Genetic modification of embryos. Regulations must be updated to reflect current realities

Last week the news broke that a Chinese scientist, He Jiankui, had edited the genome of an embryo that was carried through a normal pregnancy to birth. This is another first from China. Three years ago a Chinese scientist had reported the first use of the CRISPR technology to modify embryos that would and could not continue through a normal pregnancy. That experiment, although controversial, was well within accepted scientific practice. It nevertheless created a firestorm of responses in the Western media, painting China as a lawless country where “anything goes”. A very similar experiment was later carried out in the US, this time with much praise in many media reports.

Unlike the experiment three years ago the new research was not announced through the publication of a scientific paper, but through a YouTube video, released at the start of the Second International Summit on Human Genome Editing in Hong Kong, China. There Dr. He presented some of the details of what he had done and answered questions, but the full details and verification of the experiment are still not available. Dr. He himself claimed that the news of the experiment was leaked prematurely, and the plan apparently had been to publicize it after proper peer review and publication in a scientific journal. What is known is that Dr. He altered a gene responsible for resistance to HIV infection.

There was an immediate criticism of the experiment both from within China and from international experts. The Ministry of Health and the Ministry of Science and Technology in China announced that the experiment was illegal, that they would launch an investigation and that they would suspend his permission to do research. Although Dr. He was on leave from his regular job at his University, and did the experiments in a private capacity, they also distanced themselves from the research. A large group of Chinese scientists published open letters in the Lancet criticizing the experiment.

When evaluating what was done it is important to be clear about what the basis is for the criticism. There are those who condemn it because they believe that any modification of the human genome should be prohibited, or because no research on human embryos should ever be permitted. Given the advances in somatic gene therapy, and acceptance of IVF, relatively few people hold these opinions today. Then there are some who believe that any germline genetic modification should not be permitted. That also is increasingly a minority opinion. The first international summit on Human Genome Editing explicitly permitted some types of such research, as do countries such as the UK, China, the US and Sweden. In 2017 the Dutch Health Council recommended that the current legal restriction on creating embryos specifically for research purposes should be lifted. Finally, there are those who believe that any attempt to bring a genetically altered embryo to birth should be prohibited. Many countries have such prohibitions, including the UK and China. This position is also increasingly being rejected by influential bodies. The UK Nuffield Council has recommended that there should be a path towards clinical use of germline modification, and the consensus statement of the Second Summit in Hong Kong also affirmed that this could be permitted under the right circumstances.

The widespread criticism of Dr. He’s experiment is therefore not necessarily because he did anything that was in principle wrong, but that he had not followed proper procedures and that the technology is not mature enough at this time for a clinical trial. Procedural requirements would include proper review by research ethics review committees and regulatory authorities. The claim about the immaturity of the technology is based on expert views that not enough is known about germline modification in general and the function of the altered gene in particular to justify the experiment at this time. It is difficult to assess the strength of these arguments without access to all the details of the experiment.

The recent developments demonstrate that all countries need to consider how to regulate this new technology appropriately, but blanket prohibition of germline modification or embryo research is not the solution. Although one may reasonably hold that germline modifications of viable embryos is currently premature, it is going to be impossible to get consensus for a view that research that can reliably correct disease causing genes in embryos should remain prohibited. In fact, the consensus statement of the Second Summit rejected such a blanket moratorium or prohibition. Although they concluded that “the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at this time”, they also urge “that it is time to define a rigorous, responsible translational pathway toward such trials.”

Specifically, this means that countries should move towards implementing national laws and regulations that will facilitate such a pathway. Unfortunately, very few countries seem prepared to do so.

Paradoxically, perhaps, even for the USA this may prove to be difficult. It is one of the few countries where there is no formal legal, nationwide, prohibition against germ line modification for clinical purposes, although in practice there is. This is partly because of limitations on what federal authorities can regulate and partly because of the political nature of the issues raised by these technologies. In the US there is a prohibition against federal funding of research on embryos. Such funding can, however, be done with private or state funding. FDA regulates clinical trials and has regulatory authority over somatic gene therapy, and would presumably also have regulatory authority over germline gene therapy. FDA, however, regulates market authorizations of the medicinal products, and can deny such authorization if the rules, including those that prohibit germline modification, have not been followed during research and development. Privately funded research where no such authorization is sought would fall outside the scope of FDA’s regulatory authority. This small opening is largely theoretical. More important is the fact that the strict rules governing federal funding and FDA regulations against germline modification, largely for political reasons, makes it difficult to implement more sensible rules in the US, that would allow some types of germ cell modifications to move forward towards clinical use, but prohibit others.

The other extreme are countries that have ratified the Oviedo Convention which is legally binding in many European countries, both within and outside of the EU. (Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine from 1997). The convention is legally binding in those countries that have signed and ratified it, and they include countries such as Denmark, France and the Czech Republic within the EU, and Norway and Turkey outside the EU. There are notable countries that have neither signed nor ratified the convention, such as Germany and the United Kingdom, and some countries that have signed, but not ratified the convention, such as the Netherlands and Sweden. There are two articles that taken together basically prohibit any research that modifies the human germline modification. Article 13 states that

An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.

Article 18 prohibits the creation of human embryos for research purposes. Research can therefore only be done on leftover embryos from IVF, which makes most basic research difficult.  Germany, which has not ratified the Oviedo convention, has an even stricter national prohibition both against germ line modification and most research on embryos in general, in the Embryonenschutzgesetz from 1990 (Act for the protection of embryos). Paragraph 2 of this Act makes it a criminal offense to produce and manipulate embryos that will not be maintained through a normal pregnancy. Paragraph 5 prohibits any germline modification.

