“Doing it right” in Phase 2 clinical trials: When I was young in the pharmaceutical industry, I was on a job interview when I first heard a catchphrase that eloquently captures an attitude that one encounters every so often in drug development. The hiring supervisor, in explaining the status of his program, told me — with more than a hint of cynicism, “There’s never enough time to do it right, but there’s always enough time to do it over.” I suppose I could write a dozen entries expounding on this one concept (and maybe, eventually, I will), but the crux of the matter is this: In the headlong rush to get a clinical trial implemented, conducted, and completed, shortcuts can sometimes be taken that ultimately lead to grief in the form of wasted time and money.
Phase 2 is the stage of drug development that is most prone to this sort of thinking — which, I must emphasize, is not widespread, but is worth considering here because of the dire effects it can have on a program. Phase 1 is the learning phase, with deliberate procedures, rigorous attention to detail, and obsessive protection of subject safety. Phase 3 also rigorous, but in a different way, as pivotal trials must conform to procedures and outcomes pre-negotiated with the regulatory authorities. Phase 2 not only has more latitude than Phases 1 and 3, but there are also a myriad of clinical questions to be answered before the sponsor can plan its registration trials. Given these multiple degrees of freedom, it is not surprising that Phase 2 can present the temptation to cut a corner or two.
Several key issues come to mind include dose-finding, choice of control group, and relevance of a narrowly selected patient population; I plan on covering some of these topics in future entries. Today, I’d like to focus on the issue of how much information is needed to provide “proof of principle”, i.e., data that indicate the new drug has the intended pharmacologic (if not necessarily therapeutic) effect. The temptation here can be to study “a few patients” just to “get a quick look” at the drug’s activity and then jump into Phase 3. A more likely situation, it seems, is for the sponsor to implement a well-designed, hypothesis-driven Phase 2 trial, but to underpower it by enrolling too few patients. The result is a trial that is, yes, cheaper and quicker, but that sacrifices statistical rigor and scientific credibility.
My point is that it is critical to plan Phase 2 trials so that they enroll sufficient numbers of patients to provide all the relevant audiences — management, potential investors, strategic partners, scientists, thought leaders, regulators — with a reasonable level of confidence in the results. The data will be used to make very significant decisions with respect to resource commitment, corporate priority-setting, and fundraising, so they must be robust and credible. Short-changing the trial, on the other hand, undermines both the credibility of the results and their ability to predict future performance of the drug (i.e., in larger trials). Faced, at the end of the day, with inadequate data to drive a decision or to plan a registration trial, a sponsor may have to repeat significant chunks of Phase 2 before moving forward to registration. And in that situation, the “cheap-quick” trial turns out to be much longer, and much more expensive, than “doing it right the first time” would have been.
BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries. The goal of this blog is to provide a forum to discuss the challenges and intricacies of clinical development, as well as the testing of pharmaceutical, biotechnology and medical device products in man.
Over the next several months, I hope to address a number of issues that are of interest to you (and me). If you have any particular questions you would like me to address, send me an email at firstname.lastname@example.org
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