We have been living in the “no-A2″ regime for a number of years now, where NIH grant applicants are only allowed a single opportunity to respond to the reviews of their initial grant submissions with a revised version. If that single revised version does not get funded, it is impermissible to revise it by responding to the reviews and resubmitting a second revised version. At that point you can only write a “new” grant, which has to be substantially different from the unfunded one.
I have had a lot of experience in this regime dealing with my own grants as well consulting on those of colleagues and reviewing them in study section. Based on this experience I have arrived at the following two rules that should only in exceedingly rare circumstances be violated:
(1) If the signifiance criterion scores from the assigned reviewers on the initial grant submission were the *best* scores, and you were hammered on approach, then you have a chance, and it is worth revising and resubmitting. If, however, the significance scores were the *worst* scores, and this was driven by fundamental concerns about the impact of the planned research, then revision and resubmission is unwise. The better course is to rethink the presentation of the overall thrust of the planned research and submit as a new application. This is because it is generally impossible to convince reviewers that they were flat-out wrong about their conclusions that your proposed research is fundamentally uninteresting.
(2) Regardless of what is driving the scoring, if in order to successfully respond to reviewer concerns, you find yourself completely reorienting the thrust of two or more of the specific aims–for example, by discarding experimental approaches wholesale and employing different ones, or by replacing entire hypotheses with other ones–you should submit as a new grant. This is because you don’t want to waste an opportunity to revise and resubmit multiple brand new aims at least once with an explicit response to reviewer concerns regarding those particular specific aims. If you submit these brand new aims in a resubmission, then you lose that opportunity.
(3) You need to get detailed case-specific advice about this shitte from people who have a lot of experience with the new no-A2 regime, not from olde geezers who have been renewing the same single R01 for decades.