License Application Research Articles

What Can Be Achieved with the Estimand Framework?

The ICH E9(R1) guidance on estimands is a key tool for the creation and review of protocol design and analysis planning, for both industry and regulatory statisticians. The framework has been described as useful for improving study design, intercurrent event handling, data collection, analysis, and interpretation to align the estimand with the primary clinical question to add clarity and precision to support regulatory decision-making. In this article, we describe our experience as regulatory statisticians in review of Investigational New Drug protocols and statistical analysis plans, with an emphasis on trials used to support substantial evidence of effectiveness in New Drug Applications and Biologic License Applications. Our intent is to describe our experience with this powerful and effective framework tool, to align the clinical trial’s primary objective with its analysis outcomes and interpretation.

A sustainability review on the Indonesian job creation law

The Job Creation Law (JCL) is an omnibus law promulgated by the Indonesian government to promote investment in the nation by simplifying business license issuance and providing an exemption on previously established procedures. Business license applicants are exempted from the obligation to conduct Environmental Impact Assessment (EIA) so long as their projects are aligned with the land utilization policy and the zoning plan. This creates a threat to environmental sustainability as only 10% cities or regencies in Indonesia are equipped with detailed zoning plans. Furthermore, environmental considerations are rarely incorporated into spatial planning. This paper reviews changes in spatial and environmental planning practices based on a comparison among existing regulations, qualitative assessment of potential environmental impact based on lessons learned from various study cases, and critical evaluations on the aim to ease business establishment versus sustainability. The research method includes analysis of relevant document and descriptive quantitative analysis. We found that JCL puts sustainability aside and may lead to further environmental degradation.

Paving the Road for Chimeric Antigen Receptor T Cells: American Society for Transplantation and Cellular Therapy 80/20 Task Force Consensus on Challenges and Solutions to Improving Efficiency of Clinical Center Certification and Maintenance of Operations for Commercially Approved Immune Effector Cell Therapies

As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting, with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications. The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Task Force to consider challenges and potential solutions to these issues. The Task Force proposed that 80% of manufacturers' requirements for onboarding and ongoing operations of commercially available products could be standardized and streamlined. Task Force members interviewed dozens of stakeholders, including clinicians at large academic medical centers already using commercial and investigational immune effector cell (IEC) products, regulators, members of accrediting bodies and professional cellular therapy societies, and manufacturers of IEC therapies for oncologic indications. In November 2021, the Task Force organized and led virtual discussions in a public forum and at a private ASTCT 80/20 Workshop at the online AcCELLerate Forum, a cellular-therapy stakeholders' meeting organized by the ASTCT, National Marrow Donor Program (NMDP), and Center for International Blood and Marrow Transplant Research (CIBMTR). At the workshop, approximately 60 stakeholders worked to identify and prioritize common challenges in onboarding and maintenance of operations at clinical sites for commercial FDA-approved and future IEC therapies and ways to streamline the process. It was agreed that standardization would improve efficiency of onboarding, allowing more cost-effective, sustainable growth of approved IEC therapies at treatment centers, and facilitate wider access while maintaining safety and clinical success. This early but extensive survey of stakeholders resulted in 5 overarching suggestions for both established and emerging treatment centers: (1) eliminate duplication in accreditation and auditing of clinical sites; (2) define expectations for the education about and management of CAR-T therapy toxicities to potentially replace product-specific REMS programs; (3) streamline current REMS education, testing, and data reporting; (4) standardize information technology (IT) platforms supporting enrollment, clinical site-manufacturer communication, and logistics of maintaining chain of identity/chain of custody across multiple transportation steps; and (5) encourage the use of universal nomenclature by cell therapy manufacturers. Future discussions need to engage a broader range of stakeholders, including administrators, pharmacists, nurses, data coordinators, surgeons, pathologists, and those developing promising cellular therapies for solid tumors, as well as teams from smaller academic or community cancer center settings. Continued collaboration with stakeholders outside of clinical sites will include accrediting bodies/auditors, established and emerging cell therapy companies, software developers, professional societies, and the patients who receive these therapies. Active dialog with government regulators remains essential. Such joint efforts are critical as the number of IEC therapies for myriad oncologic and nononcologic indications grows.