This leaves only a few countries where it may be possible to develop an appropriate regulatory framework. They include countries that already have an accepted legal framework for embryo research and germline modification, such as Sweden and the UK. Although both of these countries are in the EU, they have not ratified the Oviedo convention, and they allow certain types of embryo research that involves germ line modification. Although in both countries it is currently prohibited to do germline modification of viable embryos, their regulatory structure makes it possible to relatively easily develop appropriate regulations for a pathway towards clinical use of the new tecniques.

In the UK, genetic editing of germ cells is regulated by the Human Fertilisation and Embryology Act of 1990. It basically prohibits any actions that create or manipulate human embryos except those that are approved by a licensing authority, the Human Fertilisation and Embryology Authority (HFEA). This is the independent national regulator of any treatment or research that involves the use of human embryos. Some activities are expressly forbidden by the Act itself, others are permitted under certain conditions. For example, embryos whose genome has been altered cannot be used for treatment purposes. Research on human embryos can only be carried out during the first 14 days. Research on human embryos, including genetic modification, can only be done for certain purposes. This regulatory framework is both strong enough to effectively prohibit certain types of research or clinical use, at the same time that it is flexible enough to be changed to allow appropriate modifications when that is warranted by scientific developments.

China is in many ways in a similar situation to the UK. There is currently a ban on genetic modification of viable embryos in the 2003 Guidelines. This prohibition was appropriate in 2003, but such a blanket prohibition needs now to be modified and clarified. The other problem is the absence in this Guideline of any effective oversight mechanism for such research and any sanctions for violations. China has, however, other regulations that can be used if suitably modified. First, there is the 2003 regulations for Assisted Reproductive Technologies (ART), issued by the Ministry of Health These include oversight and licensing of ART clinics, and have been used to close such clinics that are not in compliance with the rules. These could be strengthened and modified to apply to gene editing of embryos, similar to what is done in the UK. Second, there is the 2016 Ethics Review Measures for Biomedical Research Involving Human Beings. These require review by an approved research ethics committee for all health research, which does include embryo modification. These rules should also be strengthened. For example, one could explicitly require that certain types of research, such as modification of the embryo genome, should be reviewed by the provincial level or national committee of ethics experts. There is already a mechanism for such review in these regulations. And one could introduce a licensing and sanction system where only certain institutions are allowed to carry out such research, and/or only some ethics review committees can review such research. Sanctions for violations are already present in the rules. In addition, one would have to include basic principles and procedures for the review of such proposals.

There is a certain urgency to this task. China is now one of the leading countries for frontline genetic research. Fortunately, in China, there is available both a regulatory infrastructure and a vibrant community of scholars willing to have an open debate about these issues, which this latest case has demonstrated.

Dump Ethics Dumping!

In my previous blogs I have discussed two cases from the recently published book Ethics Dumping. Case Studies from North-South Collaborations. I have shown that the analysis of these two cases is flawed. Unfortunately, most of the other cases are not cases of what could reasonably be called Ethics Dumping. Basically, therefore, the project that was funded by the European Commission to illuminate an important issue for EC research policy is fundamentally flawed.

First a note about the definition of Ethics dumping.  The term dumping is taken from Economics where it describes the practice of exporting a product from one country to another, and selling it a much lower price in the receiving country so that local production suffers. It can also mean transporting (dangerous) waste from one country to another. The sending country may have strict environmental laws in order to protect their populations, which are absent in the receiving country which is typically poorer. Generally, therefore, dumping refers to an activity that provides some advantage to the person or country that does the dumping, and injures or makes the receiving country worse off.

The typical example of research ethics dumping would therefore be when a country carries out research in a poor country that harms the poor country or makes the poor country worse off, and that is carried out for the benefit of the rich country. The book, however, defines it more broadly, as intentional or unintentional exploitation of poor countries. Exploitation is, unfortunately, not defined by the authors. A standard definition is the following:

Action of treating someone unfairly in order to benefit from it

The essential part of this definition, which it shares with dumping, is that the person who does the dumping, or the exploitation, has to benefit from it. While the harm that occurs to the exploited or those who receive the products may not be intended or expected, the benefit that accrues to the exploiter or the dumper has to be expected or intended. The problem with the book is that the authors do not even attempt to show, for most of the cases, how they are supposed to benefit the sponsors of the research. In fact, most cases are examples of research that clearly are intended to benefit people in low and middle income countries.

The first case is about an NGO that undertook a research project on health seeking behavior for childhood diarrhea in a rural area in an African country. As is well known diarrheal diseases are important causes of death among children, and it is important to identify ways that will increase utilization of appropriate health care services. During the research it was discovered that one traditional treatment for diarrheal disease was genital mutilation for girls. This was unexpected. The research team decided to inform the authorities as the practice is illegal in the country, which created antagonism among the local population towards the NGO.

It is really hard to see why this should be a case of “Ethics dumping”: The project did cause unexpected harm, but it was not done in order to benefit the researcher or the funding country. On the contrary, the NGO clearly expected the project to benefit the receiving country only.

The third case in the book is about the personal experience of a local researcher who worked on a project among sex workers in a Nairobi slum. The person describes how the project has led to the empowerment of the women, and their inclusion in the decision making process. Basically, one has to conclude that this described a fairly successful research collaboration, and is not an example of ethics dumping at all.

The fourth case of the book is the cervical cancer screening trials in India that I have discussed at length. They also were not done for the benefit of rich countries, and therefore for that reason alone do not quality as examples of ethics dumping.

