Peeling the onion of financial conflicts of interest - Publishing research

Financial conflicts of interest in research bias towards results, conclusions and recommendations that favour the interests of the sources of the money.  Even though those receiving the money or financial support for their projects 

{Photo Credit - Darwin Bell}
always claim theywere not biased, abundant hard evidence shows just the contrary.

Knowing this, health sciences journals have played a leading role in helping to reveal the conflicts: Initially by providing general guidance for authors about disclosure and then, when that didn’t work, by asking explicit questions about financial relationships with individuals or institutions that might benefit or lose or otherwise be affected by the research, review or opinions expressed.  Editors hoped (without any evidence and indeed with little probability) that published revelations would help readers detect biases or at least increase levels of skepticism.

There have been, however multiple loopholes in the process of revealing and reporting conflict of interest the least of which was addressed by a recent proclamation of the prestigious International Committee of Medical Journal Editors (ICMJE).<1> 

Many authors claimed not to know that their relationship with such and such an institution, company, product or patent etc., was a financial one and therefore did not disclose it. Or they believed they needed to reveal the relationship only if they thought it influenced their research. The most recent ICMJE remedy is a set of definitions of what constitutes a financial conflict of interest along with a prototype for reporting such conflicts.

This timid step is not entirely unhelpful. We should see more honest reporting of the type that Author X owns shares in company Y making product Z that is mentioned in their research, review or commentary.  Medical journals, scarred by multiple humiliations of failure to detect and report authors with financial conflicts of interest to their readers ought to have an easier time of it. Their journals will be less likely to hear, after publication, that a particular author failed to understand that he or she had an unreported conflict of interest.

But will this help the readers, patients or other researchers? Knowing that authors of published research have conflicted financial relationships does not mean that the research is flawed. So how should we, the readers,  interpret such statements as;  author X’s study was funded by company Y or that author X, writing a commentary in a journal, receives speaker fees from company Y?  Given that research, reviews and commentary articles by authors with financial conflicts are more likely to be biased does not explain how these conflicts get translated into results, opinions and conclusions and from there to influencing the reader, often a prescribing physician.

For research articles, which form the basis of knew knowledge, this is especially important. Readers and journal editors need to know more about financial relationships between researchers and their sponsors: Not just that they exist.

We know many of the mechanisms embedded in financial conflicts of interest that result in biased studies and biased study reporting in journals.  The recent revelations made public in the class action law suit pitting Pfizer Inc., the maker of Neurontin (gabapentin), against patients who received the drug show that financial conflicts influence and are directly related to  biases in study design, analysis, interpretation, write-up and publication of research. (an in depth review of some of this is here) A summary article of part of the problem was recently published. (article here)<2> 

The law suit and discovery documents associated with it reveal the many ways that researchers lose control of their studies by relinquishing study design, execution, data collection and analysis, interpretation and even writing up of the study and subsequent publication to company sponsors of the research.

We and others have found that in random samples of researchers these sources of real bias are highly prevalent. For example in our study (in press)  only 11% of over 700 Canadian investigators of randomized trials registered in the clinical trials data base had control over 11 key aspects of their research: study design, data collection, analysis, writing up their papers, deciding when and were to publish and so on. (abstract here - then dig into program abstracts) <3> Most had very little control over multiple aspects of the research.

It is important, that ICMJE and journal editors further peel the onion of financial conflict of interest. In situations where there are declared conflicts of interest authors need to report and journals publish details of the research sponsors' roles in the research and in the write up of the manuscript and decision to publish. Editors need to know who had ultimate responsibility for study design, data collection, analysis, write-up and decision to publish.

Some will argue that supplying such detail is unnecessary, time consuming and bureaucratic. These same individuals will also argue that although they may have competing financial interests, these are not conflicts and their presence did not (and does not) influence their integrity as researchers; contrary, however, to a widening body of research that proves the opposite.

