Ethical Design for Cluster Randomized Trials

•November 22, 2012 • Leave a Comment

A team led by our friend and colleague Charles Weijer at the University of Western Ontario has just issued guideliens for what are known as “cluster randomized trials” (CRTs).

See the story here:
Western-led team delivers world-first ethics guidelines.

CRTs are clinical trials in which randomization occurs across groups of participants, or across institutions, rather than across individual participants. In other words, each participant is not randomized into one arm of the trial or another. Rather, randomization is done at the higher level — an entire institution’s patient, population is treated as a unit for purposes of randomization. This raises a number of interesting ethical issues. These new guidelines will surely help advance our understanding, as well as highlighting an important range of issues for those of us not previously aware of them.

Posted in by Chris MacDonald, clinical trials, trial design

Clinical Trials in Russia

•November 12, 2012 • Leave a Comment

Generally, when westerners think of people in foreign lands participating as human subjects in clinical trials, we think of the developing world. That image is somewhat incomplete.

This was from September, but well worth a look at this NYT piece if you missed it:
Russians Eagerly Participate in Medical Experiments, Despite Risks

As a test subject in a Russian clinical trial for an experimental weight loss drug, Galina I. Malinina had to inject herself in the stomach daily. … she threw up every day for two weeks, yet stuck to the regimen, something valued by companies, as dropouts are expensive.
“It’s wonderful,” she said of the test substance, a weight loss serum under development by the Danish biotechnology giant Novo Nordisk. In addition to losing 22 pounds in a year, she said, “I became more lively; I walk easier and I have energy.”

Why go through this? For the same reason that people sign up for clinical trials in India or rural China.

Patients, as was the case with Ms. Malinina, are eager to join trials because often it is the only way to receive modern medical care.

Is this predatory? Are drug companies testing drugs on poor Russians in order to sell drugs to wealthy Americans, Canadians, and Brits? The answer is not so simple. The Russian government, apparently, is pretty excited to provide incentives for drug companies to conduct trials there:

…under a law passed in 2010, ostensibly on health grounds, foreign drug companies must test medicine on Russians for it to be marketed in Russia.

Posted in by Chris MacDonald, clinical trials, consent, international, poverty, recruitment

Interpreting Canada’s TCPS2

•January 17, 2012 • Leave a Comment

Canada’s Interagency Advisory Panel on Research Ethics has begun putting online its interpretations of the second iteration of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (a.k.a. “TCPS2″).

“The Interagency Advisory Panel on Research Ethics (the Panel) is pleased to share a growing collection of its responses to written requests for interpretation….”

The website also explains the role of the Panel in interpreting the TCPS2, as well as featuring a nifty feedback function attached to each interpretive note.

Posted in by Chris MacDonald, interpretation, regulations

Cracking Down on Research Misconduct at a Chinese University

•January 14, 2012 • Leave a Comment

Here’s an interesting bit on one Chinese university’s efforts to crack down on research misconduct:

From Nature: Research ethics: Zero tolerance — A university cracks down on misconduct in China.

Most readers of this blog will know that research misconduct doesn’t fall under the heading of Research Ethics, as that term is normally applied to the work of Research Ethics Boards and Institutional Review Boards. But neither are the issues entirely separate.

Here’s a paragraph I found particularly interesting, about the causes of misconduct:

Cao and other experts on misconduct point to specific contributing factors. China’s research system has developed very rapidly, and universities are scrambling to train the influx of students, scientists and administrators. “As a large, newly developed system of research, China does not have the control of its research programmes that is found in the West,” says Nicholas Steneck, who studies research integrity at the University of Michigan in Ann Arbor. Some researchers are simply oblivious to the rules, says Zhong Haining, a neuroscientist who trained at Tsinghua University and is now starting a lab at Oregon Health and Science University in Portland. “The official guideline for scientific misconduct may (or may not) exist, but it’s not very well publicized, at least not emphasized so much in training,” he says.

I wonder if the causes of misconduct are so different in other places?

Posted in Uncategorized

Research Fraud Case Raises Concerns Over Ethics of Psychology Research

•November 15, 2011 • 1 Comment

It’s a big story in research ethics and it has been reported in major newspapers all over the world. There’s even a Wikipedia page already about this case. The story centres on a fraud case against Diederik Stapel, a well-known psychologist and widely-published researcher at Tilburg University. It is claimed that Dr. Stapel drew inaccurate and false conclusions from analysis of collected data and also that he also falsified and “made up” entire experiments, which were written up and published in a variety of high profile journals, including Science and The Journal of Personality and Social Psychology, a publication of the American Psychological Association. Over his career, Dr. Stapel has published more than 150 papers which each, as the New York Times story about this case notes, are designed to “make a splash in the media” through provocative titles and topics. Not only have his own published papers been found suspect, many of the PhD theses he supervised have been found to be “tainted” according to a Science on-line magazine story.

Here’s one account of the case, from one of my favourite science writers, Benedict Carey of the New York Times: Fraud Case Seen as a Red Flag for Psychology Research

There isn’t a lot to say about this case that differentiates it from others out there about fraudulent conduct in science – there are plenty of stories about research fraud out there (far too many) describing claims of falsification of data, skewing of data, or misrepresentations of data, even “making up entire experiments”. But two things stood out for me the more I read about this case.

First, the claims of fraud extend beyond Stapel’s own work and publications. It’s not unusual to read stories about fraud that may imply that colleagues or lab assistants turned a blind eye, or wondered about the veracity of findings or the ‘incredible luck’ of colleagues with seemingly perfect data. But this case extends well beyond inattentive, ignorant or silent colleagues. In this case, Stapel, as a supervisor, included his own students in his fraud and has quite possibly ruined their careers and their prospects. The Tilburg University commission investigating Stapel’s misconduct has recommended that criminal charges may be appropriate based not only on the misuse of research funds, but also on harm done to these students. While many might ask, “Why would he also ruin the careers of students?” it would appear that the fraud was so extensive that he not only had no raw data to provide to students for secondary analyses or to inform their work, but that he really may not have ever conducted a well-run psychological study himself, in order to be able to guide someone else through the process. This “trickle-down” effect of research fraud is typically not addressed at all in stories like this even though it is clear that a key role of a senior scientist is almost always the mentorship of young scientists and researchers. The negative effects of scientific misconduct on those who are junior, who are entering the field with good intentions, thoughtfulness and enthusiasm is a serious potential fallout and one that should be treated just as seriously as the fraud or misconduct.

The second part of this story that interested me most was what Carey, writing in the New York Times, had to say. According to him, this case isn’t the straw that “broke the camel’s back”, rather it’s evidence that the camel’s back has already and most certainly been broken. Benedict Carey is a New York Times science and medicine writer since 2004. I’ve read plenty of Carey’s writing and he’s a smart journalist who writes thoughtfully and articulately about all kinds of topics in the science and medical research world. What Carey notes and the Science magazine story confirms is that one reason why Stapel was able to do this so easily is that he never showed anyone his raw data, nor was he ever required to do so. Incredulously, students who wrote their thesis with Stapel as a supervisor were not allowed to view raw data or data sets that were being used for their own papers. Some never even were allowed to conduct an experiment at all. The findings Stapel cited in many of this own studies his colleagues felt were “too good to be true” and their failure to be able to replicate these results were felt to be due to their own shortcomings. “Cutting corners” with data, “statistical sloppiness, falsifying data” and “reporting unexpected findings as predicted” are claims that Carey notes are prevalent in a discipline in which raw data are rarely shared in order to back up results or requested by reviewers to verify findings and conclusions. What I’ve found is that researchers in the area of psychology tend to keep datasets for long periods of time — longer than any other human-research discipline I’ve encountered. I find it interesting that no one, at any time, requested to see an anonymized dataset or something to back up the (often) controversial claims of Stapel. In ethics review processes, we often think about what we call “the life of the data”. We are concerned with what happens to datasets after collection and analysis are complete, details about how data are stored, and who might be able to access data in the future. From what I’ve read in research protocols about data management, researchers are not always thinking about the data as the very fundamental proof that can back up any claim they wish to make and publish. I often read graduate student research protocols, from a variety of disciplines, in which they state that the raw data will be destroyed as soon as the research or thesis is published. I always tell them that’s unwise — and that data should be stored for a reasonable amount of time after publication or dissemination of findings. It’s amazing, to me, that this is very often the first time (during the ethics review process) that anyone has talked to many new researchers about the idea that the data are there (and must be there!) as the fundamental link between a hypothesis and the claims made by a researcher.

It will be interesting to see if there is any further fall-out from this story. I’ll continue to follow the story and update it.

The University of Tilburg established a commission to investigate Stapel’s work and the claims made about fraudulent scientific conduct. As of two weeks ago, it is now available in English here.

Posted in by Nancy Walton, clinical trials, database, ethics committees, international, regulations, scientists, Uncategorized

What Scorpion Bites Can Teach Us About Placebo Trials

•August 14, 2011 • Leave a Comment

A recent story in Nature highlights a few important concepts in the conduct of placebo-controlled trials. This story is about a very small placebo-controlled trial involving only 15 children who were stung by bark scorpions in Arizona. The trial’s goal was to demonstrate effectiveness of a new antivenom, Anascorp. The bark scorpion is the only scorpion in the southwestern US thought to be potentially life-threatening for humans and, according to what I’ve read, is a very frequent and very unwelcome visitor in many Arizona homes.

Here’s a link to the story, from Nature: A tiny trial of 15 people helps convince the US to approve a drug that takes the pain out of scorpion stings

“It’s a rare, potentially fatal, emergency medical disease that predominantly affects rural children, and if you put all those adjectives together, it didn’t look possible to put [a placebo-controlled trial] together at all,” says Leslie Boyer, director of the Venom Immunochemistry, Pharmacology and Emergency Response (VIPER) Institute at the University of Arizona in Tucson, who led the supporting trial reported two years ago in the New England Journal of Medicine. “We started out with a daunting task.”

For one thing, trial investigators can’t enroll participants ahead of time because there’s no way of knowing who will get stung. Then there was the problem of getting hospitals to sign up to a placebo-controlled trial….”

This story is interesting because it demonstrates some of the difficulties with conducting placebo-controlled trials, and challenges with getting clear clinical research data about yet-to-be-approved treatments in the face of a life-threatening injury. It is also pretty unheard of for a trial involving such a small number of participants to be considered as clearly definitive as this one was.

First, it was difficult to think of using a placebo in the face of a potentially life-threatening scorpion sting. It would be unethical to agree to withhold any kind of treatment and to instead give a placebo to a child with the symptoms of a scorpion bite (which are described in the article as including “severe pain, extreme nausea, blurred vision and breathing problems”.) Children who experience such a reaction have difficulty, over time, coping with the pain and nausea, and extreme demands on the cardiopulmonary system can lead to more serious situations, including death. Faced with a child who has been stung by a scorpion, most parents would not wish to take the time to (a) go through an informed consent process in the face of such a potential emergency, and (b) go through a consent process when the end result might well be a placebo. As a parent, you’d want the antivenom and you’d want it fast, understandably. The researchers fully understood this dilemma and the difficulty with using a placebo in this case.

Second, there is another older antivenom that had been used between about 1965 and 2000. Produced at Arizona State University’s Antivenom Production Laboratory in Phoenix, this antivenom, while effective, was not highly purified, leading to anaphylactic reactions in many patients. Furthermore, the laboratory that produces it stopped making it. Some doctors and emergency rooms have stockpiles of the older antivenom drug and were, again understandably, very reluctant to withhold the old antivenom (which, while imperfect, did the trick) in order to enroll patients into a placebo-controlled trial.

So the researchers knew what they were up against, in terms of being able to conduct a placebo-controlled trial. And they also knew that, in many cases, a placebo-controlled trial is one of the necessary first steps in being able to make clear, quantitative claims about drugs in order to move forward to conduct larger trials investigating dosage, safety, side effects, etc. Once they got 2 hospitals to take part, they only needed 15 patients in order to demonstrate, quite definitively, that the new antivenom was, as the researchers say, “overwhelmingly effective.” The results were impressive: for all kids treated with Anascorp, symptoms resolved completely within 4 hours — compared to long, and more complicated recoveries for the kids who got a placebo.

Once word got out about the effectiveness of this new antivenom, a new ethical dilemma emerged. No one wanted to administer the old antivenom; nor did they want to be enrolled in yet further placebo studies. So Anascorp was made available, on an “open trial” basis, to all centres who might treat patients with bark scorpion stings. In a 6 year period, they effectively conducted the largest antivenom “trial” in history, with more than 1500 patients treated with the new antivenom, with only mild side effects. They then put together an FDA proposal to approve the use of the drug in treating scorpion stings.

Good news. As of August 4, 2011, the FDA has approved the use of Anascorp for use in scorpion stings. You can read about that here, if you’re interested (or live in Arizona!): FDA approves Anascorp for Use in Scorpion Stings.

Posted in by Nancy Walton, children, clinical trials, consent, pharmaceuticals, recruitment

Disclosing Conflicts of Interest: The Case of Tamiflu

•June 3, 2011 • 1 Comment

An interesting story recently from CBC highlights some of the difficulties with the topic of conflict of interest in medicine and biomedical research.

Here’s a link to the story:

CBC Tamiflu Probe Sparks Drug Policy Review

“In the course of the CBC investigation, Zalac also reported that three of Canada’s most prominent flu experts — Dr. Donald Low and Dr. Allison McGeer of Mount Sinai Hospital in Toronto, and Dr. Fred Aoki of the University of Manitoba — had received research funding or acted as a consultant or speaker for Roche during the period when Tamiflu was being promoted.

Their research involvement with Roche and other anti-viral drug makers was not a secret within the industry.

All three would sign the now standard conflict-of-interest declarations when speaking at professional events or publishing papers. And the Public Health Agency says it has always been aware of the drug industry affiliations of its private sector advisers and takes these into account. But these relationships were rarely reported in broader public forums, in the media or even when some of these individuals would appear in marketing videos or flu-warning commercials on television produced by Roche.”

In biomedical research, typically ethics review boards ask researchers to “declare” potential conflicts of interest to them. That’s great. It’s certainly a start. But once potential for conflicts of interest have been “declared” to ethics review boards (in what is, essentially, a confidential review process), what happens then? Do research participants always know about potential conflicts of interest that researchers have? Is this made explicit in an understandable way to participants?

This story demonstrates that conflicts of interest in health care and medicine (and biomedical research) are, often, handled in a fairly superficial or limited way with an emphasis on disclosure and little beyond that. In this story, the three key “flu experts” who were, in 2009, promoting Tamiflu as a key defense against the H1N1 flu were also found to have received research funds or acted as a speaker or consultant for Roche, the company that makes Tamiflu.The Public Health Canada Agency of Canada (PHAC) states that it was aware that these experts had affiliations with the drug company, but these relationships were not reported broadly to the public. The public were watching these experts and PHAC closely for advice and guidance. Should they have known more about the relationships between these experts and Roche, the company who makes Tamiflu?

Tamiflu was seen, by much of the public, as the panacea for H1N1 and avian flu. Governments stockpiled the drug, hoping never to have to use their vast stores. Now that these stores are approaching expiry, a decision needs to be made about either replenishing them or exploring new alternatives. Over the last few years, while these stockpiles of Tamiflu have been sitting in storage, other independent researchers have been exploring whether or not Tamiflu really is all it’s cracked up to be as a first-line drug for H1N1 flu. As the story notes, researchers are challenging the “fact” that Tamiflu reduces morbidity and hospitalizations from the flu. Furthermore,the side effects (including bizarre behaviours and delusions) thought to have resulted from taking Tamiflu are viewed as serious enough to perhaps warrant exploring other options.

When we look closely at this, it may well be that the relationships that these experts had with Roche do not constitute an obvious conflict. As science moves forward, recommendations and best practices change and this may well have been the case with Tamiflu. It may also be true that Tamiflu was the first line defense in 2009 and the research since then has shown that it may not be as good as we thought. These three experts may have truly felt that Tamiflu was, in fact, the best treatment for the flu at that time, while they were vigorously promoting it. However, without full disclosure of the relationships that they had with Roche and some clarity from the PHAC on how these potential conflicts would be managed, the public may well doubt their abilities to be objective about Tamiflu. It now appears that the PHAC may well be making changes to how they manage such potential conflicts of interest, in regards to their experts and advisors.

From the CBC story:

“As for the Public Health Agency of Canada, it released a statement that said it would be inappropriate at this point to release the drug company connections of its advisers without their consent.

PHAC says that its advisory committees provide advice but that the agency makes the final decisions. However, because of the questions raised in the CBC documentary, the agency said it “intends to establish a policy on the release of information relating to members of its expert or advisory groups/committees.”"

Posted in ethics committees, pharmaceuticals, regulations, Uncategorized

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