The fifth case in the book is about a phase I/II Ebola vaccine trial in an African country in early 2015. It was a Randomized Controlled Trial, with the active vaccine against placebo, recruiting both adults and children. The public protested and the trial was suspended. The authors of the case description argue the following:

• Members of the national ethics committee that approved the trial were not really independent of the government but would be expected to do what the Minister of the Public Health decreed.
• No justification was provided for inclusion of children in the study
• The informed consent process was deficient both in terms of the process and the content of the forms. This is the main part of the criticism of the trial

In addition, there is a description of a separate phase I trial that was carried out in Nova Scotia in Canada of a Canadian vaccine candidate. In contrast with the African trial that was suspended, the Canadian trial recruited lots of volunteers. The authors explain this as a difference in level of trust between researchers and potential trial subjects in the two countries.

Again, it may very well be that there was a lack of trust in the African country, and that the local ethics review was insufficient. But that does not make this an example of ethics dumping. It was carried out for the benefit of people in countries at risk for Ebola epidemics. In fact, it is an example of reverse dumping: Canadians being willing to take risk for the sake of developing a vaccine that is not going to be useful for them.

The sixth case is a trial testing a hepatitis B vaccine in Russia. The protocol was submitted to a local research ethics review committee. The vaccine was already approved in other countries and was marketed and available there. The trial in Russia would compare the “new” vaccine against one that was already available in the Russian market. The trial was labeled as a phase I/II study. It was claimed that the trial provided benefit to the participants because they would be protected against hepatitis B. The ethics review committee found among other things that there is no benefit to the participants since an approved hepatitis B vaccine is already available, and the participation in the trial involves a lot of inconvenience for the participants, and possible risks, especially for women who might get pregnant. The trial was therefore not approved by the committee.

One important fact is left out in this description, and that is the regulatory requirement in Russia that any drug or vaccine that is to be marketed in Russia needs to be tested out first on Russians. This was probably the most likely reason for carrying out a trial of a vaccine that was already known to be effective and approved in many other countries. Therefore, this case is also not a case of ethics dumping, done primarily for the benefit of sponsors. The problem is the irrationality of the Russian requirement, which it shares with some other countries, of having to do trials on their own subjects in order for products to be approved in the country.

The seventh case is a description of the general problem of recruitment of healthy volunteers for clinical research in low income settings. The point is made that one should be particularly careful to avoid exploitation so that participants are not recruited to high risk trials against their better judgment. This, of course, is a general and important issue, but again is not really an example of ethics dumping in itself.

The eighth case is an old case from China (1990s) that has already been well described in the literature. It is a complex case, and it is impossible to do justice to it here. The same holds for the second case in the book about the San research.

The next three cases take up important ethical challenges in various types of research, but they do not provide any clear cases of ethics dumping. They simply point out that in these areas it is possible to cause harm to local communities. The ninth case takes up the issue of use on non-human primates in research. The tenth case is about trials of transgenic fruit. The eleventh case concerns the use of mobile data collection methods. The twelfth case is about CRISPR research.

The thirteenth case is about an attempt to get retrospective approval for a research project in Liberia for an anthropological study of the psychosocial and economic consequences of survivors of Ebola disease. The study was carried out before ethics approval but the protocol was sent to the local ethics committee for approval after the data had been gathered. The ethics committee naturally rejected the application. Clearly this was unacceptable behavior by the (foreign) researcher, but it is not clear that it is a case of ethics dumping.

The fourteenth, and final case is the research injury case from China that I have already analyzed in a previous blog.

In conclusion, then, at most two of the fourteen cases presented in the book are examples of ethics dumping. This does not mean that the twelve other cases describe acceptable ethical practices. Of course it is not acceptable to seek retrospective approval for human subjects research. Or use informed consent forms that do not contain appropriate descriptions of the risk and the benefits of the research. Or provide high payments in order to recruit subjects to high risk research with no benefit to them. But these are wrongs no matter where the research occurs. The term ethics dumping was presumably introduced to identify an additional wrong: causing local harm or doing something unacceptable locally, in order to benefit us. The problem with the book is that it has not provided us with many examples of that practice. And at least some of the cases that are described do not identify any problematic practice at all, in spite of what is claimed about these cases (in particular the cervical cancer case, the research injury case described at length earlier, and some of the cases described here: The Nairobi sex worker case, and perhaps also the hepatitis B vaccine case from Russia).

Bias against transplantation policies in China among western bioethicists

During the past few years there have been relentless attacks by prominent, primarily Western bioethicists, against China’s transplantation policies. The central claim is extreme: Thousands of prisoners of conscience have been killed for their organs. For example, Wendy Rogers, professor of bioethics at Macquarie University in Australia, recently claimed that “Chinese prisoners of conscience, mainly Falun Gong practitioners, Uyghurs, house Christians and Tibetans, are murdered for their organs … <creating> a living organ bank where foreign patients and wealthy Chinese citizens can be matched to potential donors, who are then killed on demand so that their organs can be transplanted”. In a co-authored article, Arthur Caplan, professor of bioethics at New York University, and others claimed that “since 2006, mounting evidence suggests that prisoners of conscience are killed for their organs in China with the brutally persecuted Buddhist practice, Falun Gong, among others, being the primary target.”

These criticisms of China are published in academic bioethics journals by well-known scholars without any acknowledgment that reputable individuals and organizations have repeatedly concluded that there is no credible evidence for these claims. This has, unfortunately, led to the establishment of a very biased view on transplantation policies in China among western bioethicists.

