A new proposal to register clinical trials is having an effect on drug companies’ disclosure of trial information, but it is still not enough. Prof. Peter Saunders
Over the past few years, and certainly well before the TGN1412 incident, there has been increasing disquiet about drug trials and their regulation. Not all clinical trials are registered with the authorities, and even when they are, the information provided may not be sufficient to allow the public, or the regulators who act on our behalf, to know how the trials were carried out and what results were obtained. This information is crucial in contributing to knowledge on both the safety and efficacy of the drugs.
Clinical trials go through several phases and there can be important questions about each of them.
Were the Phase 1 and 2 trials of the drug done in accordance with accepted ethical standards and with adequate attention to the safety and well being of the subjects? Were the subjects given enough information about the purpose of the trials and the possible hazards so that they could give proper informed consent?
As the TGN1412 trial demonstrates, under the present regime we may not be allowed full information on key aspects of a trial even after it has gone badly wrong (“Post Mortem on TGN1412 disaster”, this series)
Were the Phase 3 trials properly carried out and analysed? Have all the data been included or only those that are favourable? Phase 3 trials generally involve statistical analysis and different approaches can sometimes produce markedly different conclusions. This offers an obvious temptation (conscious or not) to someone who knows the outcome his employer wants. At the heart of Blumsohn’s disagreement with Proctor & Gamble (“Actonel: drug company keeps data from collaborating scientists”, this series) was his objection that a large part of the data had been excluded and that when it was put back in, the evidence for the conclusion was significantly weakened.
What about Phase 4? Is effective monitoring taking place, what epidemiological studies are being carried out to detect unexpected side effects, and what sorts of results will trigger a warning to physicians or even a withdrawal of the drug? The chief complaint against Merck is not that Vioxx increased the chances of heart failure and strokes – there seems to have been no reason for them to expect that would happen – but that they were slow to report this.
GlaxoSmithKline were sued in the American courts for suppressing studies that showed that the antidepressant Paxil should not be prescribed for children and adolescents. They eventually reached an out of court settlement. Eliot Spitzer, the New York State Attorney General who brought the case, specifically criticised the US Food and Drug Administration (FDA) for not compelling the drug industry to reveal negative results. [1]
The problem is even worse now that pharmaceutical companies operate in many countries. Regulations differ from place to place, and there is always a temptation to undertake trials, especially the potentially hazardous Phase 1 trials, where regulation is less strict. And without any formal registration of drug trials, it would be impossible to find out if a drug has caused serious adverse reactions, let alone whether the drug was effective.
To deal with these issues, the World Health Organisation (WHO) is setting up an International Clinical Trials Registry (ICTRP). At present there are at least 50 registers of clinical trials around the world, and the aim is to link these into a network so that the information they contain can be accessed from a single point [2]. The WHO does not intend to create its own register of trials but it will set up rules and standards on how existing registers should operate and how they should work together. Its aim is to ensure that all clinical trials are registered and thus publicly declared and identifiable and that a minimal set of data about the trials is readily available.
There seems to be a general acceptance that all clinical trials should be registered, but there is still a debate about what information should be provided. The industry tends to argue that they should be allowed considerable freedom to withhold key information on grounds of commercial sensitivity [3, 4].
This is the same argument often used by the biotech industry to justify concealing information that might be used to hold them responsible for contamination or to challenge their claims about the safety and stability of their genetically engineered crops. Governments too are prone to declaring information secret on grounds of national security when what they really mean is that it would be embarrassing to them.
As Michael Goodyear, a Canadian oncologist and medical ethicist points out [3], it is generally accepted that most manufacturers already have a good idea of their competitors’ strategies. In its submission to the WHO, the Pharmaceutical Research and Manufacturers of America (PhARMA) argued that a manufacturer would be justified in not revealing that trials were of inhaled rather than injected insulin so that competitors would not discover that a new method of delivery was being developed. Yet it has been widely known in medical circles for a long time that insulin manufacturers were testing inhalation delivery [4].
Because the only information about a drug manufacturers are asked to provide is its generic name or, for drugs not already registered, its company serial number, it is hard to see what commercial loss there might be in the vast majority of cases. Where a company was able to show that there could be commercial loss from disclosure of information, then it should still be required to provide the information to the registry, and the registry would undertake not make it public until it was no longer commercially sensitive. There should certainly be full and immediate disclosure if something goes wrong.
While the WHO has been consulting and drawing up plans for ICTRP, a small group of influential people, the editors of the leading medical journals, has been taking action. In September 2004, the International Committee of Medical Journal Editors (ICMJE) announced that the results of any Phase 3 trial that started recruiting after 1 July 2005 will be considered for publication only if the trial was registered [5]. Not only must the trial have been registered, the authors must have filled in all 20 fields in the WHO minimal data set. What is more, the journals will not accept registrations where the authors have provided deliberately uninformative responses, such as using a phrase like “investigational drug” in place of the actual name of the drug – as some consistently do.
This initiative is already having an effect. Pharmaceutical companies consider it very important to have their trial results published in peer-reviewed journals, especially prestigious ones like those edited by the members of ICMJE. It gives the work much more credibility than if it were merely an internal report written by company employees. So if the leading journals demand registration, and, what is more, registration with full information provided, manufacturers have a strong incentive to comply.
This certainly appears to be happening. A review of the records of ClinicalTrials.gov for the period between 20 May 2005 and 11 October 2005 [6] showed that the number of registrations increased by 73 per cent, from 13 153 to 22 714, and the number of name entries that didn’t actually identify the drug decreased from 10 per cent to 2 per cent – and those were all from the same four companies.
Clearly, significant progress has been made. But we still have not reached the point where all clinical trials are registered and with sufficient information that we can tell what was planned, much less, what happened. We will not be able to tell whether the trial was properly conducted and its results correctly analysed, but we will have a better idea of what questions to ask. Much will depend on how far those responsible for the trials are required to answer those questions – for example, whether a particular trial on the register was actually run; if not, why not, and further down the line, what the results were.
Article first published 24/05/06
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