The growing global health inequality of new drugs and clinical trials
At the European Cardiology Congress in Paris this week, the news is that cardiovascular medicine is still producing tonnes of new research and there are therapeutic advances in all areas from atrial fibrillation and stroke to heart failure and heart attacks. For example, there are 3 new oral anticoagulants (blood-thinning drugs) which offer true alternatives to warfarin for the first time in 50 years. All these drugs have shown superiority in recent trials presented at this meeting- rivaroxaban in ROCKET-AF, apixaban in ARISTOTLE and dabigatran in the RE-LY trial.
Salim Yusuf, arguably one of the most prolific clinical triallists and lead investigator in two of those trials, also presented the results of a different type of study, published in the Lancet this week. The PURE study included over 150000 patients with known coronary heart disease from 17 countries and showed that even in high-income countries. The drug treatments that such patients should be taking are well-established and available very cheaply-aspirin, beta-blockers, ACE-inhibitors and statins. Depressingly, the proportion of patients globally taking these drugs is less than 50% even in rich countries. In Africa, 80% of eligible patients were taking no drugs at all. As Salim Yusuf said, treatment gaps like this in the HIV/AIDS epidemic led to human rights arguments for broadening of antiretroviral treatment and mobilisation of the global health community and governments.
The inequality was also visible at concurrent “Meet the Triallists” sessions. Delegates clamoured to get to the trial update for the ARISTOTLE trial of the novel anticoagulant, apixaban, but I was one of only 20-30 people who heard Salim Yusuf talk about the PURE trial. Global health cardiology is just not sexy enough yet, even in the wake of the UN high-level meeting in September.
You could argue what is the point of all these fancy new drugs if we are failing to get simple, cheap, proven therapies to the people who need them most, even in rich countries. The tsunami of cardiovascular disease hitting all countries is not going to be touched by all the new drugs currently being trialled. We have to get better at translation. More research funders and senior researchers need to lead new trials with global health impact if we are to have any chance of focusing on problems worth researching.
Obesity: Inequalities in EBM, medical research and policy
Today’s main news story is that obesity is on the up and will continue to rise if coordinated action is not taken at local, national and international levels. A Lancet series of articles examines the evidence for the growing burden and cost of obesity globally and the policy steps needed to prevent 65 million more adults in the USA and 11 million more adults in the UK becoming obese by 2030. Successive governments have allowed the food industry to self-regulate and the evidence clearly suggests that this does not work, since the industry’s interest are profits.
What strikes me is that instructive lessons learned from a strikingly similar case-in-point over the last 60 years, namely the tobacco industry, are not being put into practice. There was good medical evidence for smoking and its detrimental effects of health since the work of Richard Doll and Austin Bradford Hill showed the link with lung cancer in the early 1950s, but it was not until 2005 that the World Health Organization adopted the Framework Convention for Tobacco Control, the world’s first and only public health treaty. Our policymakers smugly talk about tobacco as a tackled problem, but it was less than 10 years ago that UK policy started moving in the direction of smoke-free public places.
We have an obese body of evidence (pun intended) to show that the pathophysiology and epidemiology of obesity is bad for our health, and we have enough evidence to show that current methods of tackling industry problems are not working. Governments are quick to say that the food industry is different but what are the incentives for the food industry to behave differently? Is it going to be acceptable to wait 50-60 years before governments and global health policymakers put evidence into practice? Evidence-based medicine aims, at the end of the day, to institute changes which make the health of individuals better. It seems that there are inequalities in the way evidence is put into practice, based not just on societal interests, but on conflicts of interest, particularly multi-billion dollar industries. If we are serious about EBM and evidence-based policy, we should take lessons learned from other sectors and apply them accordingly.
Drugs in children: more is needed than just a spoonful of sugar
A recent study in BMJ Open used the newly developed WHO International Clinical Trials Registry Platform (ICTRP) to find out how many current studies recruiting children for drug studies collect pharmacokinetic data.