Most of what is presented in support of the claims made in the bioethics literature originate from Falun Gong members. Many in the west think that Falun Gong is simply a religious practice emphasizing meditation and self-improvement, but that is not how it is viewed by those who have studied the movement. It was started in China by Li Hongzhi in the early 1990s. It is variously described as a religion, a spiritual practice or a cult. It is well documented that its founder has propagated a high number of fringe ideas and what are generally believed to be objectionable moral ideals. These include such the views that human civilization is being invaded by aliens with the aim of destroying it, that disease can be cured by spiritual practices, and that mixed race marriages are evil. Many of its followers downplay these ideas and it is not clear whether this is for strategic reasons or that they genuinely believe that these are not central to the movement’s beliefs. Falun Gong runs a number of news outlets, such as the Epoch Times, also with a German version. The German Epochtimes has at least at times spread rumors associated with right wing propaganda against immigrant groups. In spite of these shady associations Falun Gong has been spectacularly successful at capturing the support of liberal and progressive groups in the west, also among academics, who regard Falun Gong members as suffering persecution in China because of genuine religious beliefs. It helps, of course, that its followers see themselves as staunch enemies of China’s Communist Party which is particularly useful if one wants to create a positive image among politicians and the public in the US.

The Chinese government has cracked down on the activities of the group in China, because of an understandable fear, based on a number of such episodes in the past couple of hundred years, that a mass movement such as Falun Gong can cause severe social instability. This has led to imprisonment of a high number of Falun Gong followers, based on laws against “disturbing public order”. While it may be legitimate to criticize such punitive measures as over-reactions by the government, it would be wrong to claim that such actions by the government are interference in “religious freedom”.  Falun Gong is similar to western movements such as Scientology which has also been seen as non-religious by authorities in for example Germany. Or one may mention examples of the restrictions by Western and other governments on certain muslim groups that also claim to be religious, justified with reference to the need to national security. Interestingly enough the Falun Gong movement was at first to a certain extent supported by the Chinese authorities as a way to encourage local spiritual practices as opposed to practices originating from outside of China. Once it became clear that the group was anti-science and in particular propagated fringe ideas about medical treatment, the authorities cracked down on the practice. This led to widespread protests among the followers, and then to the subsequent arrests in order to limit its influence. The authorities have been successful in limiting its influence in China. The attention the group has received outside of China as a persecuted religious group by communist China, and as victim of organ harvesting, has greatly enhanced their standing in the west.

The claim about organ harvesting got the attention of politicians and news outlets after a report published by David Kilgour (former member of the Canadian Parliament) and David Matas (a human rights lawyer) in 2006. Ethan Gutman, a journalist, made similar claims a bit later, and they jointly published an updated report in 2016. In these reports, they present evidence that they think proves that there has been, and continues to be, widespread killing of Falun Gong members for their organs in China.

There is no disagreement, and the Chinese government has confirmed this, that the main source or organs in China until at least 2010 was from executed prisoners. There is also no disagreement that unacceptable practices have occurred in China, such as illegal trade in organs and unacceptable transplant procedures in general. There is also no disagreement that some of these practices continue today. In fact, the government of China has attempted to crack down on low quality transplant centers and organ trafficking , and have sanctioned and punished both institutions and individuals for violating China’s transplantation laws and regulations. The controversial claim is that a high number of Falun Gong practitioners, with a “best estimate” of 65000 in about a decade starting in 2000, have been kept in prisons and killed on demand for their organs. According to these critics there are several pieces of evidence for this claim, some of which are:

·       Interviews with detainees, security personnel and others

·       Phone calls to institutions pretending to be persons who seek an organ for transplantation and asking whether a “Falun Gong organ” is available, with what is claimed to be affirmative answers

·       Short wait times for organs with a matched organ being available a short time after a request has been made

·       A mismatch between the number of transplanted organs and the number of judicial executions

All of this is at best circumstantial evidence. The interview and phone call evidence are also clearly biased and open to other, more plausible explanations. The short wait time is evidence for the use of organs from executed prisoners in general, which has not been denied by Chinese authorities. This leaves only the evidence that the number of transplanted organs in the period between 2000 and 2010 exceed the number of organs available from judicial executions (executions after a due process according to Chinese law). This evidence is also problematic because there are no reliable, generally available, figures for executions nor for the number of transplants in China up until around 2010. All of the claims made on the basis of these numbers are therefore to a large degree speculative. Although a number of parliamentary declarations affirming the claims have been adopted both in North-America and Europe, it is significant that independent attempts to corroborate the evidence by official groups have failed. For example, the NewZealand Foreign Affairs, Defence and Trade Committee concluded in 2011

The New Zealand Government investigated allegations made by Falun Gong of illegal organ harvesting from Falun Gong practitioners after they surfaced in March 2006 in a report written by Canadians David Kilgour and David Matas, and publicised through the Falun Gong publication Epoch Times. Neither committee members nor the Government are aware of any independent evidence verifying the Falun Gong claims on organ harvesting. This conclusion is based on both New Zealand and foreign inquiries. New Zealand officials discussed the allegations with Kilgour and Matas; the office of the United Nations Special Rapporteur on torture; human rights non-governmental organisations; and other countries interested in the human rights situation in China. Other international organisations also attempted to verify whether the claims on organ harvesting made in the Kilgour/Matas report had substance. This included a significant US State Department investigation that concluded that there was no evidence of the practice. Officials are not aware of any independent assessment that supports the Falun Gong’s claims of forced organ harvesting

