Stronger focus on drug side effects needed

Randomised controlled trials are the supreme method for determining whether a new treatment, frequently a new pharmaceutical, is superior to current best practice.

They were originally used in agriculture to assess the added value of a new plant or soil additive, but are now firmly ingrained in medical practice.

I recall 30 years ago, an eminent professor of surgery railing against randomised controlled trials, which he considered utterly inappropriate to determine the value of surgical interventions.

He wrote a scathing article in which he referred repeatedly and disparagingly to such trials as "agricultural statistics".

While the randomised controlled trial has given us the best possible evidence about the effects of new therapies for a range of conditions, especially cancer and cardiovascular disease, and have underpinned the evidence-based medicine movement, they do not cover the entire treatment waterfront. This is especially so in relation to side effects.

The way randomised controlled trials work is that they aim to find out how many patients need to be treated — either with the new therapy or the old — to determine if the new drug is better.

The expected improvement in cancer trials is small, usually less than 10%, and so these studies require larger numbers of patients to be sure that even the slightest difference in outcome can be seen.

Sample size calculations, therefore, are based on the detection of relatively rare events, such as a gain in life expectancy or quality of life.

But side effects are another matter. They often fall beyond the vision of the trial, or out of focus of its carefully calculated sample size.

Side effects may not occur for months or years after a trial has finished, or they may be so rare that the randomised controlled trial's sample size is insufficient to detect them, even if they occur during the trial.

With some medications, side effects are of huge importance — for example, if the trial is testing a preventive intervention such as immunisation, rather than a treatment for a serious illness where side effects may be tolerated.

Nobody wants to enter a trial feeling whole and well and leave it with a nasty side effect.

Publicity around claims of side effects from immunisation illustrate this point, and show how critical it is to be secure about the proposed preventive interventions.

Similar concerns surround trials of cholesterol-lowering drugs in very low-risk populations. Side effects can be hard to detect, and if the treated trial subjects are at low risk of the disease (such as an MI) that the drug is intended to reduce but then develop problems with, for example, muscle power, a hard-to-resolve problem arises. Witness the controversy around the Catalyst TV programs on exactly this topic.

So there is a sizeable challenge to be sure that we know what side effects occur, and brilliant randomised controlled trials will not necessarily tell us about rare and distant ones.

Currently, especially in the case of new drugs, the pharmaceutical company sponsoring the trial will have given serious thought to this matter and have in place systems to collect information about side effects.

Of course, it is not only in the context of randomised controlled trials that side effects occur and old remedies, especially in specific genetic subsets of the population, may cause rare problems. Often more information, especially long-term data, is needed.

An intelligence system to learn about possible side effects is far more feasible today than even 10 years ago.

The high degree of electronic connectivity that we all enjoy (and sometimes loathe) can put us in touch with agencies, such as the TGA, to report possible side effects at the click of a mouse.

Now the TGA has come up with an online reporting system for patients as it's concerned that the vast majority of side effects go unreported. Doctors report some and drug companies others, but for over-the-counter and alternative medicines, there have been no formal reporting pathways.

The TGA may easily be overwhelmed with side effect noise and it will need a good filtering system to detect the signals. But this is surely a move in the right direction; another step to ensure medication safety as well as efficacy as we continue to advance our capacity to prevent and to treat.

Professor Leeder is a member of the Menzies Centre for Health Policy at the University of Sydney, chair of the Western Sydney Local Health District Board and editor-in-chief of the Medical Journal of Australia.

Published in Australian Doctor 8 October 2014 http://bit.ly/1BRzk91