Certainly supplying more detail on the relationships between researchers and sponsors will require additional effort and a bit of time. The process can be simplified. In our work, led by Dr. Paula Rochon at the University of Toronto, we have designed an easily-used electronic reporting template that takes about 10 minutes to complete. The ICMJE should consider adopting this template. For randomized controlled trials, trial registries should insist that these key aspects of human research be revealed when studies are first registered. The financial conflicts could be published along with the other aspects of trial design and recruitment.  Research ethics boards should not approve research on human subjects that is shackled by sponsor control over critical aspects of the research. REBs should have ready access to detailed information on conflict of interest and its effects on research they are evaluating. 

The Canadian Institutes of Heath Research (CIHR) is expected to  adopted a checklist based on the one we developed for use in their grant proposal evaluations.  We urge ICMJE and clinical trials registries to push harder at conflict of interest and adopt a similar template as well.  Fuller disclosure can only be helpful.

1.Drazen JL et al.  Uniform format for disclosure of competing interests in ICMJE journals. N Engl J Med 2009;361:1896-7 (full text here)

2. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label ues. N Engl J Med 2009;361(20):1963=71 (free abstract here)

3. Investigator Experiences With Financial Conflicts of Interest in Clinical Trials. Paula A. Rochon, Melanie Sekeres, John Hoey, Joel Lexchin, Lorraine E. Ferris, David Moher, Wei Wu, Sunila R. Kalkar, Marleen Van Laethem, Andrea Gruneir, Jennifer Gold, M. James Maskalyk, David L. Streiner, An-Wen Chan. Peer Review Congress, Vancouver, 2009 (full abstract here - pdf of conference abstracts)

The sacred and overly screened female breast - new recommendations rightly recommend discontinuing screening mammograms in younger women.

The United States Preventive Task Force recently released its latest guidance on screening healthy women for breast cancer. To general astonishment the Task Force recommended that mass screening for breast cancer in healthy women between the ages of 40 ad 40 be stopped, along with efforts to teach women to regularly palpate their own breasts, searching for lumps and bumps.

Image Ductal Carcinoma in Situ From - Breast Cancer.org

The Task Force, an unbiased group of experts in cancer screening, epidemiology and disease modeling of effectiveness determined that the potential benefits were slim and greatly outweighed by the very real harms.Public and political reaction to the announcement was immediate, appropriately embedded in current socio-political narrative of women’s health and widely dismissive of science and evidence: Responses were irrational and often personal - claiming that the members of the Task Force were ‘Bush appointees’.  

I have sympathy for a cult that celebrates an organ which is both a procreative and nourishing. I too would wish it no harm: The point of the Task Force recommendation, however, is that screening for small cancers in the breasts of women between the ages of 40 and 49 years is harmful. How can this be so?

Harms and benefits need to be considered together. It is a rare human environments that sees benefits without risks or harms. For breast cancer, the benefits are often tritely and misleading summed as ‘curing’ cancer. Breast cancer advocates regularly proclaim that breast cancer can be cured, beaten, vanquished, extinguished, destroyed, survived. There are testimonials. But what exactly is a cure?

Common sense has it that ‘cure’ means the particular disease has been eliminated and will never, ever, ‘come back’. We don’t know that for sure about breast cancer, or indeed about almost all cancers. We do know that some women with breast cancer live a long time with the disease and it does not seem to bother them very much. Others suffer greatly and live only a short time. These women can have what appear to be similar types of breast cancer when they are first diagnosed.

Scientists and rationalists, therefore, don’t use the word ‘cure’: They use ‘survival’ and survival rates. What is measured is survival after diagnosis for say 5 or 10 years. Thus we can measure the effects of different treatments including screening with mammography for breast cancer in metrics of 5 or 10 year survival rates. It appears true that the 10 year survival rates for women aged 50 to 69 who are screened by mammography for breast cancer are slightly more likely to still be alive and less likely to die of breast cancer in the 10 years after screening than women who are not screened. This is not cure necessarily (and usually isn’t), but it is an improved chance of survival.

These ‘odds’ are often expressed as the number of women who would need to have a mammogram and the associated treatments if the mammogram was positive in order that one woman’s life would be extended. For women aged 40 to 49 this number is 1,904. This means that 1,904 women would have to be screened in order for 1 woman to benefit from the screening. Looked at this way we can say that 1,903 women would have had an unnecessary mammogram.

