Seroquel, Sex, and Conflict of Interest

How refreshing! A story about conflict of interest in Big Pharma that's not about money!

Here's the story, from BNET Pharma: AstraZeneca's Sex-for-Studies Seroquel Scandal: Did Research Chief Bias the Science?

An AstraZeneca executive in charge of clinical research on Seroquel had sexual affairs with a researcher and a study writer, plaintiffs in a Florida lawsuit claim. BNET first wrote about the sex-for-secrets aspect of the Seroquel litigation on Feb. 17.

Now Furious Seasons blogger Philip Dawdy revealed a dynamite legal filing describing how Dr. Wayne MacFadden, AZ’s former US medical director for Seroquel and director clincial research in CNS had affairs with a clinical researcher who authored publications favorable to Seroquel, and a medical marketer who promoted Seroquel through medical publications and other means.

Can a sexual relationship put someone in a conflict of interest? Sure. Remember, a COI is just a situation where someone (the clinical researcher in this case) is expected to exercise judgment on behalf of others, and has some "other" interest (e.g., in continuing a sexual relationship) that stands to bias his or her judgment. The court filings suggest that this wasn't exactly a marginal case, either:

The nature of their communications suggest a level of control and dependence between Macfadden and these women.

The IOP researcher suggested that Macfadden would ‘punish’ her if she even looked at studies that were favorable to Seroquel’s competitors. He actively encouraged her to conduct research the results of which would be favorable to Seroquel and AstraZeneca, and promised sexual favors in exchange for intelligence on Astrazeneca’s competitiors.

Seriously, it is refreshing to see a conflict of interest story that doesn't have money at its core. It's worth reminding ourselves that while money may be reputed to be the "root of all evil," in real life human judgment is in fact subject to a whole range of biasing influences.

Olivieri, Apotex, Academic Freedom

Here's an update from the Canadian Association of University Teachers (CAUT) about the ongoing legal battle between researcher Nancy Olivieri and drugmaker Apotex. This time, CAUT's focus is on academic freedom:

Apotex vs. Olivieri: An Attack on Academic Freedom

A recent lawsuit filed by Apotex Inc. against Dr. Nancy Olivieri is a blatant attack on academic freedom, says CAUT. “Some of Apotex’s allegations in the lawsuit appear to be obviously absurd,” said James Turk, executive direc tor of CAUT. “It appears that Apotex is simply bent on preventing Dr. Olivieri from participating in discussion about systemic issues of public interest.”
...
“It is extremely troubling that Apotex, which describes itself as a major research company, should appear to have such small regard for the academic freedom that is at research’s very core,” says [CAUT Executive Director, James] Turk. “In my view, university teachers and the public at large should not hesitate to support Dr. Olivieri in opposing such a disturbing lawsuit.”

This is, as many of our readers will know, a landmark case in Canadian research ethics. At this point, what the CAUT story emphasizes is the often overlooked notion of academic freedom that researchers (and ethics review boards) can take for granted. The freedom to speak out is one that allows researchers to meet their ethical obligations by publicizing risk, highlighting adverse events or providing new information about risk or benefit that are uncovered as the research progresses. As James Turk from CAUT notes, the notion of academic freedom in this context, is clearly a matter of public interest.

Outsourcing Clinical Trials (Criticized)

The outsourcing of clinical trials to less-developed nations is clearly one of the hot topics in research ethics these days.

(For more about what outsourcing is, see my entry on this topic over at the Business Ethics Blog, here.)

For a good overview of the worries, see this commentary by researchers at Duke University, in the New England Journal of Medicine. Here's the full text of the paper: Ethical and Scientific Implications of the Globalization of Clinical Research (PDF). (You can also get a summary of the study in this NY Times story: Outsourcing of Drug Trials Is Faulted.)

Most of the NEJM paper focuses (rightly, I think) on questions about how tightly the relevant (local and international) standards are applied when clinical trials are conducted in developing nations — though as one expert (Zeke Emanuel) cited by the NY Times suggests, the NEJM article doesn't provide evidence that outsourced trials are being done badly...it just suggests that we have too little evidence that they're being done well.

The NEJM paper's weak point, I think, is in the area of justice. The authors assert:

Developing countries will also not realize the benefits of trials if the drugs being evaluated do not become readily available there once they have been approved.

The authors suggest this conflicts with the values embodied in a key international document:

The Declaration of Helsinki expresses an expectation that every patient enrolled in a clinical trial should, at the end of the trial, be assured access to the best proven therapy identified in the study.

