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Poor access to drugs leaves important clinical questions unanswered
In May 2004, the European Clinical Trials Directive came into force. The directive made it mandatory for all clinical drug trials to follow the good clinical practice guidance, and it fuelled existing concerns that financial and organisational constraints were making it almost impossible to conduct independent trials not funded by the drug industry. In the accompanying paper, Berendt and colleagues show that the decrease in the number of new clinical trials registered each year in Denmark began well before 2004, and the decrease was similar for independent and industry sponsored trials.1 In 2006, two years after the enforcement of the EU directive, the number of independent trials actually increased. Similar results have been reported in Sweden, Norway, and Italy.2 The consistency of these findings, despite differences in registration and classification systems, supports their validity and generalisability.
So can we feel reassured about the future of independent therapeutic research? Certainly, clinical research not sponsored by the industry is alive and active. Yet, if we consider the role that independent researchers should have in directing therapeutic research towards its primary mission—meeting the needs of patients and health systems—the overall picture is more complex. The data above do not tell us how the relevance and potential impact of the independent trials compare with industry sponsored trials. For instance, the Italian data show that phase III trials, multicentre trials, and international trials are less likely to be independent.2
The trials that showed the efficacy of aromatase inhibitors for early, hormone dependent, postmenopausal breast cancer provide an example of how the aims of industry sponsored trials may differ from those of independent trials. These trials compared the use of aromatase inhibitors with the conventional regimen of five years of tamoxifen.3,4,5,6 The first published analyses of these trials, which in two cases were interim analyses that led to the premature cessation and unblinding of the trial, were conducted at median follow-ups of 2.2 to 2.7 years. All four trials found that aromatase inhibitors significantly improved disease-free survival, which is a plausible but not validated surrogate endpoint for overall survival in early breast cancer.7 In contrast, no significant effect was seen on overall survival.
Because early breast cancer has a long natural history and aromatase inhibitors may have delayed effects, decisions on the use of these drugs in this setting should be based on reliable information on their long term efficacy and safety.8 However, crossover of the control group to aromatase inhibitors in all but one3 of these studies may hamper their ability to provide this information.8 Furthermore, for ethical reasons, it is no longer acceptable to conduct a trial in which tamoxifen is given for five years as the control. Consequently, despite the inclusion of more than 20000 patients in the above trials, aromatase inhibitors are being used to treat early breast cancer on the basis of inadequate information, and this information might never become available.
These trials were industry sponsored, but were conducted by some of the most prestigious and reliable international research groups in the area, and were virtually flawless from a methodological and statistical viewpoint. However, their design and results fit much better with the expectations of their sponsors than those of the patients and of the health systems that must sustain the costs of the new treatments.
Drug companies autonomously devise the strategies for the clinical development of promising new drugs and have the resources to implement these strategies. These are usually designed to pursue the registration of the drug by both the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products as quickly as possible, perhaps with an unrestricted indication. These aims are best met by conducting very large international trials on unselected populations. The large size provides high power against marginal treatment benefits, and—most importantly—in early interim analyses.
Independent researchers are left with no option but to join these large studies because the new drug is not available for use in independent studies. Truly independent trials are possible only after the drug has been approved for clinical use, but then the costs can be prohibitive. More importantly, the characteristics of the original trials (unselected patients, early results on surrogate endpoints of questionable validity) leave important questions unanswered, and these questions cannot be answered by second generation trials because of ethical constraints. Therefore, truly independent research is condemned to focus on less important questions (such as combinations and delivery strategies).
So what can be done? As Berendt and colleagues suggest, the ability of academic researchers to handle problems related to the guidance on good clinical practice can be improved by allocating relatively modest resources to dedicated units.1 However, individual researchers and academic institutions have no power to influence the clinical research plans of drug companies. The medical research community has some power, and it should rethink the terms of cooperation with industry in clinical trials, taking into account a wider clinical and public health perspective.8 But it is up to governments, health systems, and regulatory agencies to identify new paths for drug development and to set new standards for the approval of new drugs. It is ironic that our health systems risk bankruptcy for the skyrocketing costs of drugs that were developed on their own patients using strategies that ignore the patients’ needs and priorities.
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.