Tuesday, August 14, 2018

Ethics violations in Danish study of Indonesian divers

A few months ago the Danish star researcher Eske Willerslev reported on the genetic basis for the ability of the Indonesian Bajau divers’ ability to spend a long time under water. It turns out that they have a particular genetic variant that causes them to have an enlarged spleen that can store oxygen for long periods of time. 

Last month Science reported that Professor Willerslev has been accused of conducting this research in an unethical manner by the head of a genetics institute in Jakarta, professor Herawati Sudoyo.  First, the project was not reviewed by an appropriate research ethics committee in Indonesia. Second, it only included one Indonesian as a collaborator, who is not even a specialist in the area of the research. Third, the appropriate permissions to take the samples out of Indonesia were not obtained. Professor Willerslev does not dispute any of these facts, but has pointed out that he did have a permit from the Ministry of Research and Technology (RISTEK) and that he was under the impression that this also includes an ethics approval. Both Willerslev, and the lead author of the paper, Melissa Ilardo, emphasize that they would never knowingly do anything unethical, and in fact had done everything they could to conduct this research in an ethical manner. They simply were not aware of the issues raised in the criticism, it seems.

That, of course, may very well be true, but the question is whether they should have known what the Indonesian requirements were. Most ethical misconduct does not occur by willful neglect, but by gross negligence. The question is therefore: Did professor Willerslev’s team do what one could reasonably expect them to do, to identify the ethical requirements for the type of research they planned in Indonesia?  There are several reasons why this is doubtful.

First, professor Willerslev is not exactly an inexperienced researcher but has conducted numerous studies earlier in foreign countries, and should be well aware of the complexity of regulations governing in particular genetics research. He encountered the same issues when he did genetics research in among indigenous populations in Australia and the US previously, and had to apologize then for not being aware of all the ethical issues involved. One can make an excuse once for not knowing what the regulations are, but this is at least the third time this excuse is used.  

Second, even a cursory examination of what is involved in getting a research permit from the Indonesian Ministry of Research and Technology makes it clear that this is simply a permission for a foreigner to enter the country in order to do research. It mainly involves visa related issues, in the same way as other groups, such as journalists or business people, have to fulfill certain requirements to get the appropriate visa. It specifically states that it does not provide a permission to ship samples out of the country.

Third, researchers who interact with human beings for research purposes (in this case taking spit samples and measuring spleens and therefore physically interacting with research subjects) should know that such research in most countries requires separate ethics committee approval by an in-country ethics review committee. This requirement has been in force for decades. Genetics researchers should also be aware that there in most countries are specific, additional rules governing the handling of samples that contain genetic information, and if special population groups are involved, additional restrictions apply. There is simply no basis for claiming a lack of knowledge by an experienced researcher such as professor Willerslev.

Fourth, there is the issue of involving local researchers. This is not a general legal or regulatory requirement, but it certainly has received a lot of attention in the ethics literature over the past couple of decades. It is by now well established that if a researcher from a high-income country does research in low- or middle-income countries they need to include local collaborators. In this case they included a person with no expertise in the subject area of the paper, but a person who has published on teacher evaluations. In the note on what the authors have contributed, this author is said to have “provided logistical support in Indonesia”. This is typically not enough to be listed as an author of a scientific paper, and is also an odd departure from normal practice. In this case it is particularly important. Had the researchers followed normal procedure, of having a responsible academic unit in Indonesia involved in the planning of the research, they would likely have avoided the embarrassment of not adhering to well-established rules for research conduct in the country.

The research procedures were approved by the Developing-Country Committee of the Danish National Committee on Health Research Ethics. One of the authors is associated with the Wellcome Trust, an organization that has, at least in its official statements, made a point of requiring high ethical standards in their funded research in low- and middle-income countries. One would hope that these two groups can take the necessary steps to ensure that their associated researchers do not commit such obvious ethics lapses in the future. The additional interesting question is: If it is established that the research team did not follow established rules for the ethical conduct of research, and it is accepted that they should have known about these rules, should this paper be retracted? Or at a minimum, should the journal post a note and apology about the ethics lapses? Given the high profiles of this research team and the journal it is unlikely to happen. The sad experience is that journal editors still do not take ethics seriously.

