How Many Negative Trials Do We Need?

There is a growing concern in the clinical research community about the number of negative phase 3 trials. Given that phase 3 trials are incredibly expensive to run, and involve hundreds or sometimes thousands of patient-subjects, many researchers are now calling for more rigorous phase 2 trials, which are more predictive of a phase 3 result, in the hopes of reducing the number of phase 3 negatives.

In a focus piece from this week’s Science Translational Medicine, Jonathan and I argue that more predictive phase 2 trials may actually have undesirable ethical consequences–ratcheting up the patient burdens and study costs at a point of greater uncertainty, without necessarily increasing social utility or benefiting the research enterprise as a whole. We articulate four factors that we think ought to guide the level of positive predictivity sought in a (series of) phase 2 trial(s). These are: (1) the upper and lower bounds on evidence needed to establish clinical equipoise and initiate phase 3 testing; (2) the need to efficiently process the volume of novel intervention candidates in the drug pipeline; (3) the need to limit non-therapeutic risks for vulnerable patient-subjects; and (4) the need for decisive phase 3 evidence–either positive or negative–in order to best inform physician practices.

We are confident that these four factors are valid, but they are certainly not exhaustive of the inputs needed to make a robust judgment about the appropriate levels of predictivity needed in phase 2 for a given domain. What are the total costs and benefits of a negative phase 3? How should we weigh these against the costs and benefits of a more rigorous program of phase 2 testing? How many negatives should we tolerate? And at what stage of the development process? Our piece is a first-step toward developing a more comprehensive framework that could provide researchers, funders, policy-makers, and review boards with much needed answers to these important questions.

2013 May 10 | Leave a comment | Tags: negative results phase 2 phase 3 translational research

@Manual{stream2013-44,
    title = {How Many Negative Trials Do We Need?},
    journal = {STREAM research},
    author = {Spencer Phillips Hey},
    address = {Montreal, Canada},
    date = 2013,
    month = may,
    day = 10,
    url = {http://www.translationalethics.com/2013/05/10/how-many-negative-trials-do-we-need/}
}