The findings of the study were shocking: only one-quarter of 1,081 trials studying medicines in children collect pharmacokinetic information. Further, only one-third of the medicines identified as a priority by the European Medicines Agency actually collected data (at the time of the study in 2008).
Well what is pharmacokinetic data and why is it important? Pharmacokinetics refers to the study of external substances after they are ingested in the human body. For example, when you swallow a pill, pharmacokinetics explains how long it takes your body to absorb the medication, how long it takes your body to break it down and how long the drug works for.
When children are given medication, doctors, nurses, pharmacists and patients assume that drugs would not be available for children unless they have been rigorously tested and understood. In fact, the truth is quite different. Off-label (outside the product license) and unlicensed (without a license for use in children) prescription rates in children range from 11-80%. There are significant gaps and inadequacies in research conducted in children.
Children are not just small adults and have different safety and efficacy profiles of medications than adults due to differences in physiology, disease pathophysiology, pharmacokinetics and pharmacodynamics. Even adverse drug reactions occur more frequently in children with off-label prescribed drugs.
This vital problem needs to be addressed at multiple levels and the WHO has taken a lead role. The ICTRP will help to improve awareness and make it easier to access accurate, up-to-date, understandable information about clinical trials in children.
The WHO has also launched the ‘Make medicines child size’ campaign in 2007. Hopefully this will address the lack of child studies worldwide as only 38% of trials in children are conducted outside of North America. Clearly studies conducted on children in the US or UK cannot be directly applied to children in Sub-Saharan Africa or India.
Outside of the WHO, the StaR Child Health initiative was founded to improve the design, conduct, and reporting of paediatric research.
A spoonful of sugar to help the medicine go down is not enough. More is needed to understand drugs in children.
A Risky Business
A great deal of General Practice is essentially about managing risk. Every time a patient walks through your consulting door you are basically thinking “what are the chances of this patient coming to harm from what they are about to tell me?” Some patients will fall into a category of “high risk” needing immediate or quick treatment. Others may have a degree of risk that necessitates either further investigations or monitoring. Or there may be low risk cases which can be assessed, reassured or treated. This is all supposed to happen within 10 minutes.
But how far should we go to convey that risk to our patients and what is the best way to do it? A recent scenario at my practice made me pause for thought. The cardiologists had advised us to have a discussion with a patient on the merits and risks of aspirin versus warfarin for their atrial fibrillation.
How could that conversation go?
“Right Mr X, the cardiologists have written to me and asked me to help you decide between warfarin or aspirin. They mention in the letter that the risk of you now having a stroke is about 6% per year, however aspirin reduces that risk by about 25% but with warfarin there is about a 45% risk reduction. However, the number needed to treat with warfarin is 37, but bear in mind that warfarin increases the annual absolute risk of major haemorrhage by 2%, so it’s up to you, which one would you prefer? ”
“umm…I’m sorry Doctor, I didn’t understand all of that”
“No neither did I”
So how should we explain risk to patients? The 2002 BMJ clinical review “Explaining risks: turning numerical data into meaningful pictures” by Edwards and colleagues is certainly worth a read. More recently, a study in the Annals of Family Medicine also tried to answer the question. The group surveyed 934 consecutive patients drawn from family practitioners’ waiting rooms in Auckland, New Zealand. Patients were asked to rate how much various modes of communicating the benefits of therapy, to their 5-year CVD risk score, would encourage them to take medication daily. The modes offered to them included: relative risk, absolute risk, odds, number needed to treat, and natural frequencies. The same information was presented in 2 pictorial forms (bar graphs and 10 × 10 people charts). Most patients (61.8%) preferred a doctor to give an opinion than to explain using either numbers or pictures. More than half also preferred a pictorial presentation to numbers; and of the numerical presentations patients found relative risk reduction most encouraging, with absolute risk reduction rated second overall and numbers needed to treat (NNT) the least likely to be persuasive to take their medication.
