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Industry bias in clinical trials

Industry bias
Review
Results
Comment

We have become used to finding potential sources of bias in clinical trials. What we find is usually empirical evidence of bias from some examples, and then we look for the possibility that bias from that particular source might be affecting other results we are considering. If there is sufficient information, we might test whether that bias exists in our data using a sensitivity analysis. As a simple example, we might test randomised or double blind studies against those that are not randomised or double blind.


Industry bias

The majority of clinical and laboratory work undertaken is funded by industry, small or large. Concerns have been expressed about whether this can lead to bias, and there is a considerable, if somewhat confused, literature. In part this is because at least two possible issues come under this heading:

  1. Marketing bias. Companies want to present their products in the best possible light, and will be selective about what they say. This applies to small spin-offs looking for development capital, to large organisations seeking to market new pharmaceuticals, tests, or devices.
  2. Sponsorship bias. Narrowly defined, this is whether the source of funding for a clinical trial affects the results of the clinical trials in a systematic way.

The existence of marketing bias would be conceded universally. It is part of the world we work in. You don't see adverts, for instance, saying that margarine tastes worse than butter. Every book on the bookstand is an international best seller.

Whether sponsorship bias exists, though, is another matter. Although there have been many reviews claiming the existence of industry bias, these have typically made a heap of what they could find, irrespective of criteria of quality, validity, and size, and have typically not compared like with like. A new systematic review [1] is possibly the first to look specifically at whether sponsorship bias exists in clinical trials, and gives a useful summary of some of the reviews that claim to have found industry bias.


Review

The review used existing meta-analyses of high quality acute pain and migraine interventions, which had chosen randomised and double blind trials that were valid, used a defined dose, and used consistent methods, had the same outcomes measured over the same time, and where there was a large amount of information. These were oral aspirin 600/650 mg, paracetamol 1000 mg, ibuprofen 400 mg and rofecoxib 50 mg in acute pain, and oral sumatriptan 100 mg and 50 mg for migraine; all were compared with placebo.

The intention was to compare efficacy in trials sponsored by for-profit organisations with those without for-profit sponsorship.


Results

Of 176 individual trials, only two could be identified as being definitely sponsored by non-profit sources, compared with 144 sponsored by for-profit sources. No statement was made in 31 trials. Clearly no comparison between for-profit and not for-profit sponsorship was possible.

An alternative strategy was used (Figure 1). In the 143 for-profit trials, a distinction was made between trials where a drug was being used as a test, or as a comparator. The argument was that if bias existed, there would be conflicts of interest within industry-sponsored trials. The bias should act to maximise efficacy when a drug was used as the test drug (the aim being to make it look as good as possible), and to minimise efficacy when the same drug was used as a comparator (the aim being to minimise efficacy compared to a second, newer, test drug).



Figure 1: Strategy for examining the existence of differential sponsorship bias in randomised trials in acute pain and migraine where source of sponsorship was definite





When this strategy was applied to four analgesics in acute pain trials, no difference in efficacy was found (Figure 2) as measured by the NNT for at least half pain relief over 4-6 hours compared with placebo. For sumatriptan in acute migraine, there were no consistent differences at 50 mg or 100 mg, for three different outcomes.



Figure 2: NNT for four analgesics in identical randomised, double blind acute pain trials reporting the same outcome over the same period of time, where drug was used as test or comparator






Comment

The conclusion here was that the only way of testing these studies was to look for differential sponsorship bias. When sought, no bias was found. It looks very much as if for-profit industry sponsorship does not influence the outcome of good quality, randomised trials in acute pain and migraine. There are also examples of large, high quality for-profit and not for-profit sponsorship trials of statins and finasteride giving essentially the same result.

This is very good news, and should be looked at in other areas. Had differential sponsorship bias been found, it would mean that we would probably not be able to trust randomised trials, since almost all have for-profit sponsorship. That would have been a bit of a blow.

The paper [1] gives examples, though, of marketing bias, where individual trials with particular beneficial characteristics were picked out for special marketing attention. The lesson is to treat all sources of information, industry or other, as if they were used car salespeople trying to sell you a dud. Ask for the evidence, and accept only good evidence, not airy-fairy nonsense about contented customers. If they can't show it, it may be because there isn't any. Never mind the shine, look for the quality.

Reference:

  1. J Barden et al. Bias from industry trial funding? A framework, a suggested approach, and a negative result. Pain 2006 121: 207-218.

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