Independent of what may or may not have happened in the early 2000s, there is agreement that there have been substantial reforms in China, both in terms of the number of executions and the system of organ procurement and transplantation, that began in the late 2000s. Beginning in 2005 all death sentences needed to be reviewed by the Supreme People’s Court, resulting in a gradual, but steady and significant, decline in the number of executions.  In 2007 a new regulation on Human Organ Transplantation was enacted, and in 2010 “organ trafficking” was made a crime. A nationwide organ donation program was introduced nationwide in 2013 with the Provisions on Human Organ Procurement and Allocation coming into force. In 2015 the chair of China’s National Organ Donation and Transplantation Committee, and a driving force between the reform program that began in 2005, announced that organs for executed prisoners should no longer be used. As a result of these developments registration and quality controls of donation and transplantation programs have improved dramatically in China, and there has been a crackdown on unacceptable practices such as black market sale of organs and transplant tourism. Given the size of the country nobody can claim that unacceptable practices do not still occur, as they do in many other countries, also in the west.

Independent outside observers who are familiar with the situation in China all confirm that there is now in place a transparent organ procurement and distribution program in the country, and that there is no government sanctioned black market in organs. This includes representatives from the World Health Organization and prominent transplant surgeons from theUS with extensive experience in China. A major piece recently published in the Washington Post also confirmed that the policy change in China has been successful. In spite of this, the critics continue to claim that the practice of killing Falun Gong followers for their organs continues in China (as is evident in the present tense in the quotations above). No new evidence is presented. One major piece of evidence presented in the Washington Post piece is that there is a close match between the official transplant numbers and the sale of immunosuppression drugs used by patients who have received organs. This has been contested by the critics, but the Washington Post has in their reply maintained the accuracy of their original claim.

Not only do the prominent bioethicists make the outlandish claim that thousands of people in China are being killed for their organs based on little or no credible evidence, there have also been attempts to censor articles written by Chinese bioethicists about issues related to transplantation.

When a short piece announcing the new policy ending use of death row prisoners as a source of transplanted organs was published in the Journal of Medical Ethics in 2016, professor Rogers and coauthors demanded a retraction of the article because of what they claimed were misleading statements about the situation in China. The journal did not accept the demand for a retraction, but instead required that the authors post a “correction” to their original piece, at the same time they allowed a “rebuttal” by the criticizing authors. The main correction required was a change from the claim that China had introduced a “law” to prohibit death row organ donation to “a guideline”. This labeling issue is completely beside the point, because it is difficult to translate exactly what the status of a particular piece of Chinese government action is using appropriate English terms for the corresponding Chinese ones. The piece by Rogers and co-workers merely repeated the same exaggerated and unsubstantiated claims made earlier.

When other authors tried to publish a paper in 2014 on attitudes towards cadaveric organ donation among medical and non-medical students in China, the journal, Transplantation, received a letter to the editor criticizing the article for failing to take into account the political situation of organ donation in China, presumably meaning failing to take into account what the authors of the letter think are unethical transplantation practices. There is no particular reason why the authors of a paper reporting the results of an empirical study of attitudes towards cadaveric organ donation should also discuss the issue of use of organs from death row prisoners. The authors refused to have their paper published alongside such a letter to the editor, and therefore decided to retract the paper. Although the critical letter has not been published it is fair to assume that it repeated the same unsubstantiated claims made earlier. The decision by Zhang et al is therefore perfectly understandable, but it is sad to observe the power of a small group of individuals to set the agenda for the debate in the journal literature.

Given the current climate of anti-China sentiment in the West there is little hope that we will see a more balanced reporting of what happens in China. One can still hope, though, that at least some Bioethics journals are willing to consider articles that present a more balanced description of current developments in China.

Justification for no intervention controls in the cervical cancer screening trials in India

The crucial point of disagreement is whether the placebo trials were really necessary to answer the policy relevant question: Could equivalence trials answer give policy makers the answers that they need? The Indian researchers, their funders, and WHO have clearly endorsed the randomized controlled trials with no screening in the control group. The critics disagree. What are the arguments?

Those who defend the trials claim that a local standard of care is necessary because that is to only way to obtain scientifically valid results. The critics, including Ruth Macklin, argue that all arms in a trial should get some form of cervical cancer screening. Again, it is Macklin who provides the argument. It is worth quoting at length from professor Macklin’s paper where she spells out this argument in detail:

It is simply not true that “only a ‘no care’ control arm can give definitive results.” Although the randomised controlled trial is the “gold standard” in clinical research methodology, this does not mean that the control arm must be a placebo. In settings in which the standard diagnostic method is a proven intervention and researchers want to test a new method, or even a less expensive method, it would be unethical to withhold the proven diagnostic method from the participants. The research design would then be a non-inferiority trial, which would test the experimental procedure against the proven intervention to see whether the former is as good (or almost as good) as the latter. That is a perfectly acceptable research design, although it would involve more research subjects and take longer than a placebo-controlled trial. The idea that it is ethically acceptable to design a study in resource-poor settings in which the participants do not have access to a proven diagnostic method outside the trial is flawed. If researchers in India wanted to study VIA to determine whether it is as good (or almost as good) as the Pap smear, they could do so in a tertiary care setting which has the equipment and trained personnel to allow for the routine use of the cytology-based screening method. Using the existing baseline data on the incidence of cervical cancer in India, the efficacy of the experimental method (VIA) could then be ascertained [My emphasis]

It is certainly true that a non-inferiority trial can be designed to establish that a new intervention is or is not equivalent or non-inferior to an existing intervention. The question is whether this design is appropriate in this case for the purpose of answering the question policy makers have. This depends on how we can interpret the results of such a trial. Let us proceed separately with the two possible scenarios, first that the trial establishes that the two interventions are equivalent, and second that they are not.