That argument conflates 2 different issues. One is the question of whether participants in clinical trials will keep getting appropriate care after the trial ends (and that's what Helsinki talks about). The other is whether citizens, generally, in the country where the trial takes place, will be able to get access to the drug that (hopefully) results. The question of what is owed to research participants is entirely different, and should be answered in entirely different ways, than the question of what people in wealthy countries owe to people in poorer countries.

Research integrity and principal-agent theory

Here's a very interesting perspective on the notion of misconduct in scientific and medical research. This blog, called Understanding Society, is written from a philosophy of social science perspective by Daniel Little from the University of Michigan. This particular entry addresses research misconduct as an organizational problem and describes it as a "gigantic principal-agent problem".

Here is the original blog entry: Scientific misconduct as a principal-agent problem

It falls within the scope of the more general challenge of motivating, managing, and supervising highly skilled and independent professionals. The "agent" is the individual researcher and research team. And the "principal" may be construed at a range of levels: society at large, the Federal government, the NIH, the research institute, or the department chair. But it seems likely that the problem is most tractable if we focus attention on the more proximate relationships -- the NIH, the research institute, and the researcher.

So this is a good problem to consider from the point of view of institutional design and complex interactive social behavior. We know what kind of behavior we want; the problem is to create the institutional settings and motivational processes through which the desired behavior is encouraged and the undesired behavior is detected and punished.

The principal-agent problem can be described very simply as a situation in which an agent who is contracted to carry out a particular function or role (e.g. a researcher) has unique interests, which may or may not reflect those of the principal (e.g. an employing institution). However, a principal only has a limited ability to monitor the activities of an agent and how they may or may not advance their own interests as they carry out their role.

The questions that Little raises as he views scientific misconduct from this perspective are important ones to consider. Who do we consider to be the principal in scientific research? Is it the researcher's institution, funding agency or the governmental body who provides oversight of research or even society at large? Furthermore, how do they achieve the kinds of behaviours they want to see? What kinds of constraints, rules or sanctions need to be in place to encourage the ethical conduct of research? These are all good questions and there are few clearly adequate answers. It's worthwhile to consider the problem of scientific and research misconduct from this perspective.

For those of you who are unfamiliar with the principal-agent problem, here is a link to a simple and short explanation by Khalid Abdalla in Region Focus: Jargon Alert

Facial Transplantation

Here's a new story about highly experimental transplantation. This is an example of innovative research that few ethics review board members will ever have a chance to see. From CNN:

Face transplant patient regains self-confidence

The woman who received the first-ever near-total face transplant in the United States told her doctor she has regained her self-confidence, said Dr. Maria Siemionow, head of plastic surgery research at the Cleveland Clinic and leader of the transplant team.

The patient, who prefers to be anonymous, is finally able to breathe through her nose, smell, eat solid foods and drink out of a cup, Siemionow told participants of the annual meeting of the American Association for the Advancement of Science in Chicago over the weekend.

Innovation as research is a common (and necessary) way by which the science of surgery is advanced. Some innovations in surgical procedures occur on the fly, in individual operating rooms, often as a result of necessity or desperation. Ethics review boards only learn about those kinds of innovations when larger trials are proposed to test more rigorously the innovation that worked or looked promising the first time around. This case is different, however. Siemionow, a researcher with twenty years research experience on facial transplanatation, got approval from the IRB at Cleveland Clinic to conduct the transplant.

For even the most experienced research ethics board members, a protocol like this would be challenging to review. It would, for example, be unusually difficult to assess potential benefits against risks of harm in a case like this. A review would have presumably required significant expertise on the innovative methodology as well as substantial information on the criteria for a potential patient that would be eligible for this innovation. For background reference, one would have only information from three successfully completed facial transplants (without knowledge of long term risks and outcomes). To some extent, one would be approving not just a research study per se, but essentially providing permission for a surgeon to collaborate with a patient (who has no other realistic options for treatment) seeking his or her consent to undergo a potentially life-changing surgical innovation, the long term risks and benefits of which are unclear.

Innovation is important and necessary. It provides opportunities for individual patients who, as in this case, have no other viable options. As the science of surgery and transplant continues to advance in this way, ethics review boards who deal with clinical research arguably will need to be prepared to deal with more and more innovation as research.

(I blogged back in October about Double arm transplant, and focused in particular on whether such a transplant counted as innovation or as research.)

The Wakefield story and the need for clarity

Here's another story about the ethical issues that arise in the reporting of research findings.

The Andrew Wakefield case has been the subject of many articles, blog entries and commentaries over the past few weeks. The story broke a few weeks ago in the UK Times, claiming that Wakefield misrepresented the relevant data for his February 1998 article in The Lancet, connecting autism spectrum disorder to the MMR vaccine.