Sunday, August 5, 2018

Another misleading case of ethics dumping - compensation for research injury

Another case in the book on Ethics dumping concerns the issue of compensation for research injury, written by Cong Yali: Legal and Ethical Issues of Justice: Global and Local Perspectives on Compensation for Serious Adverse Events in Clinical Trials

The case is about a phase III trial of a drug developed by the pharmaceutical company Bayer to prevent blood clots in patients after knee surgery. The clinical trial compared this drug administered once a day as a tablet against another standard anti blood clot prevention method given by injection. Two weeks after surgery the patients underwent a clinical examination and a test for blood clot formation by angiography. One patient experienced a reaction shortly after completion of the angiography: low blood pressure, chest tightness, cough and sweating. The likely diagnosis was hypovolemic shock, and the patient was treated with a saline solution and dopamine. After about one hour blood pressure was stabilized and after an additional 90 minutes the patient had recovered. The patient was discharged, but returned the next day because she was not feeling well, and was admitted to the hospital again. The doctors suspected possible pulmonary embolism as a result of a blood clot formation. They did a comprehensive examination and ordered bed rest and anticoagulant therapy. After two weeks the patient was discharged but pulmonary embolism had been excluded. Because of the necessary bed rest there was a worry that normal rehabilitation of the knee after the operation would be hampered, resulting in possible loss of function. The event was reported as a serious adverse event.

The patient wanted compensation for this adverse event. Typically, in order to be awarded compensation for research injury the patient needs to show that the cause of the adverse event was a procedure done for research purposes and that there is a compensable injury. Since the patient was discharged from the hospital, and the company had already paid the hospital bill, the patient would have to demonstrate that there is a persistent loss of function or other injury after discharge. The patient, however, refused to undergo an examination by a physician to provide evidence of such persistent injury. The company therefore naturally rejected the claim, since there was no injury to be compensated.

Instead of bringing a suit against the company based on the presence of persistent injury, the plaintiff brought a breach of contract case against Bayer. Basically, the plaintiff claimed that by signing the informed consent form to take part in the trial sponsored by Bayer, the plaintiff had entered into a contract with Bayer. This contract specified that the insurance is available for research injury. Since anaphylactic shock after angiography is mentioned in the informed consent form as a possible risk of angiography, this event should be covered by the insurance contract, and consequently by the contract between the plaintiff and Bayer. According to the insurance policy the maximum compensation amount is 500.000 Euros for each patient. This would cover all possible injuries, and it would therefore be reasonable that the plaintiff was awarded a portion of this amount for her injury. 150.000 Euros was estimated as a reasonable proportion given the seriousness of the adverse event. The court decided to award the plaintiff an amount of 50.000 Euros, the plaintiff appealed this decision. The appeal was denied, and the plaintiff was awarded 50.000 which was paid by Bayer.
The author of this chapter identifies three specific ethical issues raised by this case. First there is the cost of litigation, second is the variations in compensation between countries, and third is the inequality between the sponsor and the research subject in terms of access to resources. The second issue is to a large degree a result of differences in national laws, and would be outside the scope of most issues related to ethics. The first and the third are essentially the same: Proving causality between research participation and injury is difficult and can result in costly court procedures. This is indeed a challenge that needs more attention in research ethics. It may be possible to suggest procedures that can ease the burdens of proving causation in cases of presumed research injury. The problem is that the case that is presented in the chapter does not illustrate this problem at all, because it was not tried as a research injury case, but as a breach of contract case.

First, there is the denial of the patient to undergo an examination to provide evidence of injury. This is a necessary condition for any case of research injury compensation. Second, it is not even clear that there is a probable causal relationship between the research procedures and the adverse event. There is no disagreement that it was not caused by the investigational drug. It could either be caused by the angiography if it was a reaction to that procedure, or it could be caused by the surgery if it was a case of pulmonary embolism as a result of the blood clot. The clinical record leaves both options open. If caused by the surgery it was definitely not caused by a research procedure. If caused by the angiography it is less clear. On the one hand the procedure could be seen as part of the research to establish one of the endpoints of the study (deep vein thrombosis) or it could be seen as clinical follow to detect thrombosis and treat it if it is identified. In that case the procedure is actually of benefit to the patient even though there is an extremely small risk of shock.  Based on the questionable causal relationship and the fact that there was no evidence of injury it is likely that any court in any of the other countries where the trial also recruited patients would have awarded any research injury compensation.

The patient, however, decided to try this case as a breach of contract case. The court agreed that it could be brought forward on that basis and did award 50.000 Euros to the plaintiff on that basis. It seems that the court argued that any adverse event mentioned in the informed consent form automatically gives rise to a compensation claim, in proportion to its severity based on a maximum award of 500.000. This would be independent of whether the event led to any persistent injury. The experience of the event itself, whether it was caused by the research procedures or not, should be compensated.