ARTIFICIAL INTELLIGENCE AS A COMMON HERITAGE OF MANKIND

Artificial intelligence technologies today employ techniques known as machine learning and deep learning, which apply datasets to a suitable mathematical or statistical technique known as an algorithm. This in turn produces a model that can be employed to predict an outcome, given a new set of data that was previously unseen by the model. The principle of common heritage of mankind, which has originated in the 19th century, promotes the concept that humanity as a whole has rights and responsibilities over territories or outer space. This study aims to advance the concept of treating the components of artificial intelligence as an intellectual common in the form of a common heritage of mankind, in order to promote the discovery and the development of more novel artificial intelligence applications for the benefit of people around the world. This work employs a mix of legal doctrinal research related to intellectual property law and conceptual theoretical discussion. The potential application of open access and open data licensing is discussed. The history of the common heritage of mankind is covered, and the potential benefit of recognizing basic artificial intelligence components as a common heritage of mankind is explored. Finally, a novel method for implementing this idea is proposed. This work is significant in advancing a method to liberate certain artificial intelligence technologies from intellectual property rights protection, in order to promote greater experimentation and the development of artificial intelligence applications for the greater good of humanity.

Advanced Processes for Clinical Pharmacology Evaluation in Board Exams

As a medical educator for over 30 years, and a member of the National Board of Osteopathic Medical Examiners (NBOME) for 20 of this time, I am concerned about the burden placed on those taking boards. In the USA, an increase in Biologic License Applications (BLAs) plus New Molecular Entities (NMEs) over these past two decades is extensive. Considering that there was not an equivalent number of agents withdrawn from the market leaves a large net amount of new medicines to be learned in additional to what we are already teaching. In my opinion, this is an overload and one of the causes contributing to increased burnout among young physicians-to-be. As recently concluded, “Advances in medicine and technology mean that medical students are expected to learn significantly more information than their predecessors in the same amount of time1.” Other contributory factors cited in this article include participation in extracurricular, research and leadership activities, all designed to improve chances for admission into targeted residencies.

Effectiveness of Pfizer-BioNTech COVID-19 vaccine as evidence for policy action: A rapid systematic review and meta-analysis of non-randomized studies.

In December 2020, an interim recommendation for the use of Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years was made under Food and Drug Administration's Emergency Use Authorization. In preparation for Biologics License Application approval, we conducted a systematic review and meta-analysis to inform the U.S. Centers for Disease Control and Prevention's Advisory Committee for Immunization Practice's (ACIP) decision-making for a standard recommendation. We conducted a rapid systematic review and meta-analysis of Pfizer-BioNTech vaccine effectiveness (VE) against symptomatic COVID-19, hospitalization due to COVID-19, death due to COVID-19, and asymptomatic SARS-CoV-2 infection. We identified studies through August 20, 2021 from an ongoing systematic review conducted by the International Vaccine Access Center and the World Health Organization. We evaluated each study for risk of bias using the Newcastle-Ottawa Scale. Pooled estimates were calculated using meta-analysis. The body of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We identified 80 articles, selected 35 for full-text review, and included 26. The pooled VE of Pfizer-BioNTech COVID-19 vaccine was 92.4% (95% CI: 87.5%-95.3%) against symptomatic COVID-19 with moderate evidence certainty (eight studies), 94.3% (95% CI: 87.9%-97.3%) against hospitalization due to COVID-19 with moderate certainty (eight studies), 96.1% (95% CI: 91.5%-98.2%) against death due to COVID-19 with moderate certainty (four studies), and 89.3% (88.4%-90.1%) against asymptomatic SARS-CoV-2 infection with very low certainty (two studies). The Pfizer-BioNTech COVID-19 vaccine demonstrated high effectiveness in all pre-specified outcomes and extended knowledge of the vaccine's benefits to outcomes and populations not informed by the RCTs. Use of an existing systematic review facilitated a rapid meta-analysis to inform an ACIP policy decision. This approach can be utilized as additional COVID-19 vaccines are considered for standard recommendations by ACIP.

Conrad Seabaugh & Company: An Inside Look at an Illinois Hinterland Merchant

Conrad Seabaugh & Company: An Inside Look at an Illinois Hinterland Merchant

Identifying Key Risks to the Effectiveness of Water Use Authorization Systems through Theory of Change (ToC): The Case of South Africa

South Africa is a water-stressed country with significant water management challenges. In response, progressive and advanced water management policy and legislation have been developed that include the regulation of water uses through a water use license application (WULA) system. In recent years, the effective functioning of the WULA system has come under increased scrutiny. However, a comprehensive systematic evaluation of the effectiveness of the WULA system has not yet been conducted. This paper aims to identify key risks to the effectiveness of the WULA system in South Africa through the application of a theory of change (ToC) methodology. Workshops with more than 60 participants were held with different stakeholder groups. Ultimately, a total of 21 key risks to the effectiveness of the WULA system were identified. The results suggest that various risks have already been realized and that the WULA system is not functioning as intended and is not achieving its outcomes. It is recommended that the identified key risks provide the basis for a comprehensive system evaluation to inform a more effective WULA system design.

A CD79b Targeting ADC with Superior Anti-Tumor Activity and Safety Resulting in Significantly Improved Therapeutic Index (TI): Safe and Efficacious CD79b ADC

The Araris' site-specific and 1-step enzymatic linker conjugation technology aims at generating safe and highly potent ADCs without the need for antibody engineering prior to linker-payload conjugation. We developed a very stable anti-CD79b-MMAE ADC (ARC-02) with this technology showing a higher therapeutic index (TI) compared to the approved ADC polatuzumab-vedotin (Polivy®) in different preclinical models. Therefore, ARC-02 is considered a promising next generation treatment alternative for patients suffering from Non-Hodgkin lymphoma (NHL). Using native polatuzumab as the targeting antibody and monomethyl auristatin E (MMAE) as payload, we generated within 24 hours the highly homogeneous and pure ARC-02 development candidate with a well-defined drug-to-antibody ratio (DAR) of 1.9 and with high purity (monomer content > 98%). ARC-02 is highly stable under stressed conditions at elevated temperatures and maintains the FcyR/FcRn-binding properties of the parental mAb. In-vitro ARC-02 demonstrated potent cytotoxicity in four different NHL cell lines tested so far with similar potency (EC50 values) compared to the approved Polivy® ADC despite of the lower toxin load of ARC-02 (DAR of 1.9) compared to Polivy® (DAR of 3.5). ARC-02 clearly differentiates from Polivy® by extraordinary stability in mouse, cynomolgus monkey and human sera exemplified by the absence of payload deconjugation or linker cleavage under physiological conditions (at 37°C) and long-term incubation (>2 weeks). Exceptional stability could also be confirmed in vivo in pharmacokinetic studies in mice, rats and cynomolgus monkeys demonstrating an antibody-like exposure profile comparable to the unmodified polatuzumab parental antibody without premature toxin deconjugation in the circulation resulting in improved pharmacokinetics of ARC-02 compared to Polivy® (half-life in mice 10 days for ARC-02 vs 5 days for Polivy®). Despite the excellent stability of ARC-02 in vitro and in vivo, the MMAE toxin is still efficiently released from ARC-02 in lysosomal human Cathepsin B cleavage or human liver-lysosome release assays which is providing the foundation for the observed robust anti-tumor activity in vivo: ARC-02 was compared head-to-head to Polivy® in two different CD79b-expressing established tumor models in vivo (Granta-519 and Ramos). Single dose treatment of ARC-02 at very low payload doses induced effective and long-lasting anti-tumor responses with complete tumor eradication achieved at about half of the Polivy® payload dose in both NHL established tumor models. Based on these in vivo efficacy experiments, the minimal effective dose (MED) of ARC-02 that is still inducing eradication of established tumors is determined to be as low as 10 μg/kg based on the MMAE payload dose or 1 mg/kg based on the total ADC dose. Finally, the highest non-severely toxic dose (HNSTD) of ARC-02 in repeat dose toxicology studies was determined to be ≥30 mg/kg and ≥24 mg/kg in rats and cynomolgus monkeys, respectively, which is substantially higher than the HNSTD reported for Polivy® (i.e. 10 mg/kg in the rat and 3 mg/kg in the cynomolgus monkey as described in the Polivy® Biologic License Application). Therefore, the tolerability in rodents and non-human primates is at least 3 and 8 