treatment, in Sweden and elsewhere, seven have died. The two still alive have had their synthetic tracheas removed and replaced with a windpipe from a donor.
........

Here are the doctor's justifications

In May, Macchiarini discussed his decision to operate on Andemariam Beyene on SVT. "We had a human being that we wanted to save," he said, "And in these circumstances what would you do? Do you just leave him dying at that young age? I don't think it's correct."

Macchiarini says that the report highlights "the very great amount of pre-clinical research that has been done into synthetic tracheal scaffolds", though he concedes that Andemariam Beyene was the recipient of an untested procedure.

"I would like to add that the welfare of patients has always been my driving concern. Although there may be criticisms of decision-making processes and administrative processes, and these may have had tragic consequences that with hindsight are deeply regrettable, everyone involved in the clinical care of these patients felt that they were doing their very best for these individuals. That should never be overlooked."

When asked about the transplants, Macchiarini has often mentioned that he was not the only one responsible for the decision to operate, but discussed his patients in multidisciplinary conferences. "There were 30 or more professionals involved in the decision-making process," he told SVT, "and then even in the inter-operative and postoperative care of the patient."

Was he right? Apparently, he was not the only one who made all the decisions, but he took the sword by himself. Every clinical trial carries inherent risks and if the risks were unacceptable, the trial would not be allowed to proceed. But what about the potential rewards of successful trials? Should the threshold of what is deem unacceptable be lowered by virtue of potential groundbreaking successes? Ethical discussion often skirt that question. But I think in reality, the rewards have tremendous influences on the decision making process.

My take on this particular case is that he fell because he had let those people who allowed to proceed down. If his procedure worked, none of this would have ever be discussed. They allowed him to continued after disastrous failures, for years!

What are your takes on this? Did the doctor deserve this disgrace?

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[NimbleNavigator]

I doubt anyone on here is qualified enough to comment about the specifics of this case without looking like a fool.

I will say, though, that the reason research is necessary is because we aren't completely sure whether or not something works. The fact that 7 of the 9 patients died is regrettable, but in my opinion doesn't in and of itself have any bearing on Macchiarini's abilities as a scientist. Obviously, the goal is to gather substantial evidence to bolster the assumption that an experimental procedure or treatment would be effective prior to clinical trials. What I want to know is - did Macchiarini do his due diligence? Or did he skip steps along the way? Would an unbiased investigator think that going forward with a clinical trial was reasonable?

 

[LizzyM]

What are your takes on this? Did the doctor deserve this disgrace?

from the article:

The investigation, led by Kjell Asplund, Chairman of the Swedish Council on Medical Ethics, found that the scientific foundation for the new operation was weak, and condemned the failure to carry out risk analyses before the patients received their operations, or seek the necessary ethical approval.

This bold section alone is enough to shut down any investigator anywhere in the world. All investigators are obligated to follow the Declaration of Helsinki and the Nuremberg Code and that requires independent oversight by an ethics board. If he didn't have that, he got what he deserved. An ethics board has a duty to protect the research subjects, to assure that they have the necessary information to make an informed decision about participation, and to receive and consider reports of adverse outcomes including subject deaths. Ethics oversight might have stopped this mess before it got as far as it did or killed as many subjects as it did.

BTW, this has nothing to do with the enrollment of terminally ill patients. Typically, one does not enroll subjects who may die of an underlying disease before the outcome of interest can be assessed. Some terminally ill patients are recruited for Phase I trials of drugs designed for their condition. While the likelihood of "cure" from the low doses used in a Phase I are low, the risks of death or serious side effects are being assumed by someone who is going to die soon and who has exhausted all available treatments and so it is considered a reasonable trade off. It is unethical to let these patients believe that they are getting a miracle cure, they should go into this hoping that the benefit will be that their participation will help doctors learn more so as to help other patients with this disease in the future.

 

[Goro]

I see Nimble has been splat by the Banhammer smack...one that I missed. What did he did do to get whacked?

I doubt anyone on here is qualified enough to comment about the specifics of this case without looking like a fool.

I will say, though, that the reason research is necessary is because we aren't completely sure whether or not something works. The fact that 7 of the 9 patients died is regrettable, but in my opinion doesn't in and of itself have any bearing on Macchiarini's abilities as a scientist. Obviously, the goal is to gather substantial evidence to bolster the assumption that an experimental procedure or treatment would be effective prior to clinical trials. What I want to know is - did Macchiarini do his due diligence? Or did he skip steps along the way? Would an unbiased investigator think that going forward with a clinical trial was reasonable?

