Healthy Skepticism Library item: 5815

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Publication type: news

Chadwick , Privitera M.
Editorial : How skeptical should we be about industry-sponsored studies?
Neurology 2006 Aug 7
http://www.neurology.org/cgi/content/full/67/3/378

Full text:

NEUROLOGY 2006;67:378-379
Editorials
How skeptical should we be about industry-sponsored studies?
David Chadwick, MD and Michael Privitera, MD

From University of Liverpool (D.C.), UK; and University of Cincinnati Medical Center (M.P.), OH. Address correspondence and reprint requests to Dr. David Chadwick, University of Liverpool, Walton Centre, Lower Lane, Liverpool L9 7LJ, UK; e-mail: d.w.Chadwick@liv.ac.uk

In this issue of Neurology, Blum et al.1 report a randomized controlled study (RCT) that examines cognitive function following the addition of 500 mg/day of lamotrigine or 300 mg/day of topiramate to existing treatment with either carbamazepine or phenytoin. They show that topiramate has greater potential to harm cognitive function than does lamotrigine at the fixed doses used, something that might be expected from previous placebo-controlled regulatory studies of the two drugs, from some limited comparative studies of volunteers and patients, and from clinical experience gained post-marketing.2–5 Surely, then, we should simply applaud the fact that such careful methodology has been applied to a subject as important as the cognitive effects of antiepileptic drugs (AEDs).

But perhaps we should pause for thought and consider some of the issues that lie behind the study design and its reporting, because it highlights a number of issues about RCTs sponsored by industry. Industry of course has two main reasons for sponsoring RCTs: in order to license a drug for specific indications, usually by placebo-controlled add-on studies in epilepsy, and to support a drug’s marketing. The Blum et al. study can be considered a marketing study.

RCTs are accepted as the least biased means of detecting small but clinically important treatment effects. They have the disadvantage of being difficult to organize, and expensive, so they should not be used to prove the blindingly obvious. While they are primarily used to examine efficacy, they can also be used to look at adverse events, but it is unusual to see a trial in which the primary outcome is an adverse effect, namely a decline in cognitive function.

Furthermore, it is relatively rare for industry to sponsor direct head-to-head clinical trials of its own drug against a competitor new drug, because there may be a risk of demonstrating inferiority to a competitor, with serious commercial consequences. Of course, a full understanding of clinical utility or effectiveness demands that we understand both benefit and harm resulting from comparator drugs over a relevant and long period in a chronic condition such as epilepsy. This would include a reliable comparison of seizure outcomes (the benefits), an assessment of the range of adverse effects, and some overall assessment of how patients themselves might value the sum of benefit and harm, perhaps assessed by health-related quality of life. Even with a drug such as lamotrigine where there are a number of comparative industry-sponsored studies these have been too short to produce clear answers about comparative efficacy. The place of the drug in everyday clinical practice remains uncertain.6

It is on this background that we are presented with a study that reliably assesses one outcome (cognitive function) that would be predicted to favor lamotrigine. It has been powered to detect clinically important differences in cognitive outcomes, which can of course be detected over the short period of the study. It would have required a greater number of patients randomized to detect reliably differences in seizure outcomes: indeed the study was too short and the means of assessing seizure frequency (retrospective recall) inadequate. The differences in seizure outcomes recorded are large, although not of statistical significance. Given that there are no available studies comparing the efficacy of lamotrigine and topiramate as add-on therapy, why was the study not adequately powered to reliably detect differences in seizure outcomes? The most disappointing aspect of all the new AEDs developed in the past 15 years is their consistent inability to stop seizures in patients who have failed trials with other AEDs. Clinicians need information on patients who develop medication refractory epilepsy: Why does it occur? What factors predict it? How can we prevent it?

How do we interpret this study? It proves what most of us already knew about the relative effects of the drugs on cognitive function, but it must not be interpreted as showing that there are no differences in efficacy between the drugs, simply because few significant differences were found on testing at the arbitrary p < 0.05 level of significance. It is more likely than not that a study adequately designed and powered for seizure outcomes would have favored topiramate.

When a trial is sponsored by industry, subtle biases in its design may be invisible to all but the experienced. Were the doses and titration usual practice? In this case the targets were appropriate, but a fixed dose is a disadvantage to a drug where dose adjustments help minimize adverse effects. Did the use of the drugs as add-on therapy enhance cognitive impairment? One of the strategies to reduce topiramate’s adverse effects is to reduce the concomitant drug dose.7 Were there subgroups where cognitive impairment is more or less likely? An industry sponsor would have little incentive to find patient subgroups resistant to cognitive impairment and would prefer to convince readers that the competitor’s drug impairs cognitive function in all patients. Should it alter our clinical practice? Probably not. Fixed dosing of AEDs departs from clinical practice. Most clinicians would simply reduce drug dosage in the face of clinically important cognitive effects, to see if seizure control could be maintained.

Results of the kind provided by this report are valuable, but we need to consider carefully-as we do of all trials, regardless of their sponsorship-the research question, the design, methods, analysis, and interpretation. Ultimately, we, as consumers of medical research information, must decide on the basis of an assessment of the design and analysis whether the information is novel and useful. Admittedly, industry-sponsored trials may invite greater scrutiny, particularly if, as in this case, the aim appears to be a marketing advantage. Although a finding’s marketing advantage ought not to invalidate a scientifically sound conclusion, it points up the desirability of studies that, rather than being narrowly focused, address as fully as possible health-related quality of life issues.

References

1. Blum D, Meador K, Biton V, et al. Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy. Neurology 2006;67:400–406.[Abstract/Free Full Text] 2. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38:859–880.[Medline] 3. Tatum WO, French JA, Faught E, et al. Postmarketing experience with topiramate and cognition. Epilepsia 2001;42:1134–1140.[Medline] 4. Aldenkamp AP, Baker G, Mulder OG, et al. A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in subjects with partial-onset seizures. Epilepsia 2000;41:1167–1178.[Medline] 5. Meador KJ, Loring DW, Vahle VJ, et al. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology 2005;64:2108–2115.[Abstract/Free Full Text] 6. Gamble C, Williamson PR, Chadwick DW, Marson AG. A meta-analysis of individual patient responses to lamotrigine or carbamazepine monotherapy. Neurology 2006;66:1310–1317.[Abstract/Free Full Text] 7. Dodson WE, Kamin M, Kraut L, Olson WH, Wu SC. Topiramate titration to response: analysis of individualized therapy study (TRAITS). Ann Pharmacother 2003;37:615–620.[Abstract/Free Full Text]

Disclosure: Dr. Chadwick has received speaker’s fees, consultancy fees, research support and support for travel from GSK, Ortho-McNeil, and other companies marketing antiepileptic drugs. Dr. Privitera has received honoraria for speaking, consulting or research support from Pfizer, Ortho McNeil, UCB Pharma, Schwarz Pharma, and Glaxo Smith Kline. Research support from Ortho McNeil, UCB Pharma and Schwarz Pharma exceeded $10,000.