European Medicines Agency Perspective on Oncology Study Design for Marketing Authorization and Beyond.

In the development of highly active anticancer drugs, the European situation may be viewed as paradoxical. Limited data may support marketing authorization, but may be insufficient for the health economic appraisal needed for reimbursement and market uptake. To achieve this, conventional confirmatory studies may be needed. For products of special interest, studies aimed at optimizing cost-effectiveness may be warranted. Efficient designs of studies to meet these objectives constitute challenges to all stakeholders.

Early market access of cancer drugs in the EU.

Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access.

Genetic cooperation between p21Cip1 and INK4 inhibitors in cellular senescence and tumor suppression.

Cell-cycle inhibitors of the Cip/Kip and INK4 families are involved in cellular senescence and tumor suppression. Some of these proteins, p21(Cip1), p16(INK4a) and p15(INK4b), are coexpressed in response to antiproliferative signals such as cellular senescence resulting in cell-cycle arrest. To understand the roles of these inhibitors and their synergistic effect, we have characterized the growth properties and senescent behavior of primary cells deficient in p21(Cip1) and expressing an endogenous Cdk4(R24C) (cyclin-dependent kinase) mutant (Cdk4(R24C) knock-in cells) insensitive to INK4 proteins. Inactivation of both p21(Cip1) and INK4 pathways strongly cooperate in suppressing cellular senescence in vitro. These double mutant cells behavior as immortal cultures and display high sensitivity to cellular transformation by oncogenes. Moreover, mice double mutant in the INK4 and p21(Cip1) pathways (Cdk4(R24C); p21(Cip1)-null mice) display an increased incidence of specific sarcomas, suggesting a significant cooperation between these two families of cell-cycle inhibitors in senescence responses and tumor suppression in vivo.