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December 19, 2011
Efforts over the past decade to characterise the genetic alterations in human cancers have led to a better understanding of molecular drivers of this complex set of diseases. Although researchers in the cancer field hoped that this would lead to more effective drugs, the ability to translate cancer research to clinical success has been remarkably low, and clinical trials in oncology have the highest failure rate compared with other therapeutic areas.
A significant contributor to failure in oncology trials is the quality of published preclinical data. Drug development relies heavily on the literature, especially with regard to new targets and biology. Moreover, clinical endpoints in cancer are defined mainly in terms of patient survival, rather than by the intermediate endpoints seen in other disciplines (for example, cholesterol levels for statins). Thus, it takes many years before the clinical applicability of initial preclinical observations is known. The results of preclinical studies must therefore be very robust to withstand the rigours and challenges of clinical trials, stemming from the heterogeneity of both tumours and patients.
Scientists (including one of the authors) in the haematology and oncology department at the biotechnology firm Amgen (Thousand Oaks, California, USA) tried to confirm published findings related to their work. 53 papers were deemed 'landmark' studies but scientific findings were confirmed in only 6 (11%) cases.
Thess findings are consistent with those of others in industry. A team in Germany recently reported that only about 25% of published preclinical studies could be validated to the point at which projects could continue. Notably, published cancer research represented 70% of the studies analysed in that report, some of which might overlap with the 53 papers examined at Amgen. Some non-reproducible preclinical papers had spawned an entire field, with hundreds of secondary publications that expanded on elements of the original observation, but did not actually seek to confirm or falsify its fundamental basis. More troubling, some of the research has triggered a series of clinical studies - suggesting that many patients had been subjected to a trial of a regimen or agent that probably wouldn't work.
The authors suggest ways in which preclinical research could be made more robust, but conclude that the responsibility for design, analysis and presentation of data rests with investigators, the laboratory and the host institution. All are accountable for poor experimental design, a lack of robust supportive data or selective data presentation. The scientific process demands the highest standards of quality, ethics and rigour.
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