Survival, cost and added therapeutic benefit of drugs granted early access through the French temporary authorization for use program in solid tumors from 2009 to 2019.

Decisions on market authorization (MA) and reimbursement have different durations across countries because of health technology assessment (HTA) procedures and negotiations between manufacturers and national authorities. To overcome this delay, France has implemented a Temporary Authorization for Use (ATU) program that allows early access to drugs before MA, in order to treat patients with unmet medical needs. The objectives of our study were to establish the added therapeutic benefit (ATB) of ATUs for solid tumors and to investigate the correlations between three tools evaluating ATB and survival outcomes and drug costs. Data on ATUs granted from January 2009 to December 2019 to treat solid tumors were analyzed. An assessment of their ATB was conducted using the American Society of Clinical Oncology-Value Framework (ASCO-VF), the European Society for Medical Oncology-Magnitude Clinical Benefit Scale (ESMO-MCBS) and the French HTA criterion, clinical added value (CAV). The latter score determines reimbursement and national market access. Thirty-five drugs in 39 indications were granted ATUs. All of them obtained MA and derived a clinical benefit to be reimbursed by the Social Security. Twenty-eight (71.8%) had CAV compared to preexisting therapies. 24/38 (63.2%) had a 4-5 ESMO-MCBS score and 19/33 (57.6%) had an ASCO-VF score over 45. No correlations were found between cost, PFS, OS, CAV and ASCO-VF score, while high ESMO-MCBS scores were correlated to OS. In conclusion, many patients were treated with innovations before MA thanks to ATU, although there are discrepancies between ATB scales, hence the importance of international collaboration in the evaluation of innovative therapies.

Comparative study on anticancer drug access times between FDA, EMA and the French temporary authorisation for use program over 13 years.

INTRODUCTION: The cancer incidence continues to rise worldwide. Medical innovation has a major impact on patient survival, but within drug development, it can take more than 10 years to obtain marketing authorisation (MA). The time required for access to therapeutic innovation remains critical, so France has developed a specific expanded access program named ATU, which allows the administration of drugs before the European Medicines Agency (EMA) approval. The purpose of this study is to put in perspective the average time to access antineoplastic drugs worldwide, taking into account ATU, US Food and Drug Administration (FDA) and EMA approvals. METHODS: The ATU system allows the use of a medicine before its MA, under exceptional conditions. All antineoplastic drugs in oncology that have benefited from the ATU system are analysed in terms of tumour site, biomarkers and number of patients who have access to the drug. RESULTS: Between 1st January 2007 and 31st December 2019, 36 of 64 drugs (56.2%) that received MA in oncology were assigned an ATU, to the benefit of 16,927 patients. Thanks to the ATU, 25 of 36 drugs (69.4%) were made available early, on average 203 d (95% CI, 76-330) before FDA approval and on average 428 d (95% CI, 272-583) before EMA approval. Only three of 36 drugs were approved by the EMA before the FDA, and the average time lapse between European MA and FDA approval for these 36 drugs was 216 d (95% CI, 140-293). CONCLUSION: This article demonstrates that the ATU system allows patients to benefit from therapeutic innovations before MA in Europe and USA, with full coverage by the healthcare system.

Access to innovation through the national early access program and clinical trials for patients with malignant melanoma.

BACKGROUND: The arrival of immunotherapies and targeted therapies challenged the authorities to make them available as soon as possible. France has effective tools, such as clinical trials (CTs) and a national early access program (temporary authorizations for use [ATUs] and temporary recommendations for use [RTUs]), allowing the use of innovative drugs, whether or not they have been authorized or used off-label, for cases that have reached a therapeutic impasse. METHODS: The methodology involved real-time data collection from ATUs, RTUs (between September 1, 2009 and September 1, 2019), and CT authorizations (from December 1, 2017 to September 1, 2019) that were filed and reviewed by the French National Agency for Medicines for metastatic melanoma (MM). RESULTS: In total, 45 CTs were authorized for MM (51% early phase trials and 44% phase 2 and 3 trials), mainly for the metastatic line (86%) and with an industrial sponsor (73%). Immunotherapies and targeted therapies (63% and 24%, respectively) mostly were used in combination. Three RTUs were authorized for the adjuvant treatment of MM, whereas 13 drugs were available through nominal ATUs (nATUs), of which 5 were awarded a cohort ATU (cATU). This enabled the treatment of 6538 patients (28% through nATUs and 72% through cATUs). All of these drugs were granted marketing authorization and were included in the reimbursement list. CONCLUSIONS: Thanks to CTs and the national early access program, patients in France have been able to benefit from innovative MM treatments. LAY SUMMARY: Several tools allow the use of innovative drugs in France, even if they are not yet authorized or used off-label. From December 1, 2017 to September 1, 2019, 45 clinical trials have been authorized for metastatic melanoma, mostly using immunotherapy (63%) and targeted therapy (24%) at an early phase (51%). Since 2010, the national early access program has treated 6538 patients, including 28% under nominative temporary authorizations for use and 72% under cohort temporary authorizations for use. Fourteen drugs are available through nominative temporary authorizations for use, and 5 are available through cohort temporary authorizations for use, and all of these drugs were granted marketing authorization.

Survey by the French Medicine Agency (ANSM) of the imaging protocol, detection rate, and safety of 68Ga-PSMA-11 PET/CT in the biochemical recurrence of prostate cancer in case of negative or equivocal 18F-fluorocholine PET/CT: 1084 examinations.

INTRODUCTION: Despite growing evidence of a superior diagnostic performance of 68Ga-PSMA-11 over 18F-fluorocholine (FCH) PET/CT, the number of PET/CT centres able to label on site with gallium-68 is still currently limited. Therefore, patients with biochemical recurrence (BCR) of prostate cancer frequently undergo FCH as the 1st-line PET/CT. Actually, the positivity rate (PR) of a second-line PSMA-11 PET/CT in case of negative FCH PET/CT has only been reported in few short series, in a total of 185 patients. Our aims were to check (1) whether the excellent PR reported with PSMA-11 is also obtained in BCR patients whose recent FCH PET/CT was negative or equivocal; (2) in which biochemical and clinical context a high PSMA-11 PET/CT PR may be expected in those patients, in particular revealing an oligometastatic pattern; (3) whether among the various imaging protocols for PSMA-11 PET/CT used in France, one yields a significantly highest PR; (4) the tolerance of PSMA-11. PATIENTS AND METHODS: Six centres performed 68Ga-PSMA-11 PET/CTs during the first 3 years of its use in France. Prior to each PET/CT, the patient's data were submitted prospectively for authorisation to ANSM, the French Medicine Agency. The on-site readings of 1084 PSMA-11 PET/CTs in BCR patients whose recent FCH PET/CTs resulted negative or equivocal were pooled and analysed. RESULTS: (1) The overall PR was 68%; for a median serum PSA level (sPSA) of 1.7 ng/mL, an oligometastatic pattern (1-3 foci) was observed in 31% of the cases overall; (2) PR was significantly related to sPSA (from 41% if < 0.2 ng/mL to 81% if ≥ 2 ng/mL), to patients' age, to initial therapy (64% if prostatectomy vs. 85% without prostatectomy due to frequent foci in the prostate fossa), to whether FCH PET/CT was negative or equivocal (PR = 62% vs. 82%), and to previous BCR (PR = 63% for 1st BCR vs. 72% in case of previous BCR); (3) no significant difference in PR was found according to the imaging protocol: injected activity, administration of a contrast agent and/or of furosemide, dose length product, one single or multiple time points of image acquisition; (4) no adverse event was reported after PSMA-11 injection, even associated with a contrast agent and/or furosemide. CONCLUSION: Compared with the performance of PSMA-11 PET/CT in BCR reported independently of FCH PET/CT in 6 large published series (n > 200), the selection based on FCH PET/CT resulted in no difference of PSMA-11 PR for sPSA < 1 ng/mL but in a slightly lower PR for sPSA ≥ 1 ng/mL, probably because FCH performs rather well at this sPSA and very occult BCR was over-represented in our cohort. An oligometastatic pattern paving the way to targeted therapy was observed in one fourth to one third of the cases, according to the clinico-biochemical context of the BCR. Systematic dual or triple acquisition time points or administration of a contrast agent and/or furosemide did not bring a significant added value for PSMA-11 PET/CT positivity and should be decided on individual bases.