So should this mean to our practice? Remember EBM is the integration of the best clinical practice, personal expertise and individual patient preference. The latter component is dependent upon the patient fully understanding the risks and benefits of treatment so that a shared management plan can be reached. Having an idea of what those risks mean ourselves is the first step but finding the best way to convey it to our individual patients in as simplest way as possible is perhaps the bigger challenge.
How do we prioritise the priorities?
Evidence-based medicine aims to put best evidence into practice. Another less-publicised application EBM and epidemiology is the shedding light on the best use of resources or the “biggest” health and public health issues. The National Institute for Health and Clinical Excellence (NICE) aims to judge which treatments and technologies are most “cost-effective” in order to advise policymakers of the treatments which give most “bang-for-buck”.
We are bombarded with priorities, goals and commitments. The United Nations’ Millennium Development Goals are an example of how different stakeholders can be galvanised towards a common set of targets, which may be as important as achieving the goals. Research priorities have begun to be set in the same way. The Grand Challenges in Global Health have highlighted the areas of greatest need in global health research. These are high profile initiatives with scientific financial backing from key players including the Gates Foundation and the Wellcome Trust. Both journals and funders have continual “calls for proposals”, whether it is the Lancet’s latest call for health research in China, or the strategic goals of the Wellcome Trust.
How good are these goals at picking the right priorities? At first glance, they may be wide open to multiple biases and conflicts of interest depending on the interests, both financial and scientific, of stakeholders and the goal-setters. The Delphi method tries to avoid this problem by using the “collective intelligence” of many experts in several questionnaire-led rounds. For example, this method has been used to set the Grand Challenges in Mental Health.
At the World Congress of Epidemiology last week, during a keynote speech by Ivor Rudan, I learned about the Child Health and Nutrition Research Initiative, or CHNRI method, designed to suggest the “best bets” for health research priorities on the basis of evidence and several stages of scoring of different options.
There will inevitably be some wastage in research funding but it is surely a good sign that institutions, whether local or global, want to channel resources towards areas of greatest need and potentially greatest benefit, and that we are developing better tools to set these priorities.
Can placebos cure asthma? It depends on your point of view...
You feel better but your doctor tells you that according to a laboratory test, you are still sick. Who do you believe? A recent randomized trial compared outcomes in four groups of patients suffering from asthma:
- albuterol inhaler,
- placebo inhaler,
- sham acupuncture (a needle that either avoids known ‘acupuncture’ points or does not penetrate the skin), and
- no intervention (a waiting list).
Subjective patient reports indicated that the albuterol, placebo, and sham acupuncture all reduced subjective reports of wheezing and feeling suffocated equally. That means if you have asthma, you feel as much better after taking a ‘placebo’ or the ‘real’ drug. However, on the ‘objective’ outcome, how much air you can blow in 1 second (the ‘FEV’) the real albuterol inhaler outperformed the placebo inhaler and sham acupuncture.
Placebo sceptics might argue that patients in the placebo and sham acupuncture groups merely reported that they felt better, to please the investigator (this is sometimes called ‘reporting bias’). However, this is unlikely because the patients receiving no intervention also reported improvements and presumably they had no reason to please the investigators (who after all had ignored them!)
Many prefer ‘objective’ outcomes because they believe that they address the underlying cause. But as Dan Moerman points out, patients suffering from asthma visit the doctor because they wheeze and feel suffocated not because they suffer from a reduced FEV. Indeed for many conditions including migraine, schizophrenia, back pain, depression, asthma, post-traumatic stress disorder, neurologic disorders such as Parkinson's disease, inflammatory bowel disease and indeed any condition defined by symptoms, requires that patient-preferred (usually subjective) outcomes trump objective outcome measures.
More generally, what patients, doctors, and policymakers care about (or should care about) is whether a medical intervention makes a patient live better or live longer. Many ‘objective’ outcome measures such as FEVs, cholesterol levels or arrhythmias are, in fact, surrogates for patient-relevant outcomes. While these surrogates are often extremely helpful and can lead to living better or longer, the links to the patient-relevant outcome is often far more spurious than is generally assumed.
