A study was submitted that reported the prevalence of an intestinal infection in a tribal community. The authors did not obtain informed individual consent for stool collection from the study participants; instead they obtained consent from the leaders of each village. The study protocol was approved by the national IRB, but the protocol made no specific mention of stool collection—it referred to a study of a respiratory infection and “interdisciplinary research”, so we are unclear if the IRB knew that such collection would take place. The authors had obtained a permit for research from the country’s “national foundation”.
The handling editors, who work in the country in which this study took place, and who are very familiar with the national laws on conducting health research in tribal communities, state that:
(1) The law makes it clear that while obtaining prior consent from community leaders is very good practice, it should not dispense with efforts to obtain individual consent.
(2) Every individual must give consent; illiterate individuals should give a digital print.
We wrote to the authors to ask why they did not obtain individual consent, and whether the national IRB had approved the stool collection. We asked to see the protocol approved by the IRB.
They explained that they had published nine papers arising from this work, no journal had ever questioned them on ethical oversight (or asked to see the study protocol) and they are the only doctors to have ever offered this tribe any medical treatment. They withdrew their paper in protest.
There was obviously some ethics oversight here—ie, (1) there was national IRB approval of a related study (and perhaps the use of the word “interdisciplinary” gave the researchers license to include stool collection); (2) the village leaders gave consent; (3) the authors had some type of research permit allowing entry to tribal communities. But the editors remain concerned that: (i) national law clearly states that community leaders’ consent should not replace individual consent; (ii) it is not clear whether the IRB specifically approved the stool collection; and (iii) providing a medical service to this community arguably made it even more crucial to obtain individual consent (since provision of care might be coercive in this situation, especially if it was conditional on agreeing to be in the study). On receiving the letter from the authors withdrawing the paper, we wrote to them to share these concerns, but the authors never replied.
Does COPE feel that the editors have any further obligations?
The case caused much debate. Some argued that there was a significant ethical violation and the criteria for consent had not been met, certainly by UK or US standards. This is evident from the authors’ indignant response and their unconvincing explanations. Others argued that the editor has done enough and should not pursue the matter. It is unlikely that the patients came to any harm and the editor has taken the matter as far as he can. However, others argued in favour of contacting the IRB and the authors’ institutions as the paper, although rejected by the editor, could be submitted for publication to another journal. All agreed that this was a difficult case and the ideal solution would be to have constructive dialogue with the authors regarding the issues, but most felt this was unlikely to be achieveable.
Given the lack of consensus of the COPE Forum regarding whether or not we should pursue this case further, the editors handling the paper did not in the end contact the IRB. They have already explained to the authors their concerns about the consent process, and feel that this was probably sufficient. They consider the case now closed.
We received a paper reporting on the outcomes of treatment of an individual with obsessive–compulsive disorder and body dysmorphic disorder, which seemed not to respond to standard treatment. Following ethical review and approval, and individual consent, the individual was treated with several distinct courses of an experimental therapy. The individual’s clinical and family history, and their outcomes in response to the experimental therapy, were detailed in the paper. The editors felt that sufficient details were included to potentially identify the patient, so as outlined in our editorial policies, we asked the authors to obtain signed consent to publication from the patient.
The authors responded that they had attempted to remove all identifiers from the paper (although the editors felt that very substantial and identifying details remained), and that revealing the patient’s identity to the editorial office would violate their clinical protocol, and the principle of patient anonymity. The editors discussed this and felt that it was still very important that the patient have read the paper and agreed to its publication; secondly however, we were concerned about the journal having access to (and our ability to keep confidential) the patients’ names. We also wondered whether under HIPAA law it would even be legal for the authors to give us the patient’s identity.
Therefore, the editors proposed that we would ask the author to have the patient (or patient’s parents) sign our consent-to-publication form, and then include in the paper a statement that they had done so, but that we stop asking authors to send us copies of these forms and simply rely on the authors’ word instead. Is this acceptable?