It may very well be that this is an appropriate legal analysis of the case based on Chinese law. From an international perspective it is highly unusual and would probably be rejected by the legal systems in many countries. The case description, however, gives the reader no reason to believe that this is an accepted legal analysis in China. It was reached by a lower court, there is no reference to other court decisions, and there is no legal analysis of the reasoning of the court by an expert in Chinese law. Given the uniqueness and extraordinary nature of the decision by the court, one would have expected that the chapter contained some legal analysis. Instead it is basically an account of the reasoning of this particular court supplemented with information from the plaintiff’s family.

By now it is generally accepted that if a person is injured as a result of research participation they should be compensated for that injury. The difficult, unresolved issues are about one should understand that requirement. One issue concerns the requirement that there is a causal relationship between the research participation and the injury. Clearly, not all bad things that happen to people who are in research should be compensated. People may die in traffic accidents, they may suffer other injuries, or they may get unrelated diseases. In clinical research, the underlying disease or the ordinary treatment for the condition may also cause injury. Only injury that is caused by procedures done for research purposes should be compensated. The challenge is often how to identify what is caused by the research and what is caused by something else. Another issue concerns how much a person should be compensated. There is no disagreement that direct expenses related to treating the injury should be compensated, and expenses related to long-term effects of the injury. This could be economic loss because of need for rehabilitation or diminished ability to work, resulting in salary loss or reduction. Provisions for any additional compensation, such as for the fact that one has been injured, for the emotional effects of injury, or for the restriction in activities that one can carry out, but which do not result in any economic loss, vary between countries. It would have been useful to have some discussion of these issues in this chapter and in this book. Instead we get a misleading description of what appears to be a unique case, without any attempt at legal analysis by experts in Chinese Law. And it is difficult to see that this is a typical case of “ethics dumping”, and should form any basis for recommendations about funding decisions by the European Commission.

The court's decision is given here (in Chinese). 

Wednesday, August 1, 2018

Misgudied and controversial recommendations on "ethics dumping" from a Horizon 2020 funded project

This book is a result of the European Commission funded research project, TRUST, under the Horizon 2020 program. It contains a collection of case studies that are supposed to illustrate what the authors call “Ethics Dumping”. It is not clear exactly what the authors mean by this. According to a footnote in the book

The term was introduced by the Science with and for Society Unit of the European Commission: ‘Due to the progressive globalisation of research activities, the risk is higher that research with sensitive ethical issues is conducted by European organisations outside the EU in a way that would not be accepted in Europe from an ethical point of view. This exportation of these non-compliant research practices is called ethics dumping’ (European Commission nd).

The central phrase here is “export of non-compliant or unethical research practices”, although it is not exactly clear what is meant by “export” in this context. It seems that the consortium would want to include all research they identify as “unethical” in a low- or middle income country where researchers, sponsors or funders from high-income countries are involved. Typically, though, “dumping” is associated with activities that confer some advantage on the agent that carries out the “dumping”. In the research context this would be research that is for the primary benefit of people in rich countries, but is done in low- and middle-income countries because it is easier to do there. The problem is that many of the examples in the book are about research that is done for the benefit of people in low-income countries. Another major problem is that no attempt is made to acknowledge that the ethics judgments the authors make are controversial and highly contested. This would not be a problem if it was simply a report by the project group. After all, participants in a research project are free to reach any conclusion they feel is justified by their research. The project has, however, also developed a Global Code of Conduct to counter ethics dumping that is going to be used in the evaluation of research projects funded by the Commission, according to a press release:

The European Commission’s Ethics and Research Integrity Sector in the Directorate-General for Research and Innovation intends to propose the code as a reference document for future research projects seeking funding under the EU’s Framework Programmes for research and innovation.

The cases in the book are supposed to illustrate what practices the Code of Conduct should prevent. If the Code and the accompanying cases will be used to make decisions about what projects the European Commission will fund, we’d better be sure that there is general agreement about the recommendations, and that they continue to promote research that will improve health conditions of people in low-and middle income countries. The problem is that this is not the case. Let me illustrate this with one example from the book.

