Dutch Researcher Refused to Disclose How She Got Students to Consent to Experimental Infection
Salami-sliced publishing and gaps in adherence to international ethical standards at the Leiden University Medical Centre
Scanning electron micrograph of a pair of Schistosoma mansoni (Wikimedia)
Is it ethical to subject another person to an experiment if the researcher did not do the experiment on themselves first?
The study obtained consent for exposure to a pathogen with a 12-week delay in curative treatment. The details that were withheld in the article are relevant to human subject concerns in current COVID-19 vaccination research.
The article, published in Annals of Internal Medicine, sparked brief, intense outrage on social media from infectious disease experts, clinical trialists, and ethicists.
Little sign of this controversy is preserved in the biomedical literature. What experts said on social media about the ethics of studying infectious diseases in this unusual study should be available in a systematic search of the literature, especially given the urgency of determining the efficacy and safety of vaccines for COVID-19 with healthy research participants.
Sensitive to the fuss this article had elicited, the official Twitter account of the journal tweeted
Few on Twitter took advantage of this offer and succeeded in getting a letter published.
What experts said on social media about the ethics of studying infectious diseases in this unusual study should be available in a systematic literature search, especially given the urgency of determining the efficacy and safety of vaccines for COVID-19 with healthy research participants.
Our published letter to the editor has largely gone unnoticed because of an exceptionally stubborn journal paywall and delays and glitches in indexing letters. I could not find this letter in recent searches of the journal website or through Google Scholar.
My best friend and colleague, University of Pennsylvania Professor of Medical Ethics and Health Jon Merz, MBA, JD, Ph.D., had made polite, persistent, but ultimately futile attempts to get the details of what was told to the two students and what assurances were given in securing their informed consent.
Jon emailed the first author, senior author, and Research Evaluation Board of the Leiden University Medical Centre, Leiden, The Netherlands.
After some exchange of niceties, the response seemed to be an emphatic “Echt, niet!”
The article’s senior author observed that Jon was an ethicist and presumed that Jon might want to publish on this issue. She claimed the right to protect her team to be the first to publish what was done to ensure informed consent. The team collaborated with ethicists at Leiden University, and she suggested that they publish details.
The senior author also noted that her research staff had not seriously considered self-experimentation involving deliberately infecting themselves.
She ended further correspondence with:
Given the ethical debate around controlled human infection studies, we believe that it is important to take the utmost care in informed consent procedures, guidance of our volunteers and the public opinion.
Subsequent publications from this group have not revealed what was told to these students, not even in advisement about how to manage risks to normal volunteers in COVID-19 vaccine research.
A strong case can be made for cohort-specific informed consent, which involves disclosing risks to prospective subjects with particular personal characteristics.
The Head of the REB replied that she preferred that Jon obtain information and consent forms from the study's senior author. She did not respond to further inquiries.
Our letter that was published in the Annals of Internal Medicine
The journal did not require us to sign over the copyright of the letter, so here it is in its entirety:
We read with interest the short report by Roestenberg and colleagues about the experimental infection of 2 graduate students with male cercariae of Schistosoma mansoni.1 The overarching hypothesis of this study is quite provocative. Results would be potentially clinically relevant, except data from only 2 of the originally proposed 17 subjects proposed in the trial registration were reported.2 Information in the trial registration indicates that recruitment is no longer occurring.
No reason is given for writing up the paper with such a small subsample of what was proposed. One is left wondering whether recruitment failed because of the risks and burdens of a study requiring exposure to a pathogen and a 12-week delay in curative treatment. No information is provided about recruitment strategies, target subject population, or information disclosed in the consent form. Was an incentive offered and was it consistent with the risks and burdens of the study? We requested the consent form from the senior author and the IRB, but our request was refused.
Despite recruiting only two subjects, there were six authors and a larger coHSI clinical trials team of 20. We wonder why no members of the team experimented on themselves. The Nuremberg Code provides some guidance for dangerous experiments that hold out no prospect of therapeutic benefit: “5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury could occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.”3 While death or long-term injury from this experiment was unlikely, the principle behind this provision of the Code has a persuasive rationale.
If an experiment is too dangerous or imposes too high a risk and burden, only those who are most informed and free of undue pressures and coercion should be experimental subjects — namely, the investigators. No researcher (or IRB member) should ask others to do anything that they themselves would not do. If recruitment failure was due to the inability to find enough unaligned people willing to undertake such an experiment, we find it ironic and telling that none of the investigators would step into the breach for the good of their science.
We hope the investigators will be open and transparent about their recruitment and consent methods, as others may face similar barriers in trying to replicate and extend their important work.
