A second category is the biomarker-enriched design, in which the researchers make the "strong" assumption of larger effect in a particular subgroup and elect to enroll subjects only from that subgroup. While the use of a biomarker for this purpose is relatively novel, the concept of an enriched design is not; indeed, a generation's worth of antidepressant trials have explored severity thresholds, with mixed results. Enriched designs should be more efficient, allowing smaller sample sizes to demonstrate a given effect size. On the other hand, such enriched designs may not be feasible when the group of interest is less common or when identification of the biomarkers is more labor intensive. Also, from a regulatory as well as a scientific perspective, they will almost always entail a follow-up study to establish specificity of effect. That is, if the treatment works in the marker-positive group, does it work in the marker-negative group?