1.  INTRODUCTION

  2.  In response to the select committee's call for comments, I wish to offer an analysis that may help explain how companies can engineer a clinical consensus that will favour their product—even in the absence of a scientific basis for claims for superiority for the new and usually much more expensive product—and how this process can feed through and shape even disinterested assessments of the evidence undertaken by NICE. These processes appear to many to underpin a relatively recent "capture" of regulatory and other professional domains.

  3.  I will also comment on how the safety of pharmaceutical products might be better ensured under current arrangements and on how current arrangements may be changed to produce a safer framework for healthcare.

  4.  I bring to this commentary a background in consultancy work with pharmaceutical companies, access to company archives through medico-legal work, (as outlined in the accompanying conflict of interest statement—appendix 1), and 10 years of work on mapping the history of the development of psychotropic drugs and pharmaceutical companies in their present form as published by Harvard and New York University Presses.

5.  COMMENTARY

  6.  Clinical Consensus: The main point of note is that the scientific literature is being managed to an ever increasing extent, the most visible sign of which is that an increasing proportion of the scientific literature on aspects of therapeutics with pharmacological agents (over 50%) is now ghost-written. This is associated with a demonstrable failure to report important safety data on drugs, or with the reporting of such data in terms that mislead. The risks from ghost-writing stem from the fact that the data that ghostwriters purport to represent remain inaccessible to outside scrutiny.

  7.  As a consequence of the ghost-writing of articles, efforts to establish clinical consensus in the form of guidelines and algorithms, which depend on a review of the entire literature on a drug are compromised and can be shown to produce outcomes indistinguishable from the outcomes that would be produced by having a group of employees of the pharmaceutical company write the guidelines. Even though there may in fact be no evidence of superior efficacy or safety for newer agents, they will end being written up as superior to older agents and to be used in preference to older agents.

  8.  The effects of ghost-writing and other literature management strategies feed through into a process of pharmaco-economic modelling undertaken for new drugs, which can demonstrate that not only is a drug that is not proven to be in any way superior its predecessors better than its predecessors but is better to the extent that it should be in replace older agents, even though the costs of the new treatment may be 50 times greater than the older agent.

  9.  The details of how these processes work are laid out in appendix 2. Of note here is that I have been a participant in these processes and party to the generation of views favouring newer over older agents, unaware that pharmaceutical companies were keeping key safety data hidden from the scientific community and that they would refuse to produce such data on request.

  10.  Safety Data: Current procedures to manage the entry of drugs onto the market favour the detection of drug effects and set a higher threshold for safety effects. This shows up in two ways.

  11.  First, in order for a drug to be licensed it has to show superiority to placebo in two controlled trials. Companies however can run ten or more trials in carefully selected samples using instruments carefully designed to pick up any effect in order to demonstrate this, and even if the results show the drug failing to beat placebo in the clear majority of trials, this is not held against them. These other trials are commonly termed failed trials rather than drug failures.

  12.  In contrast, the demonstration of a safety issue is not handled in this way. In this case regulators will only act if the overwhelming preponderance of the data show a hazard.

  13.  This issue has at its heart unresolved philosophical issues about the nature of statistics. Safety data is typically presented in terms of Confidence Intervals, so that for instance in recent antidepressant studies the rate of suicides on drugs compared to placebo is typically of the order of two times greater but what is termed the confidence interval surrounding this figure of 2.0 might be for example 0.9 to 4.4.

  14.  There is a deep philosophical divide between two ways to interpret such a finding. First according to a school of thought stemming from R A Fisher is the view that nothing has in fact been shown unless the confidence interval does not include 1.0, thus for instance a confidence interval of 1.1 to 4.4.

  15.  Second, the Neymann-Pearson school of thought argues that the best estimate of the effect is 2.0, in this case. This is the figure regarding which we can be most confident.

  16.  In practice regulators, adopt the Fisher approach. This cannot be viewed as a rigorous approach to safety. Epidemiologists or a drug regulatory process on the other hand, concerned with safety, would argue that in this case the figure of 4.4 is potentially consistent with the data—that is the hazard in question may well happen up to 4.4 times more often on the drug than on placebo or non-treatment, and that therefore if the hazard is serious patients and doctors should be warned about this possibility.

  17.  Safety Procedures and Informed Consent: At present when patients enter clinical trials they are asked to sign informed consent forms, which contain ever longer lists of potential problems a treatment may cause.

  18.  These consent forms though never inform patients or others that neither patient, nor physician nor any other third party will ever have access to the raw data from this trial, particularly data on safety issues. They are not told that pharmaceutical companies may chose only to "market" the bits of the data that suit them.

  19.  Changing informed consent forms to make this explicit might have salutary effects. Alternatively transforming informed consent forms into contracts between patients and companies that provided rights of access to experts in the event of safety concerns might make a big difference.

  20.  Requiring companies to permit access to the raw data, given for free by patients as part of a "gift" arrangement with the rest of the community, would simply require companies to conform to the norms of science under whose banner they claim they sell their products.

  21.  Until some arrangement is put in place to ensure access, then every patient who enters a clinical trial in the United Kingdom (or anywhere else) is putting every Member of Parliament and all the constituents those Members represent in a state of legal jeopardy. This follows as the absence of publicly available data on hazards will be used by pharmaceutical companies to argue that the hazard does not exist, even when the datasets available to industry establish clearly that the hazard does exist.

  22.  Regulators, who typically read study summaries prepared for them by pharmaceutical company employees, rather than scrutinise and analyse the raw data themselves, can miss these issues.

  23.  This evidence is being submitted on an individual rather than a corporate basis. I would be willing to give oral evidence on these issues, and can bring some benefit to any hearings by virtue of being an active participant in the processes described above and below.

  24.  I am a Reader in Psychological Medicine in the University of Wales College of Medicine (as of August Cardiff University).

20 July 2004