The authors’ reply
We thank the authors for their interest in our research and sharing their ethical deliberations. Recruitment for this trial has been completed as proposed (n=17) and final trial visits for the last group of volunteers are currently taking place as planned. We aim to provide a full report of the trial results as soon as possible and anticipate final data collection in April 2019. Volunteers were financially compensated for their time and travel expenses according to accepted Dutch standards for medical research with healthy volunteers.
We have performed a thorough review of our informed consent procedures, volunteer expectations, risk assessments and motivation. The results of this study will also be made publicly available. Given the importance of the clinical findings of the first participants in this study to the medical community, we have been specifically requested to publish the clinical details of these initial cases as soon as possible and not await the end of the trial. We apologize for any concerns we might have caused about failed recruitment or early termination and will keep you updated on trial publications.
Note that this reply seems to promise that the results of the larger study will be published. It did not say whether these publications would include details on protecting human subjects, including this study’s procedure for ensuring informed consent.
It is very odd to publish results obtained from the first two research participants when a larger study is in progress. This article could be seen as premature and inappropriate because any effects may prove false positives with the accumulation of more data. The authors want to attract attention to their preliminary results but risk the likelihood of promising results getting more attention than the not-so-promising but more valid results they will have later.
Responsible researchers do not publish preliminary results from an ongoing study without a very good reason. That is Best Research Practices 101.
Particularly since this group is taking the extraordinary step of publishing results obtained from the first two of a planned larger study, the medical and scientific community have the right to know how consent was obtained and if any participants declined participation once they were fully informed.
If this study's results are so important that they must be shared at this preliminary stage—after collecting data from only two subjects—then so are the procedures by which the results were produced, including informed consent.
There are unaddressed ethical concerns about this study. What were prospective participants told about possible adverse events, including the risk of death? How much were participants compensated in recognition of this risk? Are there special issues with these participants being students at the research team’s university and perhaps feeling pressured to consent?
Our suggestion that the investigators consider doing this research experimentally and expose themselves — not someone else — to the pathogen has a strong precedent.
A systematic review identified 465 documented instances of medical self-experimentation, including by researchers who went on to receive the Nobel Prize.
Walter Reed’s Yellow Fever Commission in Cuba in 1900 allowed mosquitoes suspected of carrying the deadly disease to bite Commission members, but Reed excused himself from having to do so. One member of the commission developed yellow fever and suffered lifelong chronic ill health. Another member died from the disease.
A classic New England Journal of Medicine paper, regularly assigned reading in medical ethics classes, discusses auto-experimentation—An Unappreciated Tradition in Medical Science.
The paper notes:
Obermeier, in his efforts to find a cure for cholera that then was epidemic in Berlin, allegedly injected blood from a patient with cholera into himself, and died.
Swiss chemist Albert Hofmann accidentally poisoned himself with LSD and then began purposely auto-experimenting with lower dosages to discover its psychedelic effects.
A quote from the NEJM article poses an important ethical question for the Leiden research team:
Investigators cannot serve as subjects in all scientific experiments. However, the widespread practice of auto-experimentation raises a fundamental question about the philosophy of research: Is it ethical to subject another person to an experiment if the researcher did not do the experiment on himself first?
What are Katayama syndrome and schistosomiasis?
According to Lancet Infectious Disease, Katayama syndrome
…Is an early clinical manifestation of schistosomiasis that occurs several weeks post-infection with Schistosoma spp (trematode) worms…Katayama syndrome appears between 14–84 days after non-immune individuals are exposed to first schistosome infection or heavy reinfection. Disease onset appears to be related to migrating schistosomula and egg deposition with individuals typically presenting with nocturnal fever, cough, myalgia, headache, and abdominal tenderness.
According to the World Health Organization (WHO), schistosomiasis:
Is an acute and chronic parasitic disease caused by blood flukes (trematode worms) of the genus Schistosoma. Estimates show that at least 229 million people required preventive treatment in 2018. Preventive treatment, which should be repeated over a number of years, will reduce and prevent morbidity….
Transmission occurs when people suffering from schistosomiasis contaminate freshwater sources with their excreta containing parasite eggs, which hatch in water…
Chronic schistosomiasis may affect people’s ability to work and in some cases can result in death. The number of deaths due to schistosomiasis is difficult to estimate because of hidden pathologies such as liver and kidney failure, bladder cancer and ectopic pregnancies due to female genital schistosomiasis.
Are graduate psychology and medical students members of vulnerable populations?
Regulations vary by country, but in the U.S., federal rules require that institutions overseeing research conducted with human subjects take special precautions to ensure that consent is obtained in a fully informed, voluntary, and without coercion manner. The concern is heightened when individuals are in situations where they can easily be manipulated or may be a convenient and readily available study population.
