Improved thinking is also needed in specifying the end points of such studies. For example, we have mentioned the focus on longer acting products, but can a longer half-life be viewed as an automatic benefit? The actual clinical need is for the prolongation of the time during which the patients are at higher trough levels and, as Collins has shown [15], longer acting products can also result in the prolongation of suboptimal trough level periods. It should be noted that similar effects in prolonging optimal trough levels can be obtained by increasing the dosage of current established

products. Such considerations should be factored into studies for novel molecules, keeping in

mind that adverse effects, such as the possibility of inhibitors, are unlikely to be detected in the preapproval phase of assessment, Maraviroc in vivo irrespective of the design. After a drug has completed all the phases required for licensure, there is still much to learn about the real impact of the drug on the overall health of the target population for which it has been approved. Several factors come into play when routine use starts, among which the most relevant are the willingness of doctors to prescribe and of patients to be compliant to the prescribed regimen. Indeed, the effectiveness of a drug is the balance of the expected benefits, usually lower if the patient is not compliant, and the unwanted side buy CHIR-99021 effects, very often erratically related to exposure, so that the most likely consequence of non-adherence is a reduction in the net clinical Forskolin concentration benefit [26]. Furthermore, the role of anticipated

and unanticipated drug interactions, and of variability in efficacy with concomitant comorbidities such as renal impairment or in specific populations like children or the elderly, is usually unknown at the time of initial approval. In most cases, new drugs are found to be beneficial in these populations, and long-term assessment of their use generates important knowledge. Finally, side effects uncommon enough to escape the detection power of registration trials may be recognized only when large populations are exposed for a sufficient length of time. This has sometimes led to drug withdrawals, as happened with thalidomide in the 1950s or rosiglitazone in 2011; or the issuing of drug warnings even for commonly prescribed drugs, as was the case for beta-agonists in children [27] or for certain opiates [28, 29]. Factor concentrates are no exception to the need for long-term assessment of efficacy and safety, and especially so as we consider new therapeutics with enhanced characteristics, which no longer fit into the category of simple replacement therapy.