German Anesthetist Faces Massive Retraction of Published Research Articles

•February 14, 2011 • Leave a Comment

A German anesthetist, Joachim Boldt, has published over 350 peer-reviewed papers and is currently the target of a German medical board investigation for data manipulation, fabrication of data and failure to have human studies reviewed and approved by an ethics review board. This story began when the journal Anesthesia and Analgesia retracted a 2009 article authored by Boldt citing concerns of data manipulation. Now, after further investigation by a German medical review board, up to 90 of Boldt’s published articles are being considered for formal retraction.

Here’s more on the story from Retraction Watch: Unglaublich! Boldt investigation may lead to more than 90 retractions

Note: The Retraction Watch story refers to a joint letter posted to the websites of 11 major anesthesia journals, authored by their editors-in-chief regarding Boldt’s research, much of which was published in their 11 journals. Here is an excerpt from the letter that was included in the Retraction Watch story:

LÄK-RLP [the German medical board conducting the investigation] has reviewed 74 scientific articles describing clinical trials subject to the requirements of the German Medicinal Act. This includes the article by Professor Boldt recently retracted by Anesthesia & Analgesia and an article submitted by Professor Boldt to Anaesthesia but not published. By law these studies required IRB approval. Although the articles typically stated that IRB approval had been obtained, LÄK-RLP could not find evidence of approval for 68 of these articles.

The story on Retraction Watch notes that, in addition to these retractions, Boldt faces a fine of up to 100 000 Euros (approximately 140 000 Canadian dollars) and even jail time for conducting human research without ethics review board approval, a violation of German medical profession’s Code of Deontology (i.e., Code of Ethics).

The story notes that there is evidence that Dr. Boldt failed to obtain ethics review board approval for studies, forged signatures on copyright forms, fabricated data, fabricated clinical cases, and lied about the participation of co-authors. In fact, the claims and information suggest that Boldt’s 2009 now-retracted study never even took place at all. As a result of these claims, further investigation into Boldt’s other published research is taking place.

There are a plethora of ethical and practical problems with Boldt’s research, if even a few of the claims are found to be true. Certainly there are too many to discuss here. But what I did want to comment on is the burden placed on ethics review boards to “police” research, something most of us are loathe to do. As the story notes, upon submission to a scientific journal, researchers often are required to simply check a box to indicate that an institutional ethics review process took place. No one asks for confirmation of this. In this case, no one questioned the volume of research Boldt was producing. No one questioned the fact that Boldt was noting the use of albumin in his published studies when it hasn’t been used since 1999 in that institution. It seems no one asked for evidence or confirmation of some very basic science — something one would expect as part of a peer review process. The role of peer review, or scientific review is, to some degree, downplayed, with claims that scientists are too busy to do thorough reviews, can’t be expected to know everything in their discipline or that they certainly shouldn’t have to monitor their colleagues. Well, peer review is, in fact, about monitoring colleagues in a way that ensures the rigor and quality of information provided through research and science.

I know that I have had months in which I have been asked to do a number of scientific reviews of articles. I also know that I don’t sign up unless I know I can devote the time to doing a thorough review and not just “sign on the line” after reading it superficially or approving it for publication because it’s a smart friend or close colleague. There’s no clear evidence that those sorts of things happened in this case, but it is clear that, alongside other systemic problems, the process of scientific peer review failed miserably here.

Ethical research and ensuring ethical conduct in research shouldn’t be the sole responsibility of an ethics review board. Nor should concern with ethical research begin and end with the submission to an ethics review board. It should be an ongoing part of the entire research process, and a clear part of the research culture, embedded in professions, disciplines and institutions that fund, sponsor and publish research.

Parents Complain Over “Opt-Out” Consent In Kindergarten Study

•February 6, 2011 • 4 Comments

According to a recent story in Burnaby Now, a study notice sent out to parents of kindergarten-aged children has triggered complaints to the University of British Columbia’s Behavioural Research Ethics Board, which had approved the study. Parents received the notice about the the Early Development Instrument, a survey on kindergarten-aged children, which is part of a much larger project called “The Human Early Learning Partnership (HELP)“, a government-funded research consortium of universities, based at the University of British Columbia (UBC).