Here is the original story from the Times: MMR doctor Andrew Wakefield fixed data on autism

The research was published in February 1998 in an article in The Lancet medical journal. It claimed that the families of eight out of 12 children attending a routine clinic at the hospital had blamed MMR for their autism, and said that problems came on within days of the jab. The team also claimed to have discovered a new inflammatory bowel disease underlying the children’s conditions.

However, our investigation, confirmed by evidence presented to the General Medical Council (GMC), reveals that: In most of the 12 cases, the children’s ailments as described in The Lancet were different from their hospital and GP records. Although the research paper claimed that problems came on within days of the jab, in only one case did medical records suggest this was true, and in many of the cases medical concerns had been raised before the children were vaccinated. Hospital pathologists, looking for inflammatory bowel disease, reported in the majority of cases that the gut was normal. This was then reviewed and the Lancet paper showed them as abnormal.

Wakefield's response can be found here: Autism, bowel disease, and MMR vaccination: In his desperation, Deer gets it wrong once again.

Since the story broke, there have been numerous commentators on both sides of the fence, some wholeheartedly supporting Wakefield (and his co-authors) along with his data and others who are quick to vilify him. There isn't much to say that hasn't already been said or claimed.

So, what's missing?

Clarity.

While most blogs and commentaries agree that this issue is one of incredible importance, not just for parents of children with autism but for all parents making decisions about immunizing their children or not, few have tried to sort out what is a very messy story. Even Andrew Wakefield's response does little to debunk the claims of Brian Deer, the Times reporter who, according to other sources, has been on a "witch hunt" for Wakefield for many years. The response is lengthy, somewhat rambling and written in high-level medical terms. Researchers are typically encouraged to present documents such as consent forms, information sheets and debriefing material to participants in a way that is simple, easily understood and written in lay terms. Arguably, this also applies to dissemination of research data for public consumption and in the mass media. At this point, clarity and simplicity is required to help those following the story get accurate and accessible information.

Researchers owe it to the public to do their best to ensure that their findings and interpretations of their data are presented accurately and simply through the mass media. Despite the fact that the original article had a sample size of only 12 children (and Wakefield's claims are modest at best about the correlation between autism and immunization), once the media got hold of the story, many viewed the small study as a landmark article. According to the media, rates of immunization dropped from ~ 92% to 80% in the UK and many journalists claim that this is a direct result of the Wakefield article. First of all, that is a difficult claim to make. Second of all, it is quite likely due to the way that journalists actually interpreted and reported the Wakefield data rather than the data as presented in the Lancet article.

The link between autism and immunization is, for many, a seemingly never-ending and confusing debate. Now, with this disturbing story, many parents, both those with children who have autism and those thinking about whether or not to immunize their children, are simply looking for some clarity on an issue that is already both widely misrepresented and grossly misunderstood. Without taking a side about the quality or veracity of Wakefield's data or Deer's reporting, they both owe it to the public to present some simply stated facts to help clarify what is now an even more muddled topic.

Nature on Race, IQ, and Science Worth Doing

As part of it's 3-issue celebration of Charles Darwin's 200th birthday, Nature is featuring a debate over the question, "Should scientists study race and IQ?"

Here are the for & against articles:

Should scientists study race and IQ? NO: Science and society do not benefit, by Steven Rose

Are there some areas of potential knowledge that scientists should not seek out? Or, if they do, should they keep the knowledge secret, hidden from the hoi polloi? Certainly Francis Bacon, that great theorist of the birth of modern science, thought so. For with knowledge comes power — potentially dangerous power. In his utopian novel The New Atlantis, scholars determined which of their findings were too dangerous to be shared. Modern governments, obsessed with biosecurity, make similar decisions about what can be researched, how, and in what way disseminated. Private companies bind researchers with non-disclosure and confidentiality agreements. Genetic tests for disorders that have no treatment, such as late-stage Alzheimer's, are often not offered for ethical reasons. As Steven Shapin's book The Scientific Life documents, the idea of free, untrammelled and publicly-disseminated research, if it ever corresponded to reality, looks distinctly unrealistic today.

To meet the canons of scientific enquiry a research project must meet two criteria....

Should scientists study race and IQ? YES: The scientific truth must be pursued, by Stephen Ceci & Wendy M. Williams

The Soviet Union lost a generation of genetics research to the politicization of science when Trofim Lysenko, director of biology under Joseph Stalin, parlayed his rejection of Mendelian genetics into a powerful political scientific movement. By the late 1920s, Lysenko had denounced academics embracing Mendelian genetics, which some said undermined tenets of Soviet society. His efforts to extinguish 'harmful' scientific ideas ruined opponents' careers and delayed scientific progress.

