The aim of this benefit assessment was to assess the added benefit of ingenol mebutate gel (150 μg/g) for use on the face and scalp, and of ingenol mebutate gel (500 μg/g) for use on the trunk and extremities in comparison with diclofenac / hyaluronic acid gel (3%) as appropriate comparator therapy (ACT) in adult patients with non-hyperkeratotic, non-hypertrophic (non-HK/HT) actinic keratosis. The assessment was based on patient-relevant outcomes. The company did not identify any randomized controlled trials (RCTs) with direct comparisons of ingenol mebutate gel and diclofenac / hyaluronic acid gel. It therefore aimed at determining the added benefit on the basis of indirect comparisons. For both ingenol mebutate gel and diclofenac / hyaluronic acid gel, the company identified studies comparing the intervention therapy with a vehicle gel that did not contain ingenol mebutate gel or diclofenac. The company assumed that the hyaluronic acid gel itself, which served as vehicle in the diclofenac/hyaluronic acid studies, had an effect on actinic keratosis, whereas the drug-free vehicle gel in the ingenol mebutate studies did not. It therefore rejected an adjusted indirect comparison with vehicle gel as intermediate comparator. Instead, it chose a method called "chaining of direct comparisons" for the indirect comparison (comparison of ingenol mebutate gel versus vehicle gel, vehicle gel versus hyaluronic acid gel, and hyaluronic acid gel versus diclofenac / hyaluronic acid gel on the basis of the studies mentioned above). A comparison of ingenol mebutate vehicle and hyaluronic acid gel conducted in RCTs would have been necessary, however, to draw a valid conclusion on added benefit on the basis of the method chosen by the company. The company did not identify such studies. Groups with drug-free vehicle gel from different studies were compared in one step of the method. This was an unadjusted indirect comparison, which rendered randomization ineffective. Unadjusted indirect comparisons do not constitute a valid method of analysis, however. Moreover, the company included 2 non-randomized comparative studies on ingenol mebutate versus drug-free vehicle gel in the assessment of the outcome "recurrence rate". The company did not identify any studies with diclofenac/hyaluronic acid gel that recorded this outcome. Hence there were no relevant data for the research question.