Are new drug projects failing as early as possible? "The degree of advance and retreat" tests decision makers' judgment

Source: on December 11, 2015, new drug R & D investment of American and Chinese drug sources was light before and heavy after, and the final phase III clinical trial investment was sometimes more than the total investment of the whole early stage So some people suggest that new drug projects should be stopped as soon as possible when there is not a lot of investment, so as to avoid the later heavier This view now almost represents the mainstream opinion Some enterprises have adopted specific measures to encourage the timely stop of projects with poor prospects, such as Novartis courage award However, most of the new drug projects ended in failure, even in the third phase of clinical practice, the failure rate was more than 50%, so in most cases, it is more likely to be the right decision to terminate a project than to continue the project In practice, because of the heavy losses of these failures, most enterprises will reflect on how to draw lessons from them One of the most important questions is whether there are enough signals before the third phase that the project should stop The accuracy of this kind of summary can get useful experience, but like misinterpretation of efficacy and safety signals, this kind of reflection is inevitably affected by people's misunderstanding There is no doubt that, as we mentioned in the last issue, some projects have not gone through enough risk elimination, and many projects have not made substantive progress in situ for many years, so such projects need to be terminated in time However, how to distinguish these rash or zombie projects from subversive projects that encounter temporary setbacks is one of the core tasks of new drug research and development If you carefully look for no project in the long development process did not appear several project termination signals If every time there is such a signal to easily end a project, then there will be no new drugs in the world Even the subversive technology platform of tumor immunotherapy (not only a drug, an indication, but also a variety of different drugs for almost all tumors) was rated as the No 1 hoax in the pharmaceutical field by an article published in the journal Nature 10 years ago The development process of any pioneering drug has the similar experience of laying down the burden and tasting the gall In fact, the stop signal for real innovation projects is far more than the forward signal, otherwise, these projects have been done for a long time The ups and downs of new drug projects and new technologies are similar At the beginning, there are always rosy clouds, but soon negative data will appear At this time, it is easy to terminate any project This is probably mean regression at work A project starts with little data, but it's also a lack of data Those projects that move away from the average in a positive direction are more attractive than those that only have negative data, although their success rates are the same However, with the accumulation of data, these projects will generally return to the mean The difference is that those projects that start to attract data will be more competitive With the accumulation of data, both promising and mediocre projects have to start to face the reality The reality of new drug research and development is to find the only sunshine in the sky Sometimes it's easy to decide whether to go or stay For example, KRAS is an attractive target, but no small molecule drug can effectively compete with its substrate GTP, so it can't go on at all But the balance of advance and retreat for more projects is more complicated For example, the original drug king Lipitor can only be listed for the fifth time according to the schedule In front of it are giants such as mosadong under the leadership of Roy Vagelos Prozac had no significant effect in the animal model at that time because of its novel mechanism, and the first phase II clinical trial failed because of insufficient patients due to financial constraints Therefore, it is not easy to finish the projects with low success as early as possible, that is, the so-called kill the losers strategy In view of the high failure rate of new drug projects, especially initial projects, a project should have a period similar to "criminal immunity", that is, it should strive to move forward regardless of positive and negative results under certain investment restrictions The task of the team is not to consider whether to continue or stop, but to try to find a way to make the project successful Although "kill the losers" seems reasonable on the surface, it does not fully reflect the complex reality of new drug development Searching for new drugs is like climbing a mountain Even if you take the most likely route to the top sooner or later, you will encounter adverse factors such as cliff, lack of oxygen, and bad weather There will be far more excuses to return to the base camp than to move on, so it's easy to over encourage the termination of the project policy This is another seemingly opposite strategy, that is, "pick the winners" also has a considerable market reason In fact, "pick the winners" and "kill the losers" are two sides of the same coin Any successful project needs to endure a highly questioned stage, but the right project should give enough opportunity to prove itself The so-called doubt people do not need to use, use people do not doubt On the other hand, you can't be merciful when you need to tear Ma su Of course, as with any strategy, theory is one aspect, and what really plays a decisive role is execution and understanding of new drug research and development New drug research and development projects do not fail as early as possible, and perseverance does not always bring about subversive drugs The most important is the decision-maker's judgment, but the rarest is the decision-maker's judgment.