How can a mammogram be harmful? There are several harms that are relatively trivial and can be ignored - the hassle of getting the mammogram, the discomfort of the procedure, possible anxiety while waiting for the result. But there are others that are more serious.

First, there are the false-positive mammograms. The mammogram shows a potential lesion and there is then a biopsy or lumpectomy that turns out to be negative for cancer. Both procedures are more than trivial and the latter may deform the breast.

Secondly, and most importantly, by far the most common type of cancer detected is called a ductal carcinoma in situ (DCIS). The cancer is classified by looking at it under a microscope. Almost all cancers detected by mammograms are of the DCIS type. We don’t in fact know much about this type of ‘cancer’. But it is clear that many of these cancers spontaneously revert to normal with no treatment.

Unfortunately we don’t know how to separate those that require treatment fro those that don’t. So the standard practice is to treat them all as malignant (even though we know that most are not). The harms associated with treating a benign tumour are unnecessary surgery (which is often deforming) and the associated chemotherapy and radiotherapy. There is also real anxiety that persists for years and decades of follow-up visits to check for spread of the tumour. Cancer is not a trivial diagnosis.

Difficult decisions are always difficult.

The Task Force could have sidestepped this decision by simply presenting the information - the data - and leaving it to the woman to assess risk. But it didn’t. The Task Force, recognizing that such a decision is all but impossible on individual grounds, made a clear recommendation - for the average woman aged 40 to 49, the odds of improved survival from breast cancer that come from mammography are so small and the odds of having to go through unnecessary surgery and radio/chemotherapy so large that most women in this age group should not have mammograms.

The implications of this recommendation are multiple. First the recommendation ought to mean that as a society we cease to promote mammography screening for women aged 40 to 49. Promotion means organizing screening programs and advertising and promoting them. The evidence indicates that such promotion puts 1903 women at risk of harm in order to possibly prolong the 5 or 10 year survival of 1 woman.

To my mind the Task Force has it right. For the average woman aged 40 to 49, mammography is harmful and should be avoided. Individual women and their physicians might decide otherwise, based on other factors such as family history: But as a public mammogram screening program promising that benefits outweigh harms is a misleading and itself harmful.


Reference:

The Natural History of Invasive Breast Cancers Detected by Screening Mammography
Arch Intern Med. 2008;168(21):2311-2316. get article

Swine flu in the nursing home...Should patients with chronic dementia get aggressive care?

This situation will surely arise during the current influenza season.

In the Nursing Home where I work about 20% of the residents have a long standing dementia. Most are unable to recognize me although I will see each of them about every 4 weeks for one reason or another. Many have family members they do not recognize (although the bedside walls are often covered with family photographs). Most are incontinent and wear rubber panties or diapers. Almost all are getting several medications for Alzheimer’s Disease, depression, and/or behavioural problems such as continuous crying. A few have decreased food intake and are losing weight, but most eat a little. About half are bedridden. Their average age is well over 80 years.

All will be offered and probably get seasonal and pandemic 2009 A(H1N1) vaccines. All have received pneumococcal vaccine. Although this should prevent influenza infections, it may not - the very old respond poorly to vaccination and their natural host defenses are compromised by age and perhaps use.

Influenza used to be called (by those who are not yet old) ‘the old man’s friend’ because it provided relief from chronic discomfort by a quick death. But my patients, almost all, are not chronically uncomfortable. They smile, they may, if incoherently, speak. They eat, some can walk a little with assistance, they generally sleep fairly well, most with a chronic sedative of some sort administered more out of habit than necessity I expect.

Most have next-of-kin who visit regularly and have power of attorney. So it will not be for me to decide to transfer a resident with a severe respiratory infection to an intensive care bed somewhere. But I will be asked by next-of-kin for advice.

There are ponderable ethical issues; should age or dementia be disqualifiers for scarce medical care; are the demented ineligible for medical care in some circumstances; others perhaps. I don’t know the answers here.

