BMJ meeting on research misconduct and the need for a 'paradigm shift'
At the BMJ today research misconduct in the UK was discussed amongst academics, journal editors, policy makers and others.
Why does scientific fraud occur? Among the incidents of scientific fraud that David Goodstein has reviewed, three motives are more or less always present. In all the cases individuals were under career pressure, thought they knew what the result would be if they went to all the trouble of doing the work properly, and were in a field in which studies are not expected to be precisely reproducible.
Peter Wilmhurst, in the morning, talked about the case of Eastell who was suspended from Sheffield University, whislt Professor Clara Gumpert of the Karolinska Institute talked about the case of Suchitra Holgersson: a Karolinska scientist who tried to mislead with false documents.
“Substantial numbers of clinical trials are never reported in print, and among those that are, many are not reported in sufficient detail to enable judgments to be made about the validity of their results. Failure to publish an adequate account of a well-designed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions.”
Fiona Godlee, editor of the BMJ, is instrumental in the BMJ's ongoing commitment to identifying and reporting on research misconduct. She spoke recently on the importance and relevance of this exact issue on the BBC: should all medical research be published?
Who can sort the problem out? Journals and their editors are not in a position to be the custodians of integrity. “Editors are not the individuals to investigate cases of research misconduct and the responsibility lies with the institution,” said Elizabeth Wager, chair of the committee on publication ethics. COPE as it is known is a forum for editors and publishers of peer-reviewed journals to address aspects of publication ethics. It also advises editors on what to do in cases of research and publication misconduct.
The morning meeting also discussed policies in the US, Sweden and Germany and their different approaches to research misconduct. It seems there is alot of it going on at the professorial level but also within Phds. Watch out for the BMJ survey coming this afternoon on research misconduct in the UK amongst clinical researchers. I bet it shows there is substantial misconduct going on. It seems to me the incentives are so great for academic to publish, or not in some cases, that it will be a hard problem to solve.
Thomas Kuhn, in 1962 wrote, scientific advancement is not evolutionary, but is a "series of peaceful interludes punctuated by intellectually violent revolutions", and in those revolutions "one conceptual world view is replaced by another". What he referred to as a 'paradigm shift.' A shift that is needed to force action and find solutions to research misconduct.
Weighing up benefit and harm -net clinical benefit and subgroup analysis
The Hippocratic oath originally included the harm and good that doctors and their prescribed treatments can cause. The biggest challenge in today’s clinical practice is not much different. With increasing numbers of trials of different drugs in different patient groups with different comparison groups, how are patients and doctors ever going to see the wood from the trees? How do we make judgments about which drug to use in which situation?
NICE was set up in 1999 in order to help in these difficult matters. Broadly speaking, it looks at current trial evidence and uses the metrics of “cost-effectiveness” to decide whether to fund drugs and treatments in the NHS. It uses “quality-adjusted life years” (the ‘QALY') to measure effectiveness and then calculates the cost per QALY gained for a given drug. A drug must be effective in treating disease but the cost of the benefit must be below a certain threshold, usually £20000-30000 per QALY gained
One problem is that in trials, we tend to focus on benefits and not harms. Another problem is that the performance of drugs in different patients, even for simple characteristics like age and sex and poorly defined in many trials. Even more importantly, trials often do not report their outcomes based on the disease risk of the patients involved. Therefore we end up “painting all patients with one brush”. This has obvious problems. Cost effectiveness analysis is only as good as the trials which are studied and if those trials do not report outcomes (good and bad) properly, then analysis is difficult.
Atrial fibrillation (AF) is a heart rhythm problem which causes increased risk of stroke. Warfarin has been established as a safe treatment for over 50 years and reduces risk of stroke. However, it does lead to increased risk of bleeding, including intracerebral bleeds. Therefore, a way of quantifying the overall benefit of warfarin is to directly weigh up the risk of stroke and the risk of intracerebral bleeds as a “net clinical benefit”, as proposed by Singer and his colleagues in 2009. They reported that “Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category.” In other words, we should use the drug in the patients with the highest chance of benefit from the drug, or the highest chance of the adverse outcome (intracerebral bleeds).
Currently 3 new drugs (dabigatran, apixaban and rivaroxaban) have been evaluated in trials as alternatives to warfarin in the setting of AF. Each of these trials looks at different patients and uses different comparisons. In a recent analysis, we used data from the Danish National Patient registry to work out the net clinical benefit of these drugs at different levels of risk of stroke (potential benefit) and bleeding (potential harm) compared with warfarin. We also calculated the number of patients needed to treat and harm for each drug at each level of risk. Although, this is a modelling exercise, this type of analysis is needed in order to look at all the drugs side by side, using the best evidence we currently have. This idea of “net clinical benefit” could also be used in other disease areas in order to quantify to both health professionals and patients how good or bad a treatment is.
The truth, the whole truth, and 'nocebo' effects
Good practice demands that doctors inform their patients about both known and suspected side effects of any medication they prescribe. (In ethics-speak this is because of the requirement to respect patient autonomy.) On the other hand, the very act of providing information about side effects can produce negative effects (these are called ‘nocebo’ effects)! For example in a trial of a drug for unstable angina, patients were divided into two groups. The first group was given a statement outlining possible gastrointestinal (GI) side effects, and the second was not. Six times as more patients in the first group experienced subjective GI side effects.
How can doctors respect patient autonomy by revealing all information about side effects, yet avoid doing harm by causing the very side effects they describe? One answer is to give the information in the right way. We all know people who give negative feedback in a way that tends to increase anxiety. Others give the same information to evoke positive responses. Good teachers, coaches, and doctors all know how to frame information constructively.
Another solution is to ask patients. Some patients do not want to be burdened with details of all known and suspected side effects (serious side effects do, of course, need to be revealed). In these cases we can respect patient autonomy and withhold some information because the patient requested to be (partially) ignorant. Other patients do want to know about each and every side effect, in which case there may be little choice other than to reveal them, albeit in the right way.
So what’s the take home message? Tell the whole truth that the patient wants to hear and nothing but the truth in a way that will maximize benefit and minimize harm.