One chapter deals with three randomized controlled clinical trials to establish which screening program for cervical cancer was most suitable for India. The trials compared traditional cytology (“Pap-smears”), visual inspection after application of acetic acid (VIA), and testing for the presence of HPV. The trials also included a non-intervention arm. The trials were carried out in the 2000s and were funded by the US National Institutes of Health and the Bill and Melinda Gates Foundation. The criticism of the trials by the authors of the chapter is based on two premises.
First, is the claim that the “international standard of screening is cytology” (p.35). Second, is the claim that researchers have an “ethical obligation to provide <the international> standard care to participants in the control arm, as they are under their direct care during the course of research” (p. 44). It is the second premise that is contentious. Let me explain why.
There is no doubt that the “international standard” (Pap-smears) is effective at preventing cervical cancer and deaths. However, the test is not perfect. It has low sensitivity and specificity, requires highly trained personnel and qualified laboratories. The only way that this test can be a reasonable predictor of cancer is for it to be done regularly every few years. Even if the test misses a cancer once, repeating it will increase the likelihood that it will catch the cancer before it is too late. Given the low specificity the test also will give a high number of false positives requiring follow up procedures. For these reasons it has been generally agreed that a nationwide implementation of a screening program in India using this test was not feasible when the trials started, and is still not feasible. The infrastructure is not in place for an effective population screening program. However, the test has been available for people in India who want it and can pay for it themselves, or through their insurance. This means that it is effectively available only for a small proportion of Indian women.
VIA was proposed as an alternative to Pap-smears. In the early 2000s studies comparing these two methods had shown that they had similar sensitivity, but VIA had lower specificity. This has led Ruth Macklin to conclude that the effectiveness of VIA as a screening method had already been established in 2002, but this is simply a mistake. The same source that professor Macklin quotes to support her claim that VIA is effective, goes on to say that

Further research is required to improve its specificity without compromising sensitivity. Information from ongoing studies regarding its longitudinally-derived sensitivity, efficacy in reducing incidence/mortality from cervical cancer, its cost-effectiveness and safety will be useful in formulating public health policies to guide the organization of VIA-based mass population-based screening programmes in developing countries (p. 36)

In this paragraph there is a call for research that will establish its “longitudinally-derived sensitivity, efficacy in reducing incidence/mortality from cervical cancer, cost-effectiveness and safety”. This is quite important, because the critics, including Ruth Macklin, claim that all of this has already been established in 2002. For them, the only open research question is whether VIA as a screening method is implementable in a low income country such as India. But this clearly was not the prevailing expert opinion. The experts believed that it was still an open question whether VIA is effective as a screening program in low-income countries. This, of course, was precisely what the three trials that started in India was trying to address, thus meeting the call for research by the WHO consultation.

In order to justify these trials one still needs to establish that it was necessary to include a non-treatment arm. Obviously, a large number of experts believed that it was. I believe that a non-treatment arm was necessary, but will not argue for that here (will follow later).
            To sum up the argument so far: There was general agreement among experts that further research into the effectiveness of alternative methods for cervical cancer screening was necessary, and at least a substantial number of experts believed that a non-treatment arm was necessary. To complete the argument that these trials were justified, a final point needs to be established: Is it justified to withhold a known, effective intervention in the control group even though it is necessary for scientific reasons? The TRUST project participants believe that it is never justified to do so when the research deals with a major health endpoint such as cancer, or survival. Again, I shall not address the substance of the argument here, as this is also not addressed in the TRUST book.  Basically they point to agreement in international guidance documents as their main argument for their position on this issue. They claim that

Ethical guidelines governing the use of placebo in research severely restrict the use of placebo or “no intervention” if an effective treatment or test already exists for the disease being studied. This is to ensure that research participants in the control arm do not receive a lower standard of care than is already known to be effective, and are not therefore disadvantaged by their participation in the study.

The severe restriction they refer to is that no-treatment is allowed only if this would case non-serious harm. The problem with this view is that it is not a fair description of the content of international guidance documents. One should at least acknowledge that major guidelines such as both the current and last version of the CIOMS guidelines (see commentary to Guideline 5) recognize that there may be circumstances where research ethics committees may allow for exceptions to this rule. Basically, these exceptions deal with circumstances where the aim of the research is to produce knowledge that may be relevant in the local context, precisely the context of these three trials of cervical cancer screening programs in India.

And here is the problem. If the European Commission is going to use the Code of Conduct developed in the TRUST research program, with the accompanying case studies that illustrate how the Code is to be applied, as a basis for funding decisions of their research program for poverty related diseases, the Commission will use a misleading and controversial moral analysis as a basis for their decisions. There are, of course, some people who think that is good and agree. But there are also reasonable people who will disagree, and point out that the effect will be that some beneficial research to alleviate poverty-related diseases will not be funded. The TRUST project has reached their conclusion with regard to the moral issues involved, and the Commission is of course free to adopt their recommendations as a basis for their funding decisions. But at least one hopes that they recognize the controversial nature of the TRUST recommendations.