If the trial establishes that the two interventions are equivalent, we cannot from that fact alone conclude that the new intervention is generally effective due to a problem that Susan Ellenberg and Bob Temple  have identified as lack of assay-sensitivity. This is the ability of a test (clinical trial) to identify an effect reliably. If an equivalence trial demonstrates that two interventions have a similar effect, we can only conclude that the new intervention is actually effective if it is known that the control intervention is effective. In the case of cervical screening trials the only intervention that was identified as effective was systematic screening every three years for at least a decade. An equivalence trial would have to include this intervention as a control if we want the trial to establish equivalence to a known effective intervention. The active intervention arm, however, would likely only include a single screening visit, as this is the feasible policy option to be tested. But it is highly unlikely that any trial would establish the equivalence between this intervention and the worldwide best standard of care. A trial that aims to establish equivalence would therefore be a complete waste of resources. The only sensible aim and outcome is therefore a trial that establishes that the new intervention is inferior to the established intervention.

If the trial establishes that the two interventions are not equivalent, i.e. that the difference between the standard intervention and new intervention is greater than what has been identified as clinically significant, we can indeed conclude that the new intervention is inferior to the established intervention. But that does not mean that we automatically should reject the new intervention as unsuitable in a low income setting: even though it is inferior to the best current intervention. Policy makers in resource poor settings need to know how much better the new intervention is to what is available locally now. If the trial had included an arm with the local intervention, the trial data would allow us to say something about that. In the absence of such an arm in the equivalence trial, we have to use, as Macklin points out, “existing baseline data” as a comparator, and make the assumption that these data are the same as we would have found had we included a control arm in the population under study. This study would basically then have the status of a regular historical control study, and we have seen in the previous post that such data were not sufficient to establish the effectiveness of VIA. 

An equivalence trial will therefore simply not provide the knowledge that policy makers want. They do not want to know how VIA done under ideal conditions compare with PAP smear screening, i.e. done every three year with access to high quality labs. Nor do they want to know how VIA done under field conditions compares with PAP smears done under field conditions. PAP smears done under these conditions may be ineffective: establishing that PAP smear is equivalent to VIA does not establish the effectiveness of VIA. Macklin’s proposal will simply not provide us with any useful results. What we do want to know is how effective VIA is done in field conditions, with testing once or only a few times, not regularly every three years. The reason for this is directly linked to the two problems pointed out with regard to equivalence trials: the effect of VIA varies enormously with regard to how it is carried out, and the relevant comparison is not how VIA done under ideal conditions compares with PAP smears under ideal conditions, but how effective a feasible VIA screening program compares with the current situation of no screening. If that is what we want to know, then we have to have a no-intervention control.

An examination of the results of the three trials supports this analysis. The first trial was published in 2007. It demonstrated that a single VIA screening caused a 35% reduction in deaths from cervical cancer. This is a significant reduction, especially because of the simplicity of the intervention. Had they used any PAP smear intervention in the control arm, it is likely that the results would be uninterpretable. Use of a single PAP smear might have shown no difference between PAP smears and VIA, or that PAP smear screening was inferior.  Since very little is known about the effectiveness of a single PAP smear, the trial results provide no useful policy advice. The results of the second reported trial confirm this analysis. This trial had four arms, one with PAP smears, one with VIA, one with HPV testing and one control. It only found that HPV testing was effective in reducing cancer. Both PAP and VIA were not effective compared with the control group. Had the trial not included a control group we would have correctly concluded that HPV testing is more effective than PAP and VIA, in line with the argument presented by Macklin for an equivalence trial. But we would also have concluded that VIA is effective, because it is assumed that PAP is effective, and there was no difference between them. It turns out, nor surprisingly, that two screening method used in this trial, using PAP and VIA, is not effective at all, even though, under ideal conditions they might be.

In 2009, then, there are results of two trials, one showing that a single screening is effective, one showing that it is not. It is not clear why there is this difference between the two trials. But it does show that how VIA is implemented is crucial for its effect, including any follow up treatment on the basis of a positive result. To repeat the obvious, one simply cannot rely on data from outside a particular trial to infer what the results would be for the trial subjects had one used a particular intervention, or no intervention.

The results of the final and third trial was published in 2014. It was the publication of these results that prompted the last round of criticism in the Indian Journal of Medical Ethics. It demonstrated that screening four times with VIA reduced cancer mortality by 30%, showing that a relatively simple intervention, but still less than PAP smears every three years, could have a dramatic effect on cervical cancer mortality. This is a result that simply could not have been know without the results from this trial, and without a control group with no intervention.

Perhaps what is most damaging for the critics is that any alternative design would also expose a significant number of women to known inferior screening programs, without yielding any useful results. No research design avoids exposing women to known inferior interventions, but only a placebo control trial can provide knowledge useful for policy. Having a state of the art control group in the three trials discussed here would have exposed all the other women in the trial to what is known to be an inferior screening program. Having a truncated Pap smear screening program in the control group would expose all women to known inferior treatments. 

Therefore, even if we agree that these trials provided results that are essential for policy, it does not follow directly from this that the trials were justified. We also have to argue that we are not exposing the individuals in the trial to unjustified risk. Even those who advocate equivalence trials have to do this, since they also expose individuals to known inferior interventions. What alternatives are there in 1998? There is no national screening program. Only the wealthy and educated in India have access to cervical screening programs. There are no plans to introduce any national screening program, and there is agreement that the known, effective screening program, Pap-smears, is unimplementable in the foreseeable future. In fact, 20 years later there is still no national screening program in India. In 1998 there was agreement that more research is necessary to identify a suitable screening program. 