So, which outcomes should you trust? It depends on your point of view …
Is there an evidence base for children in primary care?
A recent article in PlosONE of Cochrane reviews relevant to children in primary care states there is a mismatch between the focus of published research and the clinical activity for children in general practice. Not only in the UK but in a number of countries: Australia, Netherlands, US and the UK.
What’s odd is that in a condition such as asthma despite representing 3-5% of consultations, it is the focus of nearly one-quarter of all reviews. On the other hand, despite the increasing burden of skin conditions which lead to one-quarter of all visits only 7% of reviews were relevant.
Non-drug interventions (such as counseling) are an important part of general practice yet they are virtually non-existent in evidence syntheses and research funding. Over half of the reviews studied drug interventions in children while 69% of all controlled trials in children assess drug products.
Whilst the number of systematic reviews published is skyrocketing (over 2,500 in 2007 alone) there continues to be avoidable waste in the production and reporting of research evidence (read more on cebmblog’s recent post). Yet, there has not been a similar increase in children reviews in primary care. Since 2000, the percentage of reviews on children nearly tripled compared to a much smaller increase in primary care reviews.
Why the mismatch? Likely due to multiple factors: absence of primary trials, lack of author interests, public funding poorly correlates with disease burden, more interventions in certain conditions (such as asthma) than others, lack of additional academic training in child health and lack of an overall map of the evidence.
Despite the reasons the mismatch is clear and needs to be addressed. Further work needs to be done to look at how the reviews inform clinical practice. Improving the evidence base for children in primary care is a no-brainer. So how and who should sort this out? Initial steps should include encouraging Cochrane Review Groups, funders, and other relevant organizations to prioritize topics.
The recently created PROSPERO international register of systematic reviews is a step forward to help minimize waste.
Is there an evidence base for children in primary care? Not yet.
Diet-the Cinderella risk factor
Working in cardiology, it is sometimes hard to keep up with the stream of high-tech gadgets, new drugs and treatment technologies which are constantly changing diagnosis and treatment of cardiovascular disease (CVD). For example, cardiovascular drugs (such as those against cholesterol and lipid disorders, and antithrombotic agents) account for the majority of blockbuster pharmaceuticals.
There is no question that CVD is common, causing more than 150 000 deaths annually in the UK alone, with annual costs in excess of £30 billion. That is why there have been massive, coordinated efforts to focus on every aspect of heart disease treatment and prevention.
However, we tend to focus on the expensive, labour-intensive, training-intensive strategies. For example, primary angioplasty is an invasive procedure to open up blockages in the blood supply to the heart immediately after a heart attack. It requires training of all staff, 24/7 cover and the necessary equipment and post-procedural care. A conservative analysis estimated the cost of a primary angioplasty in usual working hours to be £5176 with an extra £245 if undertaken out of hours. The authors of this study estimated that angioplasty added £4520 for each quality-adjusted life year (QALY) gained. Expensive stuff when you are providing this service to the whole population.
Are there cheaper, lower-hanging fruit? Of course there are, but no drug companies or vested interests are pushing them. Of the neglected risk factors with most public health impact, diet is the Cinderella at the Cardiovascular Ball. In this week’s BMJ, an economic model of CVD in the UK shows yet more evidence for Geoffrey Rose’s population strategy to disease. The authors give us three poignant take-home messages from the study. First, a 5% reduction in mean cholesterol or blood pressure in the population would save the UK at least £80-100 million. Second, legislation to reduce salt intake by 3 g/day (and we are currently having 8.5g/day on average) would prevent 30 000 cardiovascular events and save £40m a year. Third and perhaps most interestingly, legislation to reduce intake of industrial trans fatty acid by approximately 0.5% of total energy content may add 570 000 life years, saving £230million a year. NICE has been pushing for a dietary ban of trans-fats for some time.
Nobody is saying we don’t need the latest and best evidence-based tools and therapies for CVD prevention, but these numbers are hard to argue with. As I finish a night shift, I am going to forego my greasy fry-up for a bowl of muesli after reading this.