It is difficult to imagine this situation repeating today, when rival views feed the scientific process, and inquiry and debate trump orthodoxy. Yet the spectre of Lysenkoism lurks in current scientific discourse on gender, race and intelligence.....

Oral Sex (Yes, Oral Sex) and Academic Freedom

This isn't about the protection of human research subjects.

But it's about the value of academic freedom (and, consequently, about the value of peer-review as an internal check that is part of what justifies our claim to such freedom).

Here's the story, from the Atlanta Journal-Constitution: "Sex experts on faculties upset some at statehouse"

Criticism is building against Georgia’s University System for employing faculty members who are academic experts in such areas as oral sex and male prostitution.

Friday, several days after Rep. Calvin Hill (R-Canton) said he was “personally outraged” over the issue, a second member of the state House echoed his criticism, drawing applause from some colleagues.

Also Friday, Jim Beck, president of the Georgia Christian Coalition, said he wants legislative committee hearings to sift through the facts. “We are concerned,” he said, “if the initial reports are true.”

The dust-up has raised questions about the role of higher education, the value of research and the importance of academic freedom. It also raises the possibility of a culture war in the General Assembly over Christian values and public policy.

University System officials defended the faculty members Friday. “Our mission is defined as teaching, research and public service,” said John Millsaps, a spokesman for the state’s Board of Regents. “That encompasses a broad range of interest and expertise.”

This, of course, is precisely why principles of academic freedom — including the tenure system — are so important. They're important because you never know when some ill-informed legislator will get all fired up an demand that profs be fired just because s/he doesn't understand the value of their work.

The new draft Canadian federal guidelines: Is there more to say?

Our Canadian readers will be well aware that right now, the Interagency Advisory Panel on Research Ethics (PRE) is in the middle of doing cross country town-hall style discussions on the new draft of the Tri-Council Policy Statement (TCPS). Officially launched in December 2008, this new draft is the result of a great deal of ongoing consultation with stakeholders across Canada. For the most part, it reads very well. The kinds of changes people said that they wanted appear in the document. There is increased clarity about previously confusing issues. There is more said about research in the social sciences and humanities, about qualitative and emergent research methods. Aboriginal research is discussed in much more detail. Risk is approached in a much more realistic manner. All of these are very good things and those attending the town-halls and focus groups are echoing these sentiments.

In the spirit of keeping the TCPS a living document as was always intended, PRE is open to continuing feedback — thus the cross-country discussions. One interesting thing that came up at the Toronto focus group for research ethics board Chairs and administrators (which I attended) was that more needs to be said about what kinds of things are exempt from research ethics review. This is something with which ethics review boards are grappling more and more, and yet the TCPS says little. Here is an excerpt:

Article 2.4 Quality assurance and quality improvement studies, program evaluation, and performance reviews or testing within normal educational requirements are not subject to research ethics board review. Application Studies related directly to assessing the performance of an organization or its employees or students, within the mandate of the organization or according to the terms and conditions of employment or training, do not require REB review. Activities other than research as defined in this Policy may still raise ethical issues that would benefit from careful consideration by a body capable of providing some independent guidance, other than an REB.

Here are three points that came up in our discussion, and that hopefully PRE will take forward:

1. The number of projects that fall into one of these categories (quality assurance and quality improvement studies), and that end up coming across the desk of most ethics review board Chairs, is growing. The TCPS is clear about one thing: If there is doubt about whether a project requires research ethics review or not, it needs actually to come before the board for assessment. This is problematic for two reasons. First, it is a significant additional workload for already overworked Chairs. Second, we’re all doing it differently! So multi-centre projects are deemed to require review at one centre and then deemed to be exempt from review at another. For researchers, this looks like inconsistent application of the federal guidelines. Inconsistencies are acceptable, as reasonable people might disagree on whether a project requires review or not. However this really isn’t inconsistent application of guidelines per se, because the TCPS provides too little guidance when it comes to how to decide the difference between a quality improvement project or program evaluation and a research project.

2. The TCPS indicates that those projects that are not deemed to require research ethics review could be “covered” by discipline-specific best practices documents, codes of ethics or professional codes of conduct. But many disciplines either don’t have such a code or if they do, those documents don't relate to the ethical conduct of "research". So many researchers conducting program evaluations or quality improvement projects as their “research” aren’t sure where to go to have an expert body give their project the “ethical thumbs up” so to speak. As a result, they are asking ethics review boards to overstep their jurisdiction and review their projects. This is a new phenomenon and one that most boards are, understandably, more than a little hesitant to do. And it’s not just about hesitation to take on extra work or to overstep a boundary. The TCPS simply doesn’t address any specific issues related to quality assurance or improvement projects or program evaluations.