The Early Development Instrument is an assessment tool used to assess children’s development in kindergarten. It involves collecting information about a child’s physical health and well-being, social capabilities, emotional maturity, use of language and cognitive development and communication skills. According to the Burnaby Now story, the study notice offers brief information on what kinds of data will be collected about the children and that these data will be linked to other kinds of education and health information. It also notes that if parents do not want data collected on their child, they must contact their child’s teacher to indicate this. In other words, the consent, referred to as “passive” in the story, is an opt-out consent.

Here’s the story: ‘Passive consent’ triggers complaint: Burnaby parent says survey is ‘unethical’

The letter informs parents about the survey and mentions that data collected can be linked to education and health information. The letter also states that participation is voluntary, and that parents can contact their children’s teachers if they don’t want them to participate.

Ward [a concerned parent] has issues with the use of passive consent, meaning if parents say nothing, their kids will be included in the survey, rather than signing a consent form expressly stating they want their kids involved. Ward is also complaining about what she calls a lack of information on what the data gets linked to.

“They don’t say what they are linking it to,” Ward said. “It violates parents’ rights to informed consent.”

The parents have formally complained about two issues: the use of an opt-out consent and the reported lack of information about how data are being linked to other kinds of datasets, including health information. There’s one more issue here that interests me, in addition to these concerns. I’m wondering if the study researchers have a mechanism in place to report back to parents if serious developmental, social or health issues are identified in their children.

Here’s a few words on each of the issues raised by this story:

1. The use of an opt-out consent process is one that is discouraged across many research contexts. If an opt-out procedure is used, the burden rests with the researcher to ensure that there is thorough and explicit information about what participation really means and how consent, or in this case, non-consent, is expressed. We talk about “obtaining” informed consent in research and this does involve time and energy. It is a clear step that must be revisited and confirmed throughout the life of a research project. Here are three initial questions I would ask about this opt-out process: Are the researchers clear about sending information that is accessible in every parent’s home language and level of reading comprehension? Is it clear what opting-out or passively opting-in really means, to everyone? Is it clear that a traditional informed opt-in consent is impractical? Many potential participants will not fully understand the negative withdrawal option and will simply not make the call to the teacher for either more clarification or to exercise their right to opt out, thereby passively consenting – but this isn’t informed consent. An opt-out clause should never be used as a means to save time and energy of the researcher nor should it be used with a goal of simply “getting more participants”.

2. The notice states that linkages will be made between the data collected and other kinds of data, including health and educational data, considered to be private information. Full and detailed information should be provided to parents about the kinds of linkages being made and the kinds of other data being accessed by researchers. Furthermore, the kinds of strategies put in place to protect privacy should be outlined explicitly and clearly. From the parents’ reactions in this story, the data linkages and privacy measures have not been fully explained.

3. While the study is low-risk, it involves collecting potentially sensitive and very important data about kids. There are very likely to be findings that suggest or demonstrate mild to serious developmental, social or health-related concerns in children. Interestingly, the researchers also note that the information can be used to predict possible future criminality – something as a parent, I’d want to know, I think. The new second version of the Tri-Council Policy Statement(TCPS) discusses the notion of incidental findings, defined as “unanticipated discoveries made in the course of research but that are outside the scope of the research.” (Article3.4). The TCPS is also quite clear that a plan must be in place to inform participants of expected study results and incidental findings. In this case, the goal of the survey tool is to gather information on the development of children so concerning findings are not incidental, per se, but expected. I’m wondering what kind of information gets back to parents about their children.

The story does not include any response from the HELP project or the UBC Research Ethics Board. I found a great deal of information about The Human Early Learning Partnership on the web. I also found a great deal of information about the Early Development Instrument. But it did take time and work to read through a lot of information. If I was a parent getting a study notice like this, I’d be looking for information about the project and giving serious thought about whether or not to participate. However, I’m a researcher. Many parents are not. Many parents have low levels of literacy or are fluent in languages other than English. Many parents work long hours and at multiple jobs. So the burden of seeking information about a study like this should not be transferred to the parents.

The project itself looks like an important and laudable project with goals that are clearly in the interests of multiple stakeholders, including those providing funding to this very large undertaking. At the end of the day, however, even with multiple powerful stakeholders, the interests and the subjective experiences of participants, i.e. those providing the data, must be paramount. When participants are feeling that they are uninformed, unprotected and not being treated in an ethical manner, at the very least it appears that their interests are not being prioritized.

If Placebos Work, Why Placebo-Controlled Trials?