U.S. regulations especially cite children, economically deprived persons, and prisoners as vulnerable populations. Students and employees of an institution are not explicitly mentioned.
Yet, researchers can expect that in reviewing applications to experiment with students, consideration will be given to how consent is obtained without coercion and how students and employees can decline participation or withdraw from research without fear of reprisals.
Special issues with Leiden University graduate psychology students
The Dutch academic environment is highly competitive. Career advancement depends on demonstrating research productivity, as quantified by the number of authorships on peer-reviewed publications.
Dutch Ph.D. theses consist of a collection of peer-reviewed publications with interspersed commentary. Co-authorships on research conducted by graduate students figure heavily in the hiring, promotion, and tenure of junior and senior faculty.
The publications listed on the curriculum vitae of many department and laboratory heads in the Netherlands consist mostly and sometimes almost entirely of authors from Ph.D. student research.
Dutch psychology students face particular challenges in recruiting patients for Ph.D. research from medical hospitals and clinics staffed and controlled by other disciplines. Most of us who have researched those settings find that anyone willing to authorize access to medical patients can expect authorships. These academic administrators are responsible for securing publications for their colleagues, staff, and Ph.D. students and can be expected to look after them.
I have had to acquire a new data set at the University of Groningen Medical Center (UMCG) for an already completed manuscript that reported results based on secondary psychometric analyses of self-report measures.
The head of the clinic had permitted the use of data from a study completed long ago in the clinic, before her time. However, she did not respond to repeated emails offering authorship for a minimal effort sufficient to comply with journal guidelines for determining authorships.
At the last minute, we asked her to provide permission to name her in an acknowledgment before the manuscript was uploaded. The clinic head insisted that she recruit her two new postdocs to read and comment on the paper. The three of them should become authors, or the manuscript could not be submitted. We got a new data set elsewhere to reanalyze. As customary, we again offered the source an opportunity to become an author, but we received a note thanking us but declining.
Decision-making about authorships in Dutch medical settings often involves compromises between international ethical standards for awarding authorships and the need to maintain collegial relationships with those in control.
In recent years, Leiden University has experienced several scandals about research integrity, gift authorships, and the denial of credit for student and early career contributions to research in the Schools of Education and Psychology.
This past year, the Netherlands Board on Research Integrity (LOWI) concluded that a former professor of psychology at Leiden University was guilty of breaching several scientific integrity rules. This conclusion was based on the findings of the Academic Integrity Committee (CWI) of Leiden University:
The CWI identified four violations of scientific integrity: (1) blood sample testing without the legally required permission of the Medical Ethics Review Committee, (2) irregularities with publications, (3) repeatedly selectively omitting research results without reporting or explaining this, and (4) submitting grant applications with incorrect (incomplete and manipulated) research data.
Transparency in research ethics during the pandemic
Achieving control over the world's COVID-19 pandemic depends on unprecedented international cooperation, the sharing of data obtained from diverse settings, and the ethics and informed consent with which these data were obtained.
These were always Best Research Practices, and now, more than ever, is the time to enforce them.
Academic institutions are expected to share data and basic details of their methodology to allow their research to be replicated. Especially amid a pandemic, researchers should be forthcoming and fully disclose how they informed health volunteers about the risks of unprotected exposure to pathogens in their research and how voluntary consent was obtained.
When our letter was published in the Annals of Internal Medicine, we did not anticipate that a pandemic would soon be upon us. However, we saw no reason these authors from LUMC should not answer a reasonable question about how they protected human subjects.
Would you consent to participate in a clinical trial at Leiden University or encourage a loved one to do so?
A tongue-in-cheek response that I did not send to Professor Roestenberg
Dear Professor Meta Roestenberg of Leiden University Medical Centre,
Could you please inform the scientific community how you persuaded two students to put their health at risk in your study by getting exposed to pathogens?
Kind regards
Jim
References
Langenberg MCC, Hoogerwerf MA, Janse JJ, van Lieshout L, Corstjens PLAM, et al. Katayama Syndrome without Schistosoma mansoni eggs. Ann Intern Med 2019; Jan. 8. doi:10.7326/L18–0438.
Roestenberg M. Single-sex controlled human Schistosomiasis infection: safety and dose-finding. https://clinicaltrials.gov/ct2/show/NCT02755324 (accessed January 20, 2019).
Nuremberg Code. United States v. Karl Brandt et al., 6 Fed Rules Decisions 305 (1949).
Note
This article originally appeared in James Coyne’s Corner at Medika Life on December 18, 2020, at the height of the COVID-19 epidemic. I retain the copyright and have edited only slightly, for grammar and smooth flow. Many thanks to Medika Life for their liberal policy of granting copyrights to authors.