Short-Term Risk of Bleeding During Heparin Bridging at Initiation of Vitamin K Antagonist Therapy in More Than 90 000 Patients With Nonvalvular Atrial Fibrillation Managed in Outpatient Care.

BACKGROUND: Several studies have recently examined the risks of bleeding and of ischemic stroke and systemic embolism associated with perioperative heparin bridging anticoagulation in patients with nonvalvular atrial fibrillation. However, few studies have investigated bridging risks during vitamin K antagonist initiation in outpatient settings. METHODS AND RESULTS: A retrospective cohort study was conducted on individuals starting oral anticoagulation between January 2010 and November 2014 for nonvalvular atrial fibrillation managed in outpatient care and identified from French healthcare insurance. Bleeding and ischemic stroke and systemic embolism events were identified from the hospitalization database. Adjusted hazard ratios with 95% CI were estimated using Cox models during the first and 2 following months of anticoagulation. Of 90 826 individuals, 30% had bridging therapy. A total of 318 (0.35%) cases of bleeding and 151 (0.17%) ischemic stroke and systemic embolism cases were identified during the first month of follow-up and 231 (0.31%) and 122 (0.16%) during the 2 following months, respectively. At 1 month of follow-up, the incidence of bleeding was higher in the bridged group compared with the nonbridged group (0.47% versus 0.30%; P<0.001), and this increased risk persisted after adjustment for covariates (hazard ratio=1.60; 95% CI, 1.28-2.01). This difference disappeared after the first month of treatment (0.93; 0.70-1.23). No significant difference in the occurrence of ischemic stroke and systemic embolism was observed either at 1 month of follow-up or later. CONCLUSIONS: At vitamin K antagonist initiation for nonvalvular atrial fibrillation managed in ambulatory settings, bridging therapy is associated with a higher risk of bleeding and a similar risk of arterial thromboembolism compared with no bridging therapy.

Early changes in coronary flow physiology after balloon angioplasty or stenting: a 24-hour Doppler flow velocity study.

To evaluate early changes in myocardial microcirculation after balloon or stent coronary angioplasty, we studied 57 patients undergoing coronary angioplasty with a Doppler-tipped guidewire, with (n = 26) or without stenting. Postprocedural quantitative coronary angiography and coronary flow velocity were measured after 10 min and 24 hr. As compared to stenting, no stenting was associated with a higher postprocedural stenosis rate (21% +/- 13% vs. 12% +/- 10%; P < 0.05), smaller coronary velocity reserve (CVR; 2.2 +/- 0.4 vs. 2.5 +/- 0.7; P = 0.04), and smaller relative CVR (0.8 +/- 0.2 vs. 1.1 +/- 0.3; P = 0.001). At 24 hr, CVR and relative CVR in the unstented group increased to the level in the stented group, mainly because of a decrease in basal average peak velocity (APV). Overall, there was a significant negative linear relation between CVR and APV variations during the 24-hr period. In the subgroups with persistent abnormalities, CVR variation was closely related to the basal APV/reference APV ratio. In conclusion, coronary reserve normalization can occur within 24 hr after coronary angioplasty and is closely dependent on postangioplasty APV. Myocardial distal resistances should be considered when interpreting postangioplasty CVR.