“Open Season”

The recent joint statement(1) by the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industries and Associations(EFPIA) represents a further step in what has been a slow journey towards (one assumes) will be the achieved  goal of sharing clinical trial data. In my inaugural lecture of 1997 at University College London I called for all pharmaceutical companies to develop a policy for sharing trial results and I have repeated this in many places since(2-5). Thus I can hardly complain if what I have been calling for for over 15 years is now close to being achieved.

However, I have now recently been thinking about it again and it seems to me that there are some problems that need to be addressed. One is the issue of patient confidentiality. Ideally, covariate information should be exploitable as such often increases the precision of inferences and also the utility of decisions based upon them since they (potentially) increase the possibility of personalising medical interventions. However, providing patient-level data increases the risk of breaching confidentiality. This is a complicated and difficult issue about which, however, I have nothing useful to say. Instead I want to consider another matter. What will be the influence on the quality of the inferences we make of enabling many subsequent researchers to analyse the same data?

One of the reasons that many researchers have called for all trials to be published is that trials that are missing tend to be different from those that are present. Thus there is a bias in summarising evidence from published trial only and it can be a difficult task with no guarantee of success to identify those that have not been published. This is a wider reflection of the problem of missing data within trials. Such data have long worried trialists and the Food and Drug Administration (FDA) itself has commissioned a report on the subject from leading experts(6). On the European side the Committee for Medicinal Products for Human Use (CHMP) has a guideline dealing with it(7).

However, the problem is really a particular example of data filtering and it also applies to statistical analysis. If the analyses that are present have been selected from a wider set, then there is a danger that they do not provide an honest reflection of the message that is in the data. This problem is known as that of multiplicity and there is a huge literature dealing with it, including regulatory guidance documents(8, 9).

Within drug regulation this is dealt with by having pre-specified analyses. The broad outlines of these are usually established in the trial protocol and the approach is then specified in some detail in the statistical analysis plan which is required to be finalised before un-blinding of the data. The strategies used to control for multiplicity will involve some combination of defining a significance testing route (an order in which test must be performed and associated decision rules) and reduction of the required level of significance to detect an event.

I am not a great fan of these manoeuvres, which can be extremely complex. One of my objections is that it is effectively assumed that the researchers who chose them are mandated to circumscribe the inferences that scientific posterity can make(10). I take the rather more liberal view that provided that everything that is tested is reported one can test as much as one likes. The problem comes if there is selective use of results and in particular selective reporting. Nevertheless, I would be the first to concede the value of pre-specification in clarifying the thinking of those about to embark on conducting a clinical trial and also in providing a ‘template of trust’ for the regulator when provided with analyses by the sponsor.

However, what should be our attitude to secondary analyses? From one point of view these should be welcome. There is always value in looking at data from different perspectives and indeed this can be one way of strengthening inferences in the way suggested nearly 50 years ago by Platt(11). There are two problems, however. First, not all perspectives are equally valuable. Some analyses in the future, no doubt, will be carried out by those with little expertise and in some cases, perhaps, by those with a particular viewpoint to justify. There is also the danger that some will carry out multiple analyses (of which, when one consider the possibility of changing endpoints, performing transformations, choosing covariates and modelling framework there are usually a great number) but then only present those that are ‘interesting’. It is precisely to avoid this danger that the ritual of pre-specified analysis is insisted upon by regulators. Must we also insist upon it for those seeking to reanalyse?

To do so would require such persons to do two things. First, they would have to register the analysis plan before being granted access to the data. Second, they would have to promise to make the analysis results available, otherwise we will have a problem of missing analyses to go with the problem of missing trials. I think that it is true to say that we are just beginning to feel our way with this. It may be that the chance has been lost and that the whole of clinical research will be ‘world wide webbed’: there will be a mass of information out there but we just don’t know what to believe. Whatever happens the era of privileged statistical analyses by the original data collectors is disappearing fast.

[Ed. note: Links to some earlier related posts by Prof. Senn are:  “Casting Stones” 3/7/13, “Also Smith & Jones” 2/23/13, and “Fooling the Patient: An Unethical Use of Placebo?” 8/2/12 .]

References

1. PhRMA, EFPIA. Principles for Responsible Clinical Trial Data Sharing. PhRMA; 2013 [cited 2013 31 August]; Available from: http://phrma.org/sites/default/files/pdf/PhRMAPrinciplesForResponsibleClinicalTrialDataSharing.pdf.

2. Senn SJ. Statistical quality in analysing clinical trials. Good Clinical Practice Journal. [Research Paper]. 2000;7(6):22-6.

3. Senn SJ. Authorship of drug industry trials. Pharm Stat. [Editorial]. 2002;1:5-7.

4. Senn SJ. Sharp tongues and bitter pills. Significance. [Review]. 2006 September 2006;3(3):123-5.

5. Senn SJ. Pharmaphobia: fear and loathing of pharmaceutical research. [pdf] 1997 [updated 31 August 2013; cited 2013 31 August ]; Updated version of paper originally published on PharmInfoNet].

6. Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 4;367(14):1355-60.

7. Committee for Medicinal Products for Human Use (CHMP). Guideline on Missing Data in Confirmatory Clinical Trials London: European Medicine Agency; 2010. p. 1-12.

8. Committee for Proprietary Medicinal Products. Points to consider on multiplicity issues in clinical trials. London: European Medicines Evaluation Agency2002.

9. International Conference on Harmonisation. Statistical principles for clinical trials (ICH E9). Statistics in Medicine. 1999;18:1905-42.

10. Senn S, Bretz F. Power and sample size when multiple endpoints are considered. Pharm Stat. 2007 Jul-Sep;6(3):161-70.

11. Platt JR. Strong Inference: Certain systematic methods of scientific thinking may produce much more rapid progress than others. Science. 1964 Oct 16;146(3642):347-53.