title: Therapeutic indications in oncology: emerging features and regulatory dynamics.
abstract: The regulatory route leading to the definition of therapeutic indications of new compounds as well as extensions of indication (EoI) of already approved ones is a challenging process. If new anticancer drugs reach the market with a lack of complete evidence, this usually leads regulators to request additional data, post approval commitments or restrictions in therapeutic indications. This study aims at quantifying the time needed for anticancer drugs approved by the EMEA to get an extension, the rates and characteristics of extensions approved, and at exploring the regulatory process leading to the definition of new indications. A total of 103 therapeutic oncological indications, related to a cohort of 43 anticancer drugs, were retrieved between 1995 and 2008. The median time occurring between different indications for the same compound (defined as Time to New Extension, TtNE) significantly decrease from about 81 months in 1996 to 6 months in 2006. Twenty-four out of 43 approved anticancer medicines (about 56%) have only a single therapeutic indication, 12 of which were approved before 2005. When considering two different cohorts of drugs in relation to the time of approval (1995-2004 versus 2005-2008), although not statistically significant, the older cohort tended to have a decreased probability of having EoI when compared to the new cohort (OR=0.27; 95% confidence interval (CI): 0.07-1.04). With regard to the type of EoI (n=60), our findings showed that in 48% of cases the initially approved indication was extended to treat a different tumour, in 37% of cases the extension consisted in a switch of line within the same therapeutic indication. The other two types of indication broadening refer to a different tumour stage (8%) and to the inclusion of a new patient population (7%). The analysis of indication restrictions showed that in 20 cases out of 50 (40%) therapeutic indications were restricted by the Committee for Medicinal Products for Human Use (CHMP) during the assessment, with 60% of the restrictions occurring in 2006-2007. This study adds three main pieces of information: (i) the majority of anticancer drugs still have a single indication regardless of the year of approval; (ii) the time needed to obtain an extension of indication has decreased significantly over the last decade and (iii) a highest rate of regulatory restrictions is matched to shorter clinical developments.
authors.affiliation: Italian Medicines Agency (AIFA), via della Sierra Nevada 60, 00144 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tafuri
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.forename: Richard
authors.initials: R
authors.lastname: Laing
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017277:Drug Approval / Q000331:legislation & jurisprudence / Q000458:organization & administration*; D005060:Europe; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents