How do the EMA and FDA decide which anticancer drugs make it to the market? A comparative qualitative study on decision makers' views.

BACKGROUND: The process leading to a regulatory outcome is guided by factors both related and unrelated to the data package, defined in this analysis as 'formal and informal factors', respectively. The aim of this qualitative study was to analyse which formal and informal factors drive the decision-making process of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulators with regard to anticancer drugs, using in-depth semi-structured interviews with regulators of the two agencies. METHODS: In line with the theory and practice of qualitative research, no set sample size was defined a priori. Respondent enrolment continued until saturation and redundancy were reached. Data were collected through means of in-depth semi-structured interviews conducted either in a face-to-face setting or via Skype(®) with each regulator. The interviews were audio-recorded and verbatim transcribed. The analysis was manually carried out on the transcribed text. Data were independently coded and categorized by two researchers. Interpretation of the findings emerged through a process of triangulation between the two. RESULTS: Seven EMA and six FDA regulators, who had extensive experience with making decisions about anticancer medicines, were interviewed between April and June 2012. There is an open dialogue between the FDA and EMA, with the two moving closer and exchanging information, not opinions. Differences in decision-making between the agencies may be due to a different evaluation of end points. Different interaction modalities with industry and patients represent an additional source of divergence with a potential impact on decision-making. The key message of our respondents was that the agencies manage uncertainty in a different way: unlike the EMA, the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments. CONCLUSIONS: Although formal factors are the main drivers for regulatory decisions, the influence of informal factors plays an important role in the drug evaluation process.

Stopping a trial early in oncology: for patients or for industry?

BACKGROUND: The aim of this study is to assess the use of interim analyses in randomised controlled trials (RCTs) testing new anticancer drugs, focussing on oncological clinical trials stopped early for benefit. MATERIALS AND METHODS: All published clinical trials stopped early for benefit and published in the last 11 years, regarding anticancer drugs and containing an interim analysis, were assessed. RESULTS: Twenty-five RCTs were analysed. The evaluation of efficacy was protocol planned through time-related primary end points, >40% of them overall survival. In 95% of studies, at the interim analysis, efficacy was evaluated using the same end point as planned for the final analysis. As a consequence of early stopping after the interim analysis, approximately 3300 patients/events across all studies were spared. More than 78% of the RCTs published in the last 3 years were used for registration purposes. CONCLUSION: Though criticism of the poor quality of oncological trials seems out of place, unfortunately early termination raises new concerns. The relation between sparing patients and saving time and trial costs indicates that there is a market-driven intent. We believe that only untruncated trials can provide a full level of evidence which can be translated into clinical practice without further confirmative trials.

Phase II double-blind randomized study of lonidamine and radiotherapy in epidermoid carcinoma of the lung.

Patients with non metastatic squamous cell lung cancer were treated with radiotherapy (RT) plus lonidamine (LND) or placebo (PLAC), according to a randomized double-blind study design. Treatment with lonidamine 150 mg t.i.d. (27 patients) or placebo (23 patients) started 3 days before RT, lasted up to 7 months. Partial responses were observed in 14 and 6 patients respectively in the LND + RT and PLAC + RT groups. Statistical analysis of the survival curves showed no significant difference between the LND + RT (median 311 days) and PLAC + RT (median 193 days) groups. Stage III patients survived significantly longer (p less than 0.05) when treated with LND + RT (median 318 days) than with PLAC + RT (median 163 days). No synergistic toxic effects between radiation and LND were noted. To confirm these data a new and larger multicentric study is now in progress.