The Forum agreed that this was a curious case and raised issues relating to HIPAA law. Some argued that there is no need for a journal to know the identity of the patients reported in case reports. The authors could be asked for a statement that they have followed the correct procedures and obtained consent from the patient. But there is no need for the journal to see the consent form and hence no need to reveal the identity of the patient. If a problem arises in the future, the journal would have a reasonable defence as the onus would be on the authors to have obtained consent. The editor could request a signed assertion from the authors that they have obtained consent. Although the journal’s own consent form can be used, the Forum noted that it would be very useful to have a generic consent form so that patients need only sign a form once in the event that the paper is rejected by one journal and submitted to another journal. The Forum agreed that the editor’s proposed course of action is acceptable.
The authors were asked to confirm in their paper that the patient had seen the manuscript and agreed to its publication in an open access journal, and also to require the patient to sign our consent form, which should then be filed in case notes, but not sent to the journal. The authors did so and the manuscript went out to peer review. It was later rejected on scientific grounds. The editors discussed changing journal policy in light of this case to require that authors document, for such papers, that patients have seen the submitted paper and agreed that it could be published, and to cease requiring that authors send copies of consent forms which had been signed by patients. It was agreed to change policy along these lines and the changes are currently being made to our instructions for authors.
After a number of appeals and revisions, and having satisfied ourselves about the results being “too good to be true”, we eventually accepted a paper. In September 2007, we received a letter from the head of the institute (and also a member of the university ethics committee) expressing concern about the paper. The allegations were: the funding source could not be that acknowledged; the authors affiliations were not correct (some authors who were stated as being at his institute had never been members); and the trial had not been submitted to the local ethics committee. The authors provided us with a document signed by the head of the institute (complainant) stating that the author in question had been a member of his institute in the year that the trial was conducted. They also provided legal advice that they had complied completely with the law in force at the time of the trial. This was verified by the Minister of Health who sent a letter saying he had approved the trial as required by law. The authors acknowledged that the funding was erroneously attributed.
We are publishing a correction that makes clear the authors’ affiliations and the funding source, but we have no further concerns about ethics approval.
The Forum agreed that the editor had done everything he should and had followed the correct course of action.
June 2008 This case was brought to our attention by the head of institute (and member of the ethics committee) who told us that authors affiliations were incorrect and that ethics approval had not been appropriately sought. Our investigation suggested that ethics approval did meet the legal requirements and we stated in the previous report that we had no further concerns about the ethics of the study. Now new problems have become apparent.
It seems that there is a difference in legal opinion about the ethics approval requirements in force at the time of the study. There appear to be inconsistencies in the timings of submissions and approvals. Furthermore, there is currently a legal case against the authors concerning consent.
We have issued an expression of concern and are awaiting the outcomes of the court case and other investigations.
August 2008 We issued an expression of concern as we were made aware that there has been an investigation launched into the conduct of the study (after a patient’s court case and a parliamentary question) and that the trial registration number was invalid. The investigation has now been concluded. We are studying this at the moment and are considering taking further steps.
The editor told the Forum that the journal has now issued a retraction of the paper and published an accompanying editorial on co-authors’ responsibilities. The corresponding author still denies any wrong doing and the co-authors are claiming it has “nothing to do with them”. The Dean of the institute has been dismissed.
Professor A and professor B has been in a dispute over a certain type of treatment for over 15 years. Professor A has accused professor B of killing a patient while he was (in professor A’s view) doing research on the patient without consent. Professor B has accused professor A of research and publication misconduct because he published a paper in journal X in 1994 that included a selected group of patients from a paper already published and a selected group of patients from professor A’s hospital that had not given consent to be part of a research project. Professor A has claimed that his patients were not part of a research project, since the treatment he gave them was available to all at that time. Both cases were handled by the national board of research misconduct at the time (in 1996). The conclusion (briefly) was that none of them had behaved unethically, but that they could have done it differently.
Last year this debate “reopened” when professor A published a book were he portrayed himself as a whistleblower and told about how the hospital and the medical community had tried to “hide” the fact that professor B had in fact killed a patient while he was doing research on the patient without consent. In the debate that followed, several things were written from both “sides”. In professor B’s opinion, professor A has throughout this last debate actually admitted that the patients he included in his 1994 paper were part of a research project and that they had not given consent. He now asks the editor of journal X to retract this paper. What should the editor do?
The Forum agreed that there were no grounds for retraction of the paper. Given the very public nature of this case and the fact that it has been thoroughly aired in the public domain, the advice was to do nothing. The editor should consider the case closed. The Forum also advised against publishing any more letters of correspondence.
We received a paper describing the results of an analysis of pathogen gene sequences from patients who had been given an investigational drug as treatment for their infection. The study had been done in Europe. One reviewer said that the paper did not explain whether the patients had been treated in the context of a trial or not and that no information about study sponsorship, ethical approval or patient consent had been included.
The reviewer was concerned that an attempt was being made to publish data without the approval of the trial sponsors. The editors rejected the paper but recommended that the authors submit it to a sister journal at the same publishing company, but that they would need to address all of the points raised. The paper was then submitted separately to the sister journal but without any response to the reviewer’s points. The authors eventually explained that the patients in this study had been enrolled in an expanded access program for the investigational drug, which was underwritten by governmental sources. This was not regarded as a trial, and the authors explained that gene sequencing was carried out as part of routine clinical care, following national treatment guidelines.
The editors felt that there were insufficient grounds for them to follow-up further, and decided to withdraw the paper from consideration at the sister journal, recommending that the authors describe the context for the study more fully in their paper when they prepare it for publication elsewhere.
Should we have done more; is it reasonable that ethical approval and informed consent would not be needed for this study?
The Forum commented that this is probably an example of different rules for ethical approval in different countries. This would seem to be the issue here. The Forum agreed that no further action was required and that the matter should not be pursued.
The journal followed the COPE Forum’s advice and did not take further action.
We published a paper in the journal which reported on microarray expression profiling of cell lines from a specific type of cancer (not named here, to preserve anonymity). That paper suggested that a particular compound might affect the function of a protein expressed in the cell lines; this compound could therefore be a possible candidate drug for use in this type of cancer, which might be explored further in clinical trials. (This compound currently has approved uses for other cancers.)
A few months after publication, we received a short electronic letter from a researcher who said that as a result of reading the paper and other data, the researcher and his colleagues administered the candidate drug to three patients with the specific type of cancer mentioned above, who had not responded to other therapies. The researchers reported that one individual improved transiently but ultimately relapsed and that all three individuals eventually experienced a progression of their disease.
The authors did not say whether they had obtained ethical approval for this experimental therapy or whether the patients gave informed consent. We wrote to the authors to say that we could not offer to publish the electronic letter. We encouraged them to rewrite and submit this as a formal report of a clinical trial for our sister journal, but providing they also document ethical approval for the study and informed consent procedures. We never heard back from the authors.
What should we do now?
Although most of the Forum felt there was not much that could be done, some felt that this was an issue of informed consent and the editor had a duty to find out if consent was obtained. The advice was to contact the authors and ask them to provide information on whether or not consent or ethics approval had been obtained, with a deadline for an answer. If no or no satisfactory answer is received, the Forum suggested contacting the authors’ institute and asking them to investigate the issue. No allegation should be made and the authors should be informed of this course of action.
The journal wrote to the authors to ask for clarification regarding individual consent for the course of treatment, and ethical approval for the study. The authors replied to say that patients did give written consent, but no ethical approval was required or given because the course of these patients’ treatment was not carried out as a research study but instead as a course of off-label therapy, which was subsequently written up into a research paper. No further action was taken.
A doctor who trained in country A took the licensing examinations in country B because he wished to work in country B.
After the examinations, he carried out a survey (with a very poor response rate) of other doctors who had taken the same national licensing examination. The survey asked four major questions: How representative was the examination relative to the scope of your reading? How fair do you think this method of evaluation is to foreign medical graduates? What would be your most ideal method for evaluation of foreign medical graduates? Why did you immigrate?'
There was no IRB approval for this study and no mention of written informed consent. When asked to clarify ethical issues, the author stated: “No protocol was prewritten, as the question of what and who would constitute an IRB for such a survey on issues relating to foreign medical graduates in the transition was a difficult one to answer. Thus no ethical review was done. However, all participants were adults, of sound mind, and implied consent to have their opinions published.”
The paper has been rejected, but do the editors need to take further action? The risk of harm to the survey participants (all doctors) from this study seems low. Nevertheless, the survey might conceivably have included questions of a personal nature that could have caused distress (eg, reasons for immigration). The licensing board was not informed about the survey. If we report this doctor to the licensing board, it may well affect the author's chances of employment in country B.
As the subjects were not patients, some argued that it is not necessary to have ethics approval although others believed that ethics approval should always be sought for any study on human subjects. As the study involved a survey, all agreed that written consent was not required as the subjects could not be identified. However, the general view was that the author should have at least contacted the licensing board to ask permission to carry out the survey. The advice from the Forum was to write a strong letter to the author explaining the ethics involved in carrying out any research and suggesting that he should have contacted the licensing board before carrying out the survey.
As recommended by COPE, the editor wrote a stern letter to the author. In reply, the author thanked the editor and also noted that he himself was confused as to which institution should have been approached ahead of the study. The editor considers the case now closed.
A clinical trial was conducted in a low income country. The trial involved two schools. At the first school (the control school), children would receive a one-off drug treatment for a common infection (such “mass drug administration” is the norm for treating and breaking the transmission cycle of this infection). At the second school, children would receive the same one-off drug treatment plus a long term oral nutritional supplement. The hypothesis being tested was that the supplement might boost the effectiveness of the anti-infective drug. The researchers also wanted to assess whether this supplement might have any side effects when administered in this way. The risk of side effects was low, but nevertheless there was a risk.
In the trial protocol, the researchers stated that children would be asked to invite their parent/guardian to the school on the day that the trial was due to begin, and the parent/guardian would be asked to sign an informed consent form. The consent form stated that the parent/guardian would be free to withdraw the child from the study at any time, and that the child would not be disadvantaged in any way from such withdrawal. The protocol also stated that if the parent/guardian was absent, a representative from the Parent Teachers Association (PTA) would sign the informed consent. An IRB approved the study.
However, in the clinical trial report, the researchers stated that they did not seek parental consent. Instead, they simply asked one PTA representative at each school to sign consent on behalf of all the children in the school. In the trial report submitted to the journal, the researchers justified bypassing the parents as follows: "some children could be excluded from participating in the study and hence disadvantaged from receiving treatment if their parents/guardians did not give consent." The editors feel that the parents themselves would have been best placed to assess the relative risks and benefits of allowing their child to participate in the trial.
We have been unable to find out from the authors whether they told the IRB that they deviated from the protocol and whether the IRB approved the deviation.
One of the researchers commented that he felt the type of consent used was appropriate for this particular country’s setting. Another of the researchers commented that the PTA representatives who gave “mass consent” were themselves parents.
However, the journal editors are concerned that (a) there was inadequate protection of a vulnerable group; and (b) the researchers appeared to use a consent process that made participation more likely rather than a process that fully protected the children. The paper has been rejected due to methodological weaknesses and the editors’ concerns about the informed consent process, but do the editors need to take further action?
The advice from the Forum was to contact the local IRB and determine whether they are aware that there was a discrepancy between the proposed study and what was carried out. Were the IRB aware that the investigators deviated from the initial protocol? If it transpires that the IRB did not approve the study that was eventually carried out, the advice was to contact the authors’ institutions informing them of the situation and asking them to investigate.
The editor wrote to the IRB’s secretary and chairman. Unfortunately, as is often the case with IRBs in low income settings, there was only a mailing address (no email, no fax, no telephone number). The editor sent his letter in the post by priority mail, and so assumes that it was received. He awaits a response.
However, in the mean time, the editor received a letter from the senior author of the paper. The letter stated that he has been in contact with the IRB and the IRB has now granted retrospective approval for the consent that was used in the trial (ie, asking one PTA representative at each school to consent on behalf of all the parents). The senior author wrote to the journal asking if we would now reconsider the paper. The editors gave a firm no, saying that (a) such retrospective approval from the IRB does not allay the initial concerns about mass consent by two individuals and (b) the paper had too many scientific weaknesses to merit publication.
A team of Western researchers carried out a longitudinal study of pregnant nomadic tribeswomen in Africa between 2002 and 2003. They took blood samples during and after pregnancy to test for a specific disease. Those who tested positive were treated. An attempt was also made to trace contacts, and the women’s status was rechecked after pregnancy to ensure effective treatment.
The researchers also had institutional ethics approval and verbal consent from the women to take anonymous blood samples for antenatal HIV testing. These samples were unnamed and batch tested in a regional laboratory. Those who tested positive were not treated or told the results. Although low cost medications for the prevention of mother-to-child transmission of HIV were being recommended by the WHO and were being used in the region at that time, the research team made no attempt to provide an HIV service. They judged that any HIV testing or treatment should be implemented formally throughout the region and that it was “beyond the scope of their project”.
Did the research team fail in their ethical duty to the trial participants, and should the journal therefore refuse to publish their research?
The editor informed the Forum that although ethics committee approval was obtained for the study from respected institutions, he was not satisfied that the study was ethical. Members of the Forum shared the concerns of the editor and there was overwhelming support for the editor’s position, in that the research team may have failed in their ethical duty to the trial participants. It was also felt that funding to treat the women could have been made available at the time of the study as the costs of a single dose of HAART to avoid vertical transmission were low. Ultimately it is the decision of the editor whether or not to publish the study as ethical committee approval to conduct a research project does not extend to the editor’s duty to publish its results.
The editor wrote to the authors with their concerns and the authors replied that it had been a mistake for their researcher to have access to all of the results before the women delivered; this was not in the protocol approved by the ethics committee of the African country’s authorities). Apparently, there was a hiccup in their organisation of the study which gave this person the knowledge of the women’s test results before delivery. The proposal from the authors was to simply eliminate the section in the paper that mentioned that the researcher had access to all the results before delivery.
The editor thought this was unacceptable as it was obfuscating the truth, and moreover the authors had made matters worse by saying that in reality the study did not have ethics approval (a different one did, but not the one they actually carried out). On this basis, the paper was rejected and the authors’ supervisory bodies are being informed (the WHO said it wasn’t them, and the editor has yet to obtain the addresses of the supervisory bodies in the USA (where the researchers are based) and in Africa (where they had the approval of the governmental authorities)).
Biological monitoring is a common procedure in assessing the dose of contaminants from a workplace atmosphere. It may include measuring a contaminant, such as lead in blood, or a resulting metabolic product, such as mandelic acid in urine following styrene exposure. A related process is using adhesive tape to strip the surface layer of a small area of skin to measure the dermal deposit. Clearly these procedures require the consent of the person monitored, and this is not an issue. In Britain such procedures are included in various HSE regulations and guidance. They are commonly used in research.
The Human Tissue Act 2004 (http://www.opsi.gov.uk/acts/acts2004/20040030.htm) requires a licence from the Human Tissue Authority for the storage of material from a human body (section 16e), for purposes which include “obtaining scientific or medical information about a living or deceased person which may be relevant to any other person (including a future person)” (Schedule 1). Most of the Act came into force in April 2006.
The editor has been told by members of his Editorial Board that this is being deemed to include blood and skin samples taken for biological monitoring purposes. This is clearly an unintentional result of inadequate drafting.
This Act applies in England, Wales, and Northern Ireland. The Human Tissue (Scotland) Act 2006 focuses on tissue for transplants, and apparently does not cause a problem for biological monitoring. The BMA Medical Ethics Department has produced guidance on the Acts (http://www.hta.gov.uk/_db/_documents/Human_Tissue_Legislation_-_Sept_06_final.pdf) but this does not mention the biological monitoring problem.
Clearly this is more of a problem for researchers than for journals directly, except for the general ethical problem of supporting the law. For the moment the editor is thinking of adding to the paragraph on ethics in the instructions to authors a requirement that studies must comply with the law in the place where they are carried out, but is not proposing to question authors of English papers which include biological monitoring.
Has COPE any advice or comments, please?
Members of the Forum believed that in this situation, the onus is on the authors and the institutions to ensure that any procedures carried out are legal. Also, the ethics committees should be aware of whether or not an individual or institution has approval to carry out certain procedures. The Forum recommended that the editor write to the Health and Safety Executive explaining the issues and request further advice from them.