 

[Lost in Translation]

I see Nimble has been splat by the Banhammer smack...one that I missed. What did he did do to get whacked?

Wasn't nimble enough.

 

[wizzed101]

from the article:


This bold section alone is enough to shut down any investigator anywhere in the world. All investigators are obligated to follow the Declaration of Helsinki and the Nuremberg Code and that requires independent oversight by an ethics board. If he didn't have that, he got what he deserved. An ethics board has a duty to protect the research subjects, to assure that they have the necessary information to make an informed decision about participation, and to receive and consider reports of adverse outcomes including subject deaths. Ethics oversight might have stopped this mess before it got as far as it did or killed as many subjects as it did.

That was my point. For a clinical trial to even start, it needs such approval. But it did start. Could it be that he just submitted his request for a clinical trial to some committee and got approved? If that were the case, why was it his fault for not meeting the ethical requirement? Plus, this was a huge event: from the article, 15% of Sweden population tuned in to watch him perform; how could such oversight possible unless the ethics board was complicit in this operation? There was no proof that the surgeon actively tried to circumvent the necessary approval. And since the saga lasted for such a long time, I suspect that had the it succeeded, none of this would have ever brought up.

BTW, this has nothing to do with the enrollment of terminally ill patients. Typically, one does not enroll subjects who may die of an underlying disease before the outcome of interest can be assessed. Some terminally ill patients are recruited for Phase I trials of drugs designed for their condition. While the likelihood of "cure" from the low doses used in a Phase I are low, the risks of death or serious side effects are being assumed by someone who is going to die soon and who has exhausted all available treatments and so it is considered a reasonable trade off. It is unethical to let these patients believe that they are getting a miracle cure, they should go into this hoping that the benefit will be that their participation will help doctors learn more so as to help other patients with this disease in the future.

But is that really the motivation of those participated in clinical trials? I would argue that all of them went into trials hoping for a cure. Is it ethical then to play on this motivation to continue such practice? If the absence of hope was a requirement for eligibility, there would be no test subjects for these trials.

So was he really unethical or was he being punished for the failure of his work?

 

[LizzyM]

That was my point. For a clinical trial to even start, it needs such approval. But it did start. Could it be that he just submitted his request for a clinical trial to some committee and got approved? If that were the case, why was it his fault for not meeting the ethical requirement? Plus, this was a huge event: from the article, 15% of Sweden population tuned in to watch him perform; how could such oversight possible unless the ethics board was complicit in this operation? There was no proof that the surgeon actively tried to circumvent the necessary approval. And since the saga lasted for such a long time, I suspect that had the it succeeded, none of this would have ever brought up.


But is that really the motivation of those participated in clinical trials? I would argue that all of them went into trials hoping for a cure. Is it ethical then to play on this motivation to continue such practice? If the absence of hope was a requirement for eligibility, there would be no test subjects for these trials.

So was he really unethical or was he being punished for the failure of his work?

If he disobeyed the rules but succeeded in amazing cures of the subjects of his experimentation and no one got hurt, he might have gotten a small slap on the wrist. I know of a GYN in private practice who was using drugs off label (for a use other than those approved by the FDA and indicated on the label) without ethics board oversight with the intention of sharing his results with other physicians (making systematic observations to generate new knowledge, the definition of research as it pertains to human subjects) but no one got hurt and he got an an admonishment and was required to file the necessary paperwork once his med school (where he had an appointment as a faculty member) got wind of it through the press. On the other hand, the surgeon in Sweden put patients at risk without oversight and people died so he's going to get a major sanction.

If he had gotten approval as you said, why did Kjell Asplund, Chairman of the Swedish Council on Medical Ethics, report that the surgeon did not seek the necessary ethical approval.

A clinical trial can begin without oversight and approval if someone just marches into a patient's room and says, "we have something we think will help you." I suspect that few involved parties are going to stop a famous surgeon and say, "let me see your paperwork." I bet the assumption is that it has been done. I'd even guess that members of the local oversight committee may have assumed that he had the approval -- many times investigators like this one have numerous protocols going at the same time and you figure you (as a member of the oversight board) missed the meeting where this particular activity was discussed and approved.

Much has been written about recruiting subjects to clinical trials, about the "therapeutic misconception", about how to inform subjects of the risks and the potential benefits and the fact that there may be no benefit to them (they may even die sooner than they would have if they didn't participate), but that their participation will help other people with this problem. Sure, people are going in with some hope that this will be the miracle they've been hoping for but that doesn't always pan out. But the subjects should be well versed on the risks including the risk that things could go very, very wrong. That is one of the jobs of the ethics board, to be sure that the risks are spelled out in lay language and that the information needed to make an informed decision is presented to the subject in such a way that their consent is informed and voluntary.