•January 3, 2011 • 3 Comments

Placebos have been a hot-button issue in human-subjects research ethics for years. Many regard placebo-controlled trials as the “gold standard” for clinical research. Others see the use of placebos in clinical research as typically-unjustified (at least in cases where a decent treatment exists). (To get a sense of this debate, check out this article by Charles Weijer: “Placebo trials and tribulations”.)

So it has been interesting to see placebos popping up as a topic of discussion lately. Placebos are supposed not to work. That’s the whole point of a placebo-controlled trial — to compare an experimental drug against something “known” not to work, in order to make sure that any positive effects observed aren’t merely the result of the “placebo effect,” i.e., roughly the psychological result of patients feeling cared-for.

But if placebos are (by whatever mechanism) more effective than previously thought, that kind of throws a monkey wrench into the equation.

As a starting point, see this Wired article: Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.

For a more scholarly look at a complication, see this PLoS One article by Kaptchuk et al: Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome.

And for an overview of the whole issue, see this PLoS blog entry: Meet the Ethical Placebo: A Story that Heals.

Much of the latter blog entry is about clinical (not research) use of placebos. But still, it’s something those of us with an interest in Research Ethics need to think about. As knowledge grows about the size, limits, and exact mechanism behind the placebo effect, we may well need to rethink the role of placebos in randomized controlled trials.

Obama Announces Massive Review of Research Ethics in the US

•November 25, 2010 • 1 Comment

In a New York Times story yesterday, it was revealed that President Obama is ordering a massive review of bioethics in the US. Here’s the story: U.S. Orders Vast Review of Bioethics

“His action is a response to the revelation this year that American scientists intentionally infected people at a Guatemalan mental hospital with syphilis in the 1940s. In a memorandum released by the White House, Mr. Obama announced a review of federal and international standards to guard the health and well-being of research participants, known as human subjects. He also ordered a fresh inquiry into what happened in the widely condemned experiment in Guatemala….”

From this brief story, it appears that his greatest concern is, in fact, research ethics and the regulations, rules and standards that are in place in the US (and internationally) to protect human participants. While there are significant variations among national standards for the ethical conduct of research, many countries have used US standards as guidelines in creating or amending their own sets of regulations and standards. Furthermore, there are many international researchers who are involved in multi-centre projects or have links to researchers and research institutions in the US. Therefore, a major overhaul of US research ethics standards (if that is the result of this review) would have far-reaching implications.

We’ll continue to watch this story and keep you updated.

Tragedy and the Clinical Trial: Part 2

•November 21, 2010 • Leave a Comment

On October 1, I wrote about the New York Times Story about two cousins in the US, Brandon and Thomas, both with a lethal form of melanoma, who were also both enrolled into a Phase III Clinical Trial to test a new, breakthrough cancer drug. One cousin got the wonder drug, PLX4032, while the other cousin got what the author claims that oncologists consider to be the significantly inferior “standard of care” drug dacarbazine (alongside a plaintive apology from his treating physician). Here’s a link to the original blog entry: A Tale of Two Cousins: Tragedy and the Clinical Trial

As I noted in the original blog entry, there are a number of very serious questions and issues raised by this story. The first is about clinical equipoise. What’s clinical equipoise? Well, here’s an “Equipoise 101” version. We think of clinical equipoise as genuine uncertainty over whether a treatment will be beneficial. In clinical trials, where researchers are comparing one treatment to another, it refers to the uncertainty over what the preferred treatment might be. Most of the time, researchers and clinicians have a suspicion or a hypothesis that one treatment may be superior to another in, for example, treating a particular condition or illness. Until adequate evidence exists in favor of one treatment over another, the hypothesis remains unproven and some degree of clinical equipoise still exists. Once sufficient evidence favoring one treatment over another exists, researchers have an ethical obligation to end a trial as equipoise no longer exists.

The current treatment that is provided and recommended for patients is known as the “standard of care”. In this case, it’s clear that clinical equipoise no longer exists, if it ever did. The standard of care in this case is dacarbazine, a drug that, according to the story, no oncologist wants to give. It’s ineffective at both shrinking tumours in a significant way and prolonging life. So to compare (by experimental use in seriously ill patients) a clearly inferior agent to what has been proven to be a markedly better drug seems, at first glance, unethical.

The structured phases of clinical trials, in some ways and in some cases, are antithetical to the notion of clinical equipoise as a measure of collective doubt at a particular point in time. Rigour demands that we strictly follow the phases of clinical trials to, in part, protect the best interests of patients. Yet, in the case of PLX4032, it’s difficult to see that the best interests of anyone are actually being protected. With a standard drug that is felt to do more harm than good, and an experimental “wonder” drug that has, in early phases of testing, produced dramatic responses but caused few serious side effects, this might seem like a case in which the highly-structured and years-long process of conducting clinical trials might be re-evaluated. Many might understandably object, saying that the clinical trial structure ensures that by the time a drug is actually available on the market, it has been through enough experimentation that physicians can be confident in prescribing it without worrying about unexpected harms to individual patients. True. But it’s not surprising that, in the case of what is seemingly a “wonder” drug for seriously ill patients with few to no other options, many oncologists in this story wondered if it’s time to reexamine whether the demands of rigour or the demands of ethics really require continuation of a two-armed trial.

It’s certainly something to think about. It seems to me that once the physicians involved in a trial are apologizing to a participant for being enrolled in a particular arm of a trial, we are no longer in a state of clinical equipoise.

China’s New Research Ethics Guidelines

•November 13, 2010 • 4 Comments

Flag of the People's Republic of ChinaThere has been plenty of concern, in North America and Europe, about Western drug companies conducting clinical trials in Africa and Asia. There have been calls for Western ethics boards to exercise extra scrutiny, but another piece of the puzzle, obviously, is good local regulations. In that regard, it’s interesting to note that just this week, the People’s Republic of China issued guidelines on the mandate and composition of research ethics committees. Here’s the story, from China Radio International: China Issues First Guidelines on Medical Ethics Committee

China on Monday issued its first guidelines regarding the operation and power of the medical ethics committee, which would strengthen the committee’s role of supervision and protecting the rights and interests of human subjects involved in clinical medical trials.

The guidelines, posted on the website of the State Food and Drug Administration (SDFA)….

Here’s the SDFA’s brief statement on the Guideline for Ethical Review of Drug Clinical Trials issued [Link no longer works]. The CRI article and the SDFA’s short statement are short on details, and the Guideline document itself does not yet seem to be available online. Stay tuned.

(Here’s the English-language version of the State Food and Drug Administration’s main website.)

Zamboni: “Wait for trials.”

•October 17, 2010 • 5 Comments

It’s encouraging to see a scientist urging caution, and citing the need for further research prior to implementation of his theories — especially when those theories are scientifically highly contentious, but yet offer a glimmer of hope to thousands of desperate people.

Here’s the story, from Adrian Morrow, writing for the Globe & Mail: ‘Liberation therapy’ doctor now warning MS patients to wait

The Italian doctor who gave multiple sclerosis sufferers hope their condition could be treated with a simple procedure – and prompted many of them to cross borders and shell out thousands of dollars to receive it – has now warned patients against receiving the treatment until further clinical trials have been conducted….

Of course, clinical trials may not happen soon. We blogged before, for instance, about Canadian recommendations against funding clinical trials: Canadian Working Group Recommends Against Funding for Controversial MS Trial.

It’s worth noting that lack of funding isn’t the only issue. A clinical trial (in any developed country, at least) would also have pass through some sort of ethical review process. In Canada, for example, any university-affiliated researcher would have to gain the approval of a Research Ethics Board in order to conduct a trial based on Zamboni’s hypothesis. And at this point, it seems unlikely such approval would be granted. Why? Well, because Zamboni’s hypothesis doesn’t have enough support among experts to warrant subjecting humans to the risks. That’s the point of the notion of clinical equipoise. We don’t test hunches on humans, even when those hunches are supported by anecdotal evidence. The anecdotes are intriguing, to be sure. But we need more than that to ethically justify a full clinical trial. We need things like:

  • strong evidence that Zamboni’s hypothesis is supported by our best understanding of the physiological basis of MS;
  • evidence from animal trials;
  • systematic analysis of individual human case-studies;
  • etc.

Someday that kind of evidence may exist. But for now (based on the expert analysis provided by the Canadian Institutes of Health Research and The MS Society of Canada), we’re just not there yet. So it’s too soon for clinical trials. Even if the risks of the procedure are not huge, neither are they trivial.

Now, advocates quoted in the G&M story suggest that patients should be allowed to judge the risks and benefits for themselves. It’s an understandable point of view, but one that doesn’t generalize very well. The role of ethics boards is to evaluate proposals to determine whether the likely social benefits of a trial are commensurate with the risks to participants. And then if approval is given, it is up to individual participants (in consultation with their own doctors) to judge whether participation in the trial makes sense for them. But that initial level of expert scrutiny is particularly important when the population being studied is desperate for a cure, as is the case here.

None of this is to say that trials won’t happen. They almost certainly will. Somewhere. But before well-justified trials can happen, a few more hurdles are going to have to be cleared.

Human Stem Cell Trial Approved in U.S.

•October 11, 2010 • Leave a Comment

From the Washington Post: First patient treated in stem cell study*

The first patient has been treated with human embryonic stem cells in the first study authorized by the Food and Drug Administration to test the controversial therapy.

A patient who was partially paralyzed by a spinal cord injury had millions of embryonic stem cells injected into the site of the damage, according to an announcement early Monday by the Geron Corp. of Menlo Park, Calif., which is sponsoring the groundbreaking study….

This Reuters story gives additional detail: First patient treated in Geron stem cell trial), including the fact that this is a Phase I trial, which will “not be aiming to cure patients but to establish that the cells are safe to use.”

An obvious question: what prior evidence justifies subjecting human subjects to such a clinical trial? As we’ve noted here before, the ethical standard for enrolling patients in a trial is provided by the notion of clinical equipoise — basically there has to be some legitimate disagreement in the expert community about the best treatment for the ailment in question. In this case, given that spinal injuries are generally not very treatable at all, what we’re looking for is some evidence that the embryonic stem-cell based treatment might well work. In that regard, an article in WebMD notes that:

In preclinical studies, animals with severe spinal injuries regained the ability to walk after treatment with OPC1 cells. The animals did not develop teratomas, reject the cells, or suffer nerve pain.

In addition to showing clinical improvement, treated animals’ damaged nerves became coated with new myelin and there was new nerve growth in the vicinity of the injected cells.

FYI, here’s Geron’s page about the trial: Phase I Trial of GRNOPC1

Interestingly (and sadly), of the handful of news reports I’ve seen so far, none of them has specifically mentioned the role of ethics review boards.

*Note: the headline of the WaPo story would be more accurate if it specified embryonic stem cells.

Guatemala Update

•October 2, 2010 • 1 Comment

We blogged yesterday about the revelation of U.S.-funded STD research carried out in Guatemala. (See: Guatemala’s Own Tuskegee)

Today, the New York Times has further details: U.S. Apologizes for Syphilis Tests in Guatemala

In a twist to the revelation, the public health doctor who led the experiment, John C. Cutler, would later have an important role in the Tuskegee study in which black American men with syphilis were deliberately left untreated for decades. Late in his own life, Dr. Cutler continued to defend the Tuskegee work.

Professor Reverby said she found some of Dr. Cutler’s papers at the University of Pittsburgh, where he taught until 1985, while she was researching Dr. Parran.

“I’m sifting through them, and I find ‘Guatemala … inoculation …’ and I think ‘What the heck is this?’ And then it was ‘Oh my god, oh my god, oh my god.’ My partner was with me, and I told him, ‘You aren’t going to believe this….’ ”

p.s. here are Susan Reverby’s books on the Tuskegee study:

Guatemala’s Own Tuskegee

•October 1, 2010 • 1 Comment

Here’s another sad example to add to the annals of why-research-ethics-is-important.

Here’s the story, by Robert Bazell for MSNBC: U.S. to Apologize for STD Experiments in Guatemala

U.S. government medical researchers intentionally infected hundreds of people in Guatemala, including institutionalized mental patients, with gonorrhea and syphilis without their knowledge or permission more than 60 years ago.

Many of those infected were encouraged to pass the infection onto others as part of the study.

About one third of those who were infected never got adequate treatment.

On Friday, Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius offered extensive apologies for actions taken by the U.S. Public Health Service.

For people familiar with the world of Human Subjects Research, this story will immediately bring one word to mind: Tuskegee. (For everyone else, see here: Tuskegee syphilis experiment.) Like Tuskegee, this was a government-funded study. And like Tuskegee, the topic was STDs. And, like Tuskegee, there were serious violations of what we now see as absolutely basic ethical standards for research on human beings. The similarities between the two cases is not incidental. The records of the Guatemala study were apparently unearthed by Susan Reverby, a Wellesley College professor who has written extensively about Tuskegee.
See an update here: Guatemala Update