But what are the medical issues? A recently published study of 323 nursing home residents with advanced dementia in the U.S. demonstrated that over a period of 18 months, 55% had died and that during their last 3 months of life41% underwent at least one burdensome intervention (hospitalization, emergency room visit, parental therapy or tube feeding). <1>
Certainly a viral or bacterial pneumonia would be one further cause of dying. I expect that few of these patients would survive even if admitted to an intensive care unit. But then, dyspnoea (shortness of breath) is a distressing symptom and patients deserve relief whatever their mental status or functional state. In my nursing home we have no oxygen available: such patients will have to be transferred to hospital emergency rooms for simple symptom relief even though there is a very high probability of death.

There is no algorithm for this ethical and clinical care dilemmas. Case by case, with the goal being to bring comfort to the patient.


1. Mitchell SL et al. The clinical course of advanced dementia. N Engl J Med 2009;361:1529-38

Pop’s up again...

I’ve had a year. Well almost a year since the last post.

Here goes again.

A brief explanation involves describing a move to this Island off the coast of Maine and New Brunswick http://www.flickr.com/photos/bubbalouie
~ about 2,000 permanent residents along the 15 or so miles of coastline on the East side of the island (there is no road on the West side), living in 3 or 4 villages (numbers depending on definitions) situated each in a cove that once sheltered fishing boats alas now almost gone (except for lobster and whales-watching tourists), a thriving high school (surprising in a way), a small hospital and nursing home (where I do a little internal medicine - aka geriatrics) and a fabulous bakery (that operates in the tourist season), a tourist season that thrives because of the beauty of the place and ancient migratory bird routes that touch down along the its coasts and archipelago.

In the interim - it’s almost as if I returned from space - we have Obama and hope, Michael Jackson and death, the US moving distinctly to public health care, the Canadian Medical Association moving in the opposite (and self-interested) direction, a continuous stream (perhaps now a river) of revelations of pharmaceutical company driven manipulations of drug trials (doing, analyzing and interpreting and reporting all designed to promote drug benefits and minimize drug harms), and perhaps not much else worth noting.

I did speak at the annual COPE meeting in London earlier this year. COPE (Committee on Publication Ethics) is the brilliant idea started about a decade ago by the Richard’s Smith (BMJ) and Horton (Lancet). The editors were dealing with issues of misconduct - author, publisher, sponsor and had: A) no place to discuss these problems - were they problems? Yes - an B) no UK national organization to deal with them - What does an editor do when he/she discovers an author has fabricated scientific data? For example.

COPE has carried on and is now an international organization with a growing audience and membership. Liz Wager is the current President. Worth checking out if you are a journal editor. http://publicationethics.org/

Equator-Network www.equator-network.org is also working in the same area, but is focused on improving the reporting of research studies. Most published studies - and I mean most - probably well over 50% - are incomplete when published. Incomplete means missing key information that permits the discerning reader (and we should all be discerning or better discerning and extremely skeptical) to determine if the design, methods, results and interpretations are valid. Part of my COPE talk www.slideshare.net/hoeyj/editorial-integrity-conflict-of-interest showed how Pfizer published manipulated research on its drug gabapentin (Neurontin) that eventually found its way into national US guidelines for treatment of patients. Work done by Kay Dickerson for the plaintiffs - full report worth reading is at http://dida.library.ucsf.edu/tid/oxx18r10

And to wrap up for today’s post a few observations on medical practice in 2009 vs. medical practice in 1993. Yes 1993, the last year that I saw patients. I went back into practice for a couple of reasons not worth discussing here, but the really striking differences between practice in ’93 and practice in ’09 are:

A) Lots of new drugs - and so many are but minor atom changes on the underlying chemical (i.e. within a class they’re all pretty much the same).
B) But most of them - pretty much all so far that I’ve encountered - are largely ineffective or so mildly effective that patient’s don’t get any better
C) A few new laboratory tests - especially imaging - that produce such exquisite diagnostic information that physicians find test ordering irresistible because of curiosity and, and fear of malpractice suits for ‘missing’ something, usually untreatable.
D) Except in the nursing home where because of age or dementia, patients seem to be diagnostically neglected.
E) Information availability. It is so much fun to be able to look things up - books, recently published papers, systematic reviews, and so on - sitting here in my study. I think I’ll be a better physician, even after the decade long layoff.

More on practice later.