 

[Lucca]

If you are interested, there is a vast literature on informed consent out there to look at and a lot of really interesting work goes into studying how best to conduct clinical research in Bioethics. It's one of those things that sounds really technical and boring at first but it's actually really interesting

 

[deleted480308]

I don't know any of the details of this case.....my overarching principle for questions like this is full disclosure to the patient. If the patient knew the risks/rewards/results so far, then it's fair game in my mind

 

[Vladimir7]

I see Nimble has been splat by the Banhammer smack...one that I missed. What did he did do to get whacked?

I gotyu @Goro http://forums.studentdoctor.net/threads/would-this-psychology-course-be-counted-in-sgpa.1221050/

Poor Nimble wouldn't let a DO give advice in MD...shame really.

Disclaimer: I do not agree with Nimble

 

[wizzed101]

If he disobeyed the rules but succeeded in amazing cures of the subjects of his experimentation and no one got hurt, he might have gotten a small slap on the wrist. I know of a GYN in private practice who was using drugs off label (for a use other than those approved by the FDA and indicated on the label) without ethics board oversight with the intention of sharing his results with other physicians (making systematic observations to generate new knowledge, the definition of research as it pertains to human subjects) but no one got hurt and he got an an admonishment and was required to file the necessary paperwork once his med school (where he had an appointment as a faculty member) got wind of it through the press. On the other hand, the surgeon in Sweden put patients at risk without oversight and people died so he's going to get a major sanction.

I see. But why did that GYN not seek the board approval? Was it because for whatever reason, they thought that it would not pass? And since (I assumed) the project yielded good results, it would be approved. Or would the board only consider the circumstances then, and if they disapproved it on that ground, would that invalidate the whole project? Did the researchers do that to gamble on the otherwise-not-probable post hoc approval? This sounds extremely unethical... The worst manifestation of this practice was Japanese Unit 731 doctors who got off scotch-free because they handed their results to the US.

If he had gotten approval as you said, why did Kjell Asplund, Chairman of the Swedish Council on Medical Ethics, report that the surgeon did not seek the necessary ethical approval.

What I meant was that the surgeon might have assumed that he got the approval, and so did everyone else. Still, he was the leader of the group so he should take all the credits and the blames.

 

[LizzyM]

I see. But why did that GYN not seek the board approval? Was it because for whatever reason, they thought that it would not pass? And since (I assumed) the project yielded good results, it would be approved. Or would the board only consider the circumstances then, and if they disapproved it on that ground, would that invalidate the whole project? Did the researchers do that to gamble on the otherwise-not-probable post hoc approval? This sounds extremely unethical... The worst manifestation of this practice was Japanese Unit 731 doctors who got off scotch-free because they handed their results to the US.


What I meant was that the surgeon might have assumed that he got the approval, and so did everyone else. Still, he was the leader of the group so he should take all the credits and the blames.

Based on what I saw in a newspaper story (years ago), the GYN didn't believe the rules applied to him because he was working in his private office and not on school property or with federal funding. It was not that he doubted that he'd be approved. For the purposes of treating a patient's condition, a physician may prescribe a drug for a reason that is not on the label (off label). This is legal and is not research. When physicians make decisions driven by research interests rather than the best interest of the patient (randomizing treatment decision, for example) then it crosses the line from clinical care to research.

When a project is submitted for review, whether it will yield good results is unknown and does not factor into the equation. The potential risks are weighed against the potential benefits. One benefit that accrues if the study is done well is that it generates new generalizable knowledge that can be used to advance the research agenda.

A study can be expected to yield good results but still be unethical if the subjects will be treated badly, denied necessary care, misled about the risks, or placed at unnecessary risk.

 

[wizzed101]

Based on what I saw in a newspaper story (years ago), the GYN didn't believe the rules applied to him because he was working in his private office and not on school property or with federal funding. It was not that he doubted that he'd be approved. For the purposes of treating a patient's condition, a physician may prescribe a durg for a reason that is not on the label (off label). This is legal and is not research. When physicians make decisions driven by research interests rather than the best interest of the patient (randomizing treatment decision, for example) then it crosses the line from clinical care to research.

When a project is submitted for review, whether it will yield good results is unknown and does not factor into the equation. The potential risks are weighed against the potential benefits. One benefit that accrues if the study is done well is that it generates new generalizable knowledge that can be used to advance the research agenda.

A study can be expected to yield good results but still be unethical if the subjects will be treated badly, denied necessary care, misled about the risks, or placed at unnecessary risk.

Thanks for the answer!