One of the main aims of Anaxomics is helping researchers and pharma companies in drug development. In this blog, we have previously talked about one of the possible early stages of drug development, target profiling, as well as about many alternative technologies that can be used in this process, such as mechanism of action identification, drug repositioning, identification of therapeutic targets, drug efficacy prediction and combination therapies.
The ultimate goal of drug development is to bring a new compound with proven therapeutic effect to the market. In this context, the transition from preclinical research to clinical stages marks a critical turning point, as it nears the new medicinal product to the market. With the promise of marketing authorization, though far ahead in the road, hanging on the horizon, the approval of a clinical trial usually attracts investors and leads to a respectable rise of the company shares.
However, everything comes at a price. Clinical trials are not without risks, and while the perspective of success is encouraging, the crude reality is that most compounds fail before reaching the market. As explained in previous entries, despite higher R&D expenditures, attrition rates are high and, what is worse, on the rise. Data collected between 1990 and 2004  show that the number of unsuccessful clinical trials has been steadily increasing during the last years: from 30 % to 50 % at Phase 1, from 40 % to 70 % at Phase 2 and from 20 % to nearly 50 % at Phase 3 (Figure 1). As a result, less than 10 % of the drugs that enter clinical trials end up being approved by regulatory agencies.
Because of this high probability of failure, each new step in the drug development path gives both the company and shareholders a glimmer of hope. Nevertheless, although moving from one stage to the next is undoubtedly great news, it also increases the risk of financial catastrophe. More advanced phases require larger numbers of participants, leading to much higher costs. In total, clinical studies represent more than a 50 % of the cost of developing a new compound from scratch (although, as our readers know, this is not the only option to market a drug!), with Phase 2 and Phase 3 studies accounting for 20 % of the expenses each. If the drug fails to show the expected efficacy at the end of this process, all the previous work –and investment– goes to waste. Therefore, ensuring success is critical at any point of the drug development process, all the more so in later stages.
The primary reasons for attrition in 2000 were mostly safety issues and lack of efficacy, accounting for a 30 % of failures each. In 2012, the percentage of failures due to lack of efficacy had risen to a 56 % and efficacy remained at 30 % . On the other hand, the temporal distribution of these factors is uneven: as the new compound moves on to registration, serious adverse events give way to lack of therapeutic benefit as the main reason for failure, particularly in complex diseases.
Many different avenues have been proposed to tackle this challenge, but reason suggests that any realistic attempt to reverse the current trends in R&D productivity must be directed at the very root of the problem: the poor predictive capability of the current experimental models. Not surprisingly, the use of animal models that do not properly recapitulate human features has been proposed as the main underlying cause of both lack of clinical efficacy and unsuspected adverse events .
A decade ago, AstraZeneca realized this when its cancer drug candidate Iressa fell short on improving survival in a 1,700-patient clinical trial. Despite a sound scientific rationale and outstanding results in preclinical research and early clinical studies, it did not seem to extend life significantly. The British pharmaceutical company could have just surrendered, but their investment had been high and their scientific advisors had confidence on the product, so they persevered. In the country where Sherlock Holmes was born, a detective was needed to solve the enigma. And that was how systems biology came into scene.
But that is another story and shall be told another time. Keep an eye out for the next entry in our blog to learn how systems biology turned a failed clinical trial into a success, and how it could do the same for you thanks to Anaxomics’ TPMS.
This is our first article of a series on clinical trials. We invite you to check its second post: The role of clinical trials in drug development –Systems biology to the rescue?
- Pammolli, F.; Magazzini, L.; Riccaboni, M. The productivity crisis in pharmaceutical R&D. Nature Reviews Drug Discovery 10, 428-438 (June 2011). doi:10.1038/nrd3405.
- Arrowsmith, J.; Miller, P. Trial Watch: Phase II and Phase III attrition rates 2011–2012. Nature Reviews Drug Discovery 12, 569 (2013). doi:10.1038/nrd4090.
- Kola, I.; Landis, L. Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 3, 711-716 (August 2004). doi:10.1038/nrd1470
Latest posts by Jose Manuel Mas (see all)
- Applying Anaxomics’s TPMS to improve clinical trial results (4) – Sample size reduction:Homogenizing the population by means of mechanistic-based exclusion criteria - May 28, 2014
- Applying Anaxomics’s TPMS to improve clinical trial results (3) – Sample size reduction: the basics - May 26, 2014
- Applying Anaxomics’s TPMS to improve clinical trial results (1) – Efficacy and safety - May 19, 2014