Issue 10 / 23 March 2015

RESEARCHERS designing clinical trials often exclude people with multiple health problems for fear they might make it harder to assess the true effects of the treatment being studied.

It sounds sensible, but it means drugs often end up being tested on people who don’t bear much resemblance to those who end up using them in the real world.

Clinical trials in adults, for example, commonly recruit people aged 18‒65 years, even when the treatment is one that will mostly be used by the elderly.

The consequence can be a lack of data on the safety, efficacy and ideal dose of drugs in the very people who need them most.

This is not just a question of the elderly. A viewpoint article in The BMJ argues obese people may not be receiving the best care because of inadequate data on “pharmacobariatrics” — how drugs work in the seriously overweight.

“How should we decide the optimum drug doses for morbidly obese people”? asks Dr Stephen Head, clinical director of the Nottinghamshire Health Care Trust in the UK.
“With many drugs this is uncertain, and we use guesswork. Or we simply prescribe as though the patient weighed 45 kg, because increasingly risk averse doctors are more reluctant to prescribe a dose outside the recommended range”, he writes. (Dr Head explains that recommended doses for adults need to be effective and safe for slender, shorter than average people who might weigh less than 45 kg).

When obese people receive inadequate doses, the resulting treatment failure may mean they are then prescribed stronger, potentially more harmful drugs — and often more expensive —when the initial treatment might have worked if it had been given at an effective dose.

Dr Head suggests this may be happening across a range of treatments, including antihypertensives, antibiotics (where underdosing may also promote antibiotic resistance), metformin for diabetes, and treatments designed to give symptom relief in musculoskeletal conditions.

Musculoskeletal conditions are, of course, extremely common in obese people and “giving an insufficient dose may inadequately control symptoms and limit physical activity, promoting a vicious cycle, with further weight gain or a failure to lose weight”, Dr Head writes.

With all of these drugs, it is not just a question of multiplying the dose to account for a higher body mass index, he stresses.

Obesity may affect pharmacodynamics in various ways, as it changes the rate of absorption, distribution, metabolism and excretion of a particular drug.

As Dr Head says, “guessing the best dose will not suffice”, but for many agents we don’t really have the data to do much more.

Getting reliable safety and efficacy data for different levels of obesity would require a massive research effort that, as Dr Head puts it, “won’t come cheap”.

The research effort could only really be funded by government, since the most relevant drugs are mostly out of patent and therefore of little interest to industry.

Dr Head suspects a major public financial commitment could prove controversial.

“Investment may be contentious”, he writes, “especially among those who regard obesity as a self-induced condition for which they have little sympathy.”

Sympathy aside, it may be a simple question of pragmatism.

With rising rates of obesity, the costs of treatment failure for individuals and the health system may mean we have little choice.

Jane McCredie is a Sydney-based science and medicine writer.

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