Authorization For Use Research Articles

See "through the front line": reliability of questionnaires in wartime

Diagnosis and screening of individuals, both civilian and military, is typically done through a clinical interview and\or self-report questionnaires. This information is used to adjust treatment strategies, psychological and psychotherapeutic interventions, and to predict the patient's condition. In modern science, methods that have been shown to be effective and have satisfactory test validity and reliability are considered the gold standard for testing. Adhering to this standard ensures that the tool being used is performing its intended functions to a certain degree of quality providing decent results. Many Ukrainian studies are based on methods that were adapted or created during the era of the Soviet Union and have not been reviewed since. On the other hand, we have methods that were translated from another languages without going through the proper adaptation process. These questionnaires are used in a clinical practice too, by psychologists, psychiatrists and psychotherapists. Moreover, there is no known or open data about the performance of these tests amid the war, both in original and in translated versions.
 The aim of this article was to explore the reliability of the most frequently used screening tools. The study took place in one of the rehabilitation center in Kyiv, Ukraine. Overall, 28 participants joined, all of whom were soldiers who are currently enrolled in the Armed forces of Ukraine. Measurements were taken 3 times with a one week gaps. GAD-7 and STAI (modified by Hanin) were used to screen anxiety, PCL-5 for PTSD screening and ISI helped us to determine sleep problems. The GAD-7, ISI, and PCL-5 questionnaires, in the versions we tested, demonstrated more than satisfactory levels of reliability and are recommended by the authors for use in clinical conditions and for screening soldiers in the armed forces. The STAI, on the other hand, showed unsatisfactory indicators and is not recommended for use in screening procedures or for research purposes. In conclusion, it is recommended that Ukrainian researchers adopt international methods properly, conducting validation studies adhering to so-called “golden standards”.

DNA Vaccines for Epidemic Preparedness: SARS-CoV-2 and Beyond.

We highlight the significant progress in developing DNA vaccines during the SARS-CoV-2 pandemic. Specifically, we provide a comprehensive review of the DNA vaccines that have progressed to Phase 2 testing or beyond, including those that have received authorization for use. DNA vaccines have significant advantages with regard to the rapidity of production, thermostability, safety profile, and cellular immune responses. Based on user needs and cost, we compare the three devices used in the SARS-CoV-2 clinical trials. Of the three devices, the GeneDerm suction device offers numerous benefits, particularly for international vaccination campaigns. As such, DNA vaccines represent a promising option for future pandemics.

COVID-19 Vaccine Safety First Year Findings in Adolescents.

The Food and Drug Administration expanded Emergency Use Authorization for use of Pfizer-BioNTech (BNT-162b2) coronavirus disease 2019 vaccine to include people ages 12 years and older on May 10, 2021. We describe adverse events observed during the first full year of the US coronavirus disease 2019 vaccination program for adolescents ages 12 to 17 years. We conducted descriptive analyses using data from 2 complementary US vaccine safety monitoring systems: v-safe, a voluntary smartphone-based system that monitors reactions and health impacts, and the Vaccine Adverse Event Reporting System (VAERS), the national spontaneous reporting system. We reviewed reports and calculated adverse event reporting rates using vaccine administration data. Among 172 032 adolescents ages 12 to 17 years enrolled in v-safe, most reported reactions following BNT-162b2 were mild to moderate, most frequently reported on the day after vaccination, and more common after dose 2. VAERS received 20 240 adverse event reports; 91.5% were nonserious. Among adverse events of interest, we verified 40 cases of multisystem inflammation syndrome in children (1.2 cases per million vaccinations), 34 (85%) of which had evidence of prior severe acute respiratory syndrome coronavirus 2 infection; and 570 cases of myocarditis (17.7 cases per million vaccinations), most of whom (77%) reported symptom resolution at the time of report. During the first year BNT-162b2 was administered to adolescents ages 12 to 17 years, most reported adverse events were mild and appeared self-limited. Rates of myocarditis were lower than earlier reports. No new serious safety concerns were identified.

Olaparib First-Line Maintenance Monotherapy in BRCA-Mutated Epithelial Ovarian Cancer: Descriptive Analysis of the First French Real-World Data Study.

Olaparib, a poly(ADP-ribose) polymerase inhibitor, was approved by the European Commission in June 2019, following the results of the SOLO-1/GOG 3004 trial as maintenance monotherapy in adult patients with BRCA-mutated epithelial ovarian cancer. This study aimed to provide a descriptive analysis of the first real-world data from patients with BRCA-mutated ovarian cancer who received olaparib as first-line maintenance monotherapy in the French cohort Temporary Authorisation for Use (Autorisation Temporaire d'Utilisation de cohorte, ATUc) programme from 11 March, 2019 to 16 January, 2020. Eligible patients were aged 18 years and over with confirmed epithelial ovarian, primary peritoneal or Fallopian tube cancer and a deleterious or suspected deleterious germline or somatic BRCA 1/2 mutation. Patients were in complete or partial clinical response at the end of first-line platinum-based chemotherapy. Olaparib maintenance therapy was initiated within 8 weeks of the patients' last dose of chemotherapy. Real-world data were collected through treatment access request forms completed by physicians. Clinical and safety data were collected monthly until the end of the ATUc programme. A total of 107 centres in metropolitan France and the French Overseas Departments and Territories requested the inclusion for 238 patients, of whom 194 received maintenance olaparib. In total, 87.6% of the primary tumour locations were ovary, the most common histology was high-grade serous (93.0%) and the most common International Federation of Gynaecology and Obstetrics (Fédération Internationale de Gynécologie et d'Obstétrique) stage was IIIC (56.8%). BRCA testing was performed in routine practice, prior to inclusion into the ATUc programme. All patients had a BRCA mutation: 52.5% had a somatic mutation, 38.4% had a germinal mutation and 9.1% had germinal and somatic mutations. Twenty-four (12%) patients experienced serious adverse drug reactions at the last safety follow-up (17 February, 2020). The most common were anaemia (12 [6%] patients), neutropenia (3 [2%] patients) and thrombocytopenia (3 [2%] patients). The rapid enrolment into the ATUc programme highlighted the strong unmet need for patients with ovarian cancer and a BRCA mutation in first-line maintenance treatment. Olaparib was well tolerated and no new safety signals were observed in this real-world patient population.

Translation and cross-cultural adaptation of the anchor points of the Cornell Assessment of Pediatric Delirium scale into Portuguese.

To translate and cross-culturally adapt the Cornell Assessment of Pediatric Delirium anchor points from English to Brazilian Portuguese. For the translation and cross-cultural adaptation of the anchor points, all steps recommended internationally were followed after authorization for use by the lead author. The stages were as follows: translation of the original version into Portuguese by two bilingual translators who were native speakers of the target language, synthesis of the versions, reverse translation by two translators who were native speakers of the source language, review and synthesis of the back-translation, review by a committee of experts and preparation of the final version. The translation and cross-cultural adaptation of the anchor points was conducted in accordance with recommendations. The linguistic and semantic issues that arose were discussed by a committee of judges, with 91.8% agreement, as determined using a Likert scale, after changes by consensus. After reanalysis by the authors, there were no changes, resulting in the final version, which was easy to understand and administer. The translation and cross-cultural adaptation of the anchor points of the Cornell Assessment of Pediatric Delirium scale into Portuguese spoken in Brazil were successful, maintaining the linguistic and semantic properties of the original instrument. The table of anchor points is easy to understand and will be helpful during the assessment of children younger than 24 months using the Cornell Assessment of Pediatric Delirium scale.

Child leisure and public space occupation, mental health support tools amid the COVID-19 pandemic and possibilities for the city of São Paulo

Social distancing was considered the main strategy found to contain the spread of the Sars-Cov-2 virus around the world in 2020 and 2021. Much has been discussed regarding how this strategy directly impacted the routines, school performance and mental health of children. In this context, the purpose of this paper is to look at how public spaces offering temporary recreational uses in the city of São Paulo can contribute to the sociability of a generation of children which endured the quarantines prompted by the pandemic, as well as in any future periods in which social distancing may occur. The methodology consists of documental and programmatic analysis of a case study as per UN-HABITAT’s guidance regarding a COVID-19 urban response system. The “Paulista Aberta” program has been selected and reviewed, seeing as it saw the authorization of use of Paulista Avenue, one of São Paulo’s main avenues, as a temporary leisure space, even amid the easing of restriction measures. The relevant contribution of transitory leisure spaces to children’s routines was verified, in line with the existing adoption of temporary leisure uses of the spaces involved in the day-to-day of São Paulo’s population. Those results led us to conclude that temporary public spaces such as Paulista Avenue proved to be a child leisure facilitation tool as social distancing measures eased, seeing as such spaces amount to previously established temporary leisure hubs in the face of the spread of the Sars-Cov-2 virus.

Massive presence of off-label medicines in Danish neonatal departments: A nationwide survey using national hospital purchase data.

There is currently insufficient knowledge of gestational age dependent medicine disposition in neonates. Accordingly, the use of off-label medication, i.e., use of medicines outside its approved marketing authorization, is high in the neonatal departments. By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medications and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Data covered the 4 high-level NICUs and 10 of 13 of the intermediate/standard level Danish neonatal departments. Of the identified medication, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore, one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, off-label medication was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50% (range 50%-100%). Finally, in 21% of medications, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. In conclusion, off-label medication in the Danish neonatal departments is widespread. The pharmaceutical industry is unlikely to solve this problem, and we may for a very long time be occasionally forced to use off-label medication. Practical solution must therefore come from multidisciplinary clinical and academic collaboration. Use of formulation list as guidance for prescriptions and NICU-friendly galenic formulations may mitigate the problem temporarily while waiting for definitive studies.

LB746. Safety and Immunogenicity of a Booster Dose of Novavax COVID-19 Vaccine, Adjuvanted (NVX-CoV2373) in Adults from the PREVENT-19 Trial in the United States

Abstract Background Novavax COVID-19 Vaccine, Adjuvanted (5 µg recombinant spike protein/50 µg Matrix-MTM adjuvant; NVX-CoV2373) has received regulatory authorizations for use in adults ≥ 18 years globally. Methods Participants from PREVENT-19 (NCT04611802), a phase 3, randomized, observer-blinded, placebo-controlled trial that evaluated the efficacy, safety, and immunogenicity of a primary series of 2 doses of NVX-CoV2373 given 21 days apart, in adults ≥ 18 years in the United States and Mexico, were eligible to receive a booster dose at least 6 months after the initial vaccination series. Short-term safety and immunogenicity of the booster dose was assessed in an ad hoc analysis of 298 participants. Results There was an incremental increase compared to the initial vaccination series in local and systemic reactogenicity, which was transient and mostly mild-to-moderate in intensity. Most unsolicited adverse events were also mild-to-moderate in severity; there were no deaths or treatment-related SAEs and 2/298 booster recipients in this analysis reported unrelated SAEs. Neutralizing, anti-S IgG, and hACE2 receptor binding inhibiting antibodies against the ancestral (Wuhan) strain 28 days after booster were higher than those 14 days after primary vaccination (Table). Overall, humoral responses were high regardless of interval between priming and booster vaccination, but a longer interval yielded stronger responses. Higher immune responses against the Omicron BA.1, BA.2, and BA.5 variants were also observed after the booster dose than after the primary series in a subset of 14-18 participants tested. Overall, humoral responses were high and broad regardless of age after any vaccination, but higher responses were observed in adults < 65 years after initial and booster vaccinations. A booster dose induced more robust antibody responses compared with the primary series in adults ≥ 65 years. Conclusion A single booster dose of NVX-CoV2373 demonstrated a satisfactory safety profile, and high levels of neutralizing, anti-S IgG, and hACE2 inhibition antibody responses against the SARS-CoV-2 prototype Wuhan as well as against the Omicron variant including recently emerged sub-variants. Disclosures Germán Áñez, MD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds Lisa M. Dunkle, MD, Novavax, Inc: Employee|Novavax, Inc: Stocks/Bonds Nita Patel, MS, CRP, Novavax, Inc.: employer|Novavax, Inc.: Stocks/Bonds Joyce S. Plested, PhD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds|Novavax Inc.: Stocks/Bonds Alice McGarry, MPH, Novavax: Employee|Novavax: Stocks/Bonds Wayne Woo, MS, Novavax: Employee|Novavax: Stocks/Bonds Rongman Cai, PhD, Novavax Inc.: employer|Novavax Inc.: Stocks/Bonds Iksung Cho, MS, Novavax, Inc.: employer|Novavax, Inc.: Stocks/Bonds.

Effectiveness of Shock-Absorbing Insole for High-Heeled Shoes on Gait: Randomized Controlled Trials.

This study was carried out to identify the influence of a shock-absorbing insole, developed by the author for use with high-heeled shoes, on walking. The research design included single-blind randomized parallel groups; namely, a group of 26 participants who wore the shock-absorbing insoles and another group of 26 participants who did not wear the insoles, both carried out walking while wearing 7 cm high-heels. During walking, plantar pressure analysis (via in-shoe plantar pressure measurements), surface electrode electromyography (surface EMG), gait analysis, subjective comfort evaluation, and functional movement (functional mobility) analysis were carried out. In order to compare the two groups, statistical verification (paired t-test) was performed. Wearing the shock-absorbing insole with the high-heeled shoes improved posture stability during walking, as well as increasing the walking speed. In addition, the heel pressure, the pressure of the front foot at the inner side, and the shock ability were decreased. For these reasons, the wearers reported higher comfort. Changes in the muscle activities of the tibialis anterior muscle (TA) and the gastrocnemius muscle (GA) heightened the stability of the ankle joints. Overall, the proposed shock-absorbing insole for use with high-heeled shoes improved the postural stability when walking, as well as improving the distribution of pressure on the soles. A decrease in the diverse side-effects of wearing high-heeled shoes can thus be expected.

553P Real-world data on dostarlimab in post-platinum mismatch repair deficient (dMMR)/ microsatellite instability high (MSI-H) advanced/recurrent (A/R) endometrial cancer: Descriptive analysis of the French cohort temporary authorization of use (ATU)

Dostarlimab is an anti-PD-1 antibody approved by the EMA in April 2021 as monotherapy for patients (pts) with dMMR/MSI-H A/R endometrial cancer (EC) that have progressed on/after platinum-based therapy, based on the results of the GARNET trial1 (NCT02715284). The French Health Authorities granted early access for dostarlimab in this setting in Oct 2020.

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.

PB1805: INSIGHTS FROM ORAL AZACITIDINE EARLY ACCESS PROGRAM IN FRANCE: PATIENT POPULATION WITH ACUTE MYELOID LEUKEMIA RECEIVING ORAL-AZA FOR MAINTENANCE OF COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY

Background: While many older patients with acute myeloid leukemia (AML) reach complete remission (CR) with intensive chemotherapy (IC), ~80% will ultimately relapse. Treatment options in relapse settings are limited and outcome is usually poor. The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial evaluated oral azacitidine (Oral-AZA; formerly CC-486), a hypomethylating agent, in patients with AML in first remission (CR1) after IC, who were not eligible for hematopoietic stem cell transplantation (HSCT). Unprecedentedly in AML, maintenance treatment with Oral-AZA was associated with significantly longer overall survival and relapse-free survival compared with placebo. Therefore, Oral-AZA received a marketing authorization in the EU as maintenance therapy in adult patients with AML who achieved CR or CR with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, HSCT. Also, French health Authority enabled an early access to Oral-AZA in this indication via a Temporary Authorization for Use (ATU) that started in June 2021. Aims: The aim of the study was to describe the characteristics of patients with newly diagnosed AML who received Oral-AZA for maintenance of CR/CRi after IC and consolidation treatment, who were not eligible for HSCT and were enrolled into ATU in France. Methods: ATU is a French early access allowing administration of the drug under a Therapeutic Use Protocol approved by health authorities. Data presented in this abstract were collected on a declaratory basis and were not monitored. A total of 52 patients were included in 32 centers across France and treated with Oral-AZA during the period from 09-Jun-2021 to 14-Sep-2021. Oral-AZA monotherapy was administered at 300mg once daily for 14 days per 28-days cycle. Results: Overall, 52 treated patients were included with a median age of 67.5 years [range: 35-85]. Regarding Performance Status, 22/52 (42.3%) had an ECOG 0, 25/52 (48.1%) 1 and 5/52 (9.6%) ≥2. The majority (43/52 [82.7%]) had a diagnosis of de novo AML, and the genetic risk (according to ELN2017 criteria) was favorable for 13/52 (25.0%), intermediate for 22/52 (42.3%) and adverse for 17/52 (32.7%) of the patients. Most of the patients had received 1 cycle of IC induction (45/52 [86.5%]). The induction regimen was 3 + 7 for 42/52 (80.8%) patients, among those, 3 (5.8%) received midostaurin along with the 3 + 7. Also 7/52 (13.5%) received CPX-351 as induction regimen. The median number of consolidation cycles was 2 [range: 0-6]; 8/52 (15.4%) patients did not receive any consolidation and 6/52 (11.5%) had >3 cycles of consolidation. The majority of patients (27/52 [61.4%]) received IDAC consolidation. The median time between AML diagnosis and Oral-AZA ATU request approval was 6.8 months [range: 1-98]. Because of the limited time frame of the ATU, follow-up is available for 14/52 patients, and the median follow-up is 21.8 days [range: 1-35]. During the follow-up period, one patient had a temporary interruption of Oral-AZA treatment due to grade 4 neutropenia. There was no reported permanent discontinuation of treatment related to an adverse event. Summary/Conclusion: The characteristics of the patients included in the Oral-AZA Early Access Program in France are in line with European label. These real-life results bring new insights in this population of patients who are not eligible to HSCT with high unmet need to prolong CR1. No unexpected safety signal was registered. Updated results will be presented at the meeting.

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study.

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Assessment of the Performance of Orthopedic Residents in Clinical Practice.

Objective To evaluate the performance of orthopedic residents while conducting clinical examinations. Methods The Mini Clinical Evaluation Exercise (Mini-CEX) was applied by three teaching doctors at four different moments. The instrument was adapted by the authors for use in orthopedics, with the development of descriptors for each evaluated skill. Supervisors were trained to use the Mini-CEX by the principal investigator through teaching materials and discussions, with standardization of the instrument descriptors. Results The mean scores obtained in the 4 evaluations for each of the 21 residents reveal improvement in the performances of residents in all skills assessed from the 1 st to the 4 th meeting. Conclusions We have found that the performance of orthopedic residents presented a satisfactory evolution, with progressive improvement in all skills.

CFD modeling and laboratory studies of dust cleaning efficacy of an efficient four stage non-clogging impingement filter for flooded-bed dust scrubbers

Fibrous-type filters are used to capture dust particles in mining and other occupations where personnel are exposed for prolonged periods. Dust cleansing devices including flooded-bed dust scrubbers use these mesh-type multi-layered filters. These filters trap dust particles efficiently on their surface and inside their mesh. However, their continued operation leads to dust build-up and clogging. This results in increased resistance of the filter and lowered airflow rate through the scrubber. This could potentially enhance the exposure of the miners. A non-clogging self-cleaning impingement screen type dust filter was designed by the authors for use in mining and industrial dust cleansing applications. The filter guides dirt-laden air through rapidly turning paths which forces it to shed heavier particles. The particles impact one of the impermeable solid metallic filter surfaces and are removed from the airstream. A full cone water spray installed upstream prevents any surface build-up of dust. This paper summaried the computer models generated to show the filter operations and laboratory experiments including optical particle counting to establish the cleaning efficiency.

Effective Letermovir Prophylaxis of CMV infection post allogeneic hematopoietic cell transplantation: Results from the French temporary authorization of use compassionate program.

We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n=16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.

Safety and efficacy of the feed additive consisting of Lactobacillus acidophilus CECT 4529 (Lactobacillus acidophilus D2/CSL) for all poultry species and categories and all ornamental birds (Centro Sperimentale del Latte S.r.l).

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of the feed additive consisting of Lactobacillus acidophilus CECT 4529 (tradename: Lactobacillus acidophilus D2/CSL) when used as a zootechnical additive for all poultry species and categories and all ornamental birds. The additive is authorised for use in laying hens, chickens for fattening, cats and dogs. With this application, the company requested a new authorisation for use in feed and water for drinking for all poultry species and categories and ornamental birds. The Panel concluded that Lactobacillus acidophilus D2/CSL is presumed safe for the target species, consumers and the environment. As in previous opinions, the Panel also concluded that it is considered an eye/skin irritant and a skin/respiratory sensitiser. Lactobacillus acidophilus D2/CSL when supplemented at 1 × 109 CFU/kg complete feed or 5 × 108 CFU/L water for drinking has the potential to be efficacious in to improving either laying or growing performance in all poultry species/categories and ornamental birds.

Chronic hepatitis D-What is changing?

Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.

Esketamine nasal spray in patients with treatment-resistant depression: the real-world experience in the French cohort early-access programme

Objective To present the first real-world data of patients with treatment-resistant depression (TRD) treated with esketamine through a French cohort Temporary Authorisation for Use (ATUc) programme. Methods In 2019, the French Health Authorities exceptionally granted the first ATUc in psychiatry for TRD patients. Clinical characteristics, safety and efficacy data were reported by physicians. The ATUc ended ∼6 months after initiation. Results The cohort (n = 66; median age 53.0 years; 62.1% female; 78.8% with severe major depressive episodes; resistance to a mean of 4.2 previous antidepressants) received esketamine treatment for a median of 30 days. Among 46 analysed patients, 22 (47.8%) achieved response (Montgomery–Åsberg Depression Rating Scale [MADRS] total score reduction ≥50.0%) and 17 (37.0%) achieved remission (MADRS total score of ≤12) at least once at a median of 18.5 (2.0–77.0) and 21.0 (2.0–46.0) days after initiation, respectively. By Week 4, patients had a 31.6% probability of achieving remission (Kaplan–Meier method). Sedation, somnolence, dizziness, hypertension, anxiety and dissociation were the most frequently reported (>10.0%) adverse events. No new safety signals were identified. Conclusions Patient characteristics of this cohort demonstrate high-level treatment resistance. The safety and efficacy of esketamine in patients with TRD in real‐world clinical practice were consistent with Phase 3 trials. Key points Patients with treatment-resistant depression (TRD) exceptionally received esketamine nasal spray ahead of its launch through a French cohort Temporary Authorisation for Use (ATUc) programme. The clinical characteristics of 66 adult patients with TRD included in this cohort demonstrated a high-level of resistance to conventional treatments at the time of treatment request prior to esketamine initiation. No new safety signals were observed with esketamine initiation during the ATUc period compared with the Phase 3 clinical trials. The safety and efficacy of esketamine in the real world remain consistent with that established in Phase 3 clinical trials. The data collected during this ATUc also provide the first real-world data on the management and practical use of esketamine in a hospital setting in France.

Abstract P2-13-26: Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France

Abstract Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-26.