The challenge for the critics is that any research design will expose a large group of people to a known inferior screening program.  And if the design of these trials is not able to answer the policy question, then the critics are exposing all these women to an inferior intervention for no good reason whatsoever. The only way to avoid exposing women to known inferior interventions is to do no research at all. But that would mean that no women get access to something that may be of benefit to them. Doing the research will at least save some lives, even in the control group because of the increased monitoring of this group, and useful knowledge is generated that may be used to benefit future women. Finally, even with a no intervention control group, no woman in the control group is denied any treatment that they would be able to get outside of the clinical trial.

Let me conclude this examination of the ethics of the cervical cancer screening trials by making a few remarks. Most people intuitively object to having no intervention in a control group when there is an effective intervention available, even somewhere else. In an ideal world everyone should have access to useful interventions. However, it should also matter morally whether a given scientific design actually produces useful results, and whether alternative designs allow us to avoid the moral challenge of providing everyone with known effective interventions. The role of bioethicists should be to examine carefully the arguments provided by those who argue in favor of having a no intervention control arm. It is simply not acceptable to simple refer to the Helsinki Declaration, and think that this settles the question of the suitability of alternative scientific designs, in the way that writers in the Indian Journal of Medical Ethics and the Ethics Dumping project tend to do. Once it is clear what the scientific issues are, it is still necessary to weigh the harms and benefits of alternative courses of actions, and then reach a conclusion about how to proceed. But simply claiming that it was already known in 2000 that VIA was an effective screening method, or that equivalence trials can answer the relevant policy questions, do not change the empirical facts that are needed to make morally sound judgments.

Justification for the cervical cancer screening trials in India

What did policy makers need to know in the 1990s?

In the 1990s the established screening method for cervical cancer in developed countries was regular Pap smears. This method is not particularly sensitive, i.e. it misses a relatively high number of potential cancers. The Pap smears therefore need to be done at regular intervals, such as every two or three years. This method also requires highly specialized labs, and highly skilled personnel to interpret the microscopic images. Finally, the women need to come back again to get the results and to get treatment if necessary. If the screening program is carried out with appropriate facilities and personnel, and women come in for regular screening every two to three years between the ages of 20 to 60, the program is effective. Women in India who would follow the recommended procedures, and had access to high quality labs, would have access to an effective diagnostic tool. But there was, and still is, near consensus among experts that at the current stage of development of India, both in general and in its health system, it would not be appropriate to introduce regular Pap smears as a general population based screening program.

In the 1990s researchers were trying to identify a simpler screening tool, that requires fewer visits to clinics, less sophisticated clinics, and personnel that can get the necessary skills with less extensive training.  One such method is visual inspection after application of acetic acid (VIA). This requires less infrastructure both in terms of labs and personnel, and the screening and treatment (cryotherapy) can be done in one visit. Around 2000 VIA was seen as a promising method in low-income settings, but there were worries about its low specificity: it would lead to overdiagnosis and therefore unnecessary treatments. That is, doing VIA once was better at detecting cancers than Pap smears, but less specific, underscoring the previous emphasis on the need to do repeated tests conscientiously in order for a Pap smear screening program to be effective.

Policy makers who want to decide on any alternative screening programs, such as VIA, need to know the answers to two questions:

1. Do we know enough about alternative screening programs to recommend population wide implementation in India?
2.  If we do not know enough, what additional knowledge is needed, and how do we go about getting that knowledge? 

Was it already known in 2000 that cheaper screening methods were effective?

Ruth Macklin has attempted to provide arguments that address the two questions. Her first claim is that it was already known around 2000 that VIA was effective. Therefore, any clinical trial that investigated the effectiveness of VIA was unnecessary, and therefore unethical. Policy makers already know enough to implement VIA as a population based screening method. Her main argument to back up her claim is a report published by WHO in 2002:

The efficacy of VIA was already well established. According to a World Health Organisation (WHO) consultation report in 2002, “The test performance of VIA suggests that it has similar sensitivity to that of cervical cytology in detecting CIN, but has lower specificity. Further research is required to improve its specificity without compromising sensitivity” (2). The WHO report also pointed out the need for training personnel in the use of the method, as well as that for developing standard procedures for quality control. Also needed at the time was research on the development of a simple scoring system to objectively report the results of VIA. However, the important point is that the efficacy of VIA as a screening method had already been established when these trials were conducted in India.[My emphasis]

The problem is that Macklin seriously misrepresents what the WHO report actually says. Here is a statement that Macklin has decided not to refer to:

Information on test characteristics alone does not suffice for making decisions regarding whether VIA may be adapted for use in population-based organized screening programmes in routine public health practice. Evidence on its comparative efficacy and cost-effectiveness versus cytology screening in reducing incidence and/or mortality, as well as information on short-term and long-term consequences arising from decisions taken based on screening test outcomes, is essential for recommendations leading to public health policies. Such evidence may ideally be generated from randomized controlled trials.