3. PRE is correct in stating that it isn't only research projects that should be carried out in an ethically sound manner. Few would disagree with the assertion that program evaluations and quality improvement projects should also be done with integrity, protecting the rights and autonomy of participants without exposing them to an undue risk of harm while producing benefit.

Most ethics review board Chairs share the same three concerns related to the issue of assessing and reviewing these kinds of projects: First, it represents additional responsibilities for Chairs who are in positions most institutions view as simply an “additional duty”. Second, it is clearly overstepping the jurisdiction of ethics review boards to review projects deemed exempt according to federal guidelines. Finally, there are significant inconsistencies between ethics review boards in their decision-making about what is exempt in the first place.

PRE is conducting further discussion of the new document at their half-daypre-conference session one day prior to the NCEHR 2009 Annual Conference in Ottawa from February 21-22.

When Alternative Medicine Researchers Go Wrong

Research ethics scandals aren't common in alternative medicine, presumably mostly because there's, well, so little research done. When you start actually verifying whether your treatments work, you can get into new kinds of trouble.

See this item, from China's Xinhua News Agency:

Fake research papers cast TCM to shame

A Chinese researcher on traditional Chinese medicine (TCM) has been caught "plagiarism and fake research" in papers published in international journals, according to newspaper reports.

The four papers, each with the same lead author, He Haibo, associate professor with the Zhejiang University, had been retracted by the international journals, the Guangzhou-based 21st Century Business Herald reported Tuesday.

One of China's top TCM experts, Li Lianda, a member of the Chinese Academy of Engineering, was also implicated in the scandal as Li was listed as one of the co-authors of all the four papers.

The nice music shop clerk who recommended "ginger tea with honey" for my cold, this morning, can be forgiven for having no clue about the clinical efficacy of her prescription. People who call themselves health professionals can't.

FYI, here's Wikipedia's entry on Traditional Chinese medicine.

Is Behaviour Tracking Minimally Invasive?

Here's an interesting story about research into using RFIDs (radio frequency identification tags) to detect early signs of dementia.

From MIT Technology Review: Wireless Detectors for Dementia

Researchers at the University of South Florida (USF) have developed a wireless network that evaluates walking patterns in an attempt to detect early signs of dementia.

Currently, doctors ask patients to answer a series of questions to determine whether they may be suffering from Alzheimer's or another form of dementia. But by the time a patient is diagnosed, she may have already begun to experience symptoms such as memory loss. Drugs that are currently available can only slow the progression of related diseases, so the earlier dementia is caught, the better a patient's treatment will be.

Researchers are exploring ways to identify the condition earlier--for example, by detecting biomarkers, conducting new brain scans, or monitoring movements such as walking. The USF researchers have developed an RFID system that allows walking patterns to be monitored in a natural setting.

It's a neat technological idea, if they get it to work. In the meantime, it's research.

I wonder if USF regarded this as human-subjects research? Wearing a tracking device isn't terribly invasive, but having your movements precisely monitored, 24 hours a day, might be. Informed consent should have been sought from the patients wearing the monitors (all were residents in a long term care residential setting) or their proxy decision-makers. It might not be invasive physically, just wearing a wrist monitor, but certainly it is an invasion of privacy to have someone else monitoring and tracking your every movement — if you haven't consented to it.

Also worth noting that this is research going on within an institutional setting. Does that raise the bar? Yes. We consider research on persons who are institutionalized, such as offenders or patients in any kind of residential treatment centre or mental health facility, to be more "vulnerable" because of the inherent constraints on their ability to make choices. Whether a choice to participate in research, by someone who is institutionalized, is "freely made" or voluntary is difficult at best, to assess. So, yes, it raises the bar in terms of all sorts of considerations — not just the volition aspect of consent &ndash but also how participants are compensated as well as what types of research can and should be done on what are essentially, captive subjects.

This research — and it is clearly research — is a worthwhile endeavour. But hopefully it wasn't done at the expense of persons' dignity and privacy or without consideration for the voluntary nature of participation, a right to which all participants, in all contexts, are due.

Just to clarify: I'm certainly not claiming that any of the researchers in this story did anything wrong, or that the research wasn't properly vetted. But to a casual reader, what appears to besimply a fascinating advance in patient care actually raises noteworthy research ethics issues.