According to Macklin, and against WHO, the only type of trial that what was needed at that time was either an implementation trial or a demonstration project. For Macklin, implementation research is

A study design that compares cancer rates following the introduction of VIA in urban wards or rural primary health centres with the past rates of cancer among women who used the same health facilities before VIA was introduced [and it] could provide results demonstrating that the implementation of the new technique was successful

Macklin gives an example of a demonstration project in several African countries where a screening program using VIA and cryotherapy was introduced. Quoting from the report from the project, Macklin goes on to say that

This demonstration project has shown that the ‘screen and treat’ approach can be introduced into existing reproductive health services in low-resource countries. Screening for precancerous lesions using VIA and treatment with cryotherapy is acceptable and feasible at low level health facilities in six African countries

The problem is again that Macklin seriously misinterprets the results of this demonstration project. Fewer than 10% of eligible women in the areas targeted were actually screened. Of the around 1000 who were scheduled for cryotherapy 600 were lost to follow up. Of the 326 women who were identified as having serious lesions requiring treatment, only 96 were followed up. The demonstration project showed that one could implement a screening program, but not a very successful one. The problems in the project were precisely those raised in a 2002 WHO report: There was no evidence that VIA could identify cancer cases reliably in a population wide screening program, because one does not know if such a program will achieve high enough follow up rates of the screened women, and therefore does not know if the program will achieve its goal, reducing the number of cervical cancer cases in the screened population.

As is evident in the WHO recommendations published in 2002 there was general agreement that the evidence was NOT sufficient for implementation of a policy of nationwide screening in a country such as India, and existing mentioned above confirms that. Contrary to what Macklin claim, the 2002 actually endorses the three Indian trials as necessary to obtain knowledge for policy, in addition to, and not instead of, demonstration projects. Here is the full quotation:

Currently, there are three large randomized trials ongoing in India (Dindigul district, Tamil Nadu; Mumbai (Bombay) city and Osmanabad district, Maharashtra) that are addressing the efficacy of VIA screening in reducing the incidence of and mortality from cervical cancer. The programme in Osmanabad district addresses the comparative efficacy of conventional cytology, VIA and HPV testing. The programmes in Dindigul district and Mumbai address the efficacy of VIA in reducing the incidence of cervical cancer. A three-arm, prospective randomized intervention trial in South Africa is currently addressing the comparative safety, acceptability and efficacy of screening women with VIA and HPV DNA testing. This trial is also investigating the effects of immediately treating women who screen positive with cryotherapy, performed by nurses in a primary health care setting. Outcome measures include reduction of high-grade cervical cancer precursors in treated versus untreated women, followed over a 12-month period. A large demonstration project of VIA, which is ongoing in the San Martin region of Peru, aims to investigate the effectiveness and acceptability of VIA integrated with the health services. Those screening positive by VIA are referred for magnified visual inspection after application of acetic acid (VIAM) and immediate biopsy and cryotherapy are provided if indicated by VIAM. A similar intervention involving VIA and VIAM has been initiated in Western Kenya. These studies are likely to provide the required evidence on the longitudinally-derived sensitivity and the cost-effectiveness of VIA in decreasing cervical cancer incidence and mortality.

It should therefore be abundantly clear that there is not enough evidence in 2000 to implement large scale population based screening methods in low- and middle-income countries such as India. It is only by selective quotations from a key 2002 WHO guidance document that Macklin can make her case.

In my next blog I will examine the second, and more important question of relevance for policy makers: If not enough is known about the value of alternative screening methods, what type of research is needed? Specifically, what should be the control group in a Randomized Clinical Trial?

The cervical cancer screening trials in India

Over the next few weeks I will post an analysis of the criticism made by several authors associated with the Indian Journal of Medical Ethics against three trials in India to test various screening methods to prevent cervical cancer. The reason is that these trials have been used by the Ethics Dumping Project funded by the European Commission as paradigmatic examples of unethical research. They also form an important backdrop to the recent controversy over articles published by the same journal by vaccine critics, notably of the HPV vaccine. It is remarkable that these attacks on scientific research in the name of ethics are against interventions that have the potential to improve the health of women.

On April 21, 2014 this headline appeared in the Times of India: “Row over clinical trial as 254 women die”. The newspaper claims that the women in several US funded trials on the prevention of cervical cancer died because they were part of a control group of 140,000 women that did not receive any screening method. According to the critics the trials were unethical because the women in the control group should have received one of the available, proven effective cancer screening methods. Denying them access caused the unnecessary deaths. One of the critics, writing in the Indian Journal of Medical Ethics, pointed out that “these studies would not have been permitted in the country of the funding organizations (US National Cancer Institute and the Bill and Melinda Gates Foundation”.

In parallel, a US physician, Eric Suba, filed a complaint with the US Office of Human Research Protection (OHRP), charging that these trials were unethical because they did not provide any effective screening in the control groups. OHRP did not find any violation of the US regulations in the design of the studies (which was the basis for the criticism). However, they did conclude that the informed consent form in one of the trials was defective. The form did not adequately inform the participants about alternatives for screening outside of the clinical trial. The English version of the informed consent form did contain language that effective screening was available in clinics and the women could avail themselves of this opportunity. The translated local version did not contain this information.

The Indian Journal of Medical Ethics has carried a number of critical articles about these trials over the years. A respected bioethicist, Ruth Macklin, has strongly supported their arguments in the same journal. The EU funded and endorsed project on “Ethics dumping” has flagged these trials as typical examples of unethical practice. So how can this be? Trials funded by major organizations, endorsed by respected scientists in India, approved by Ethics Review Committees in India, reviewed by the main regulatory body in the US without any comments on the design, have nevertheless been criticized by the main bioethics journal in India, respected international bioethicists, and by a project endorsed and funded by the European Commission. Also, international organizations such as WHO have endorsed the trials as providing important results directly relevant for policies in low- and middle-income countries. It is clearly important to be clear about which version is true: Should these trials never have started? Or did they provide knowledge essential for public policy and not procurable by any other design? I will examine these questions in several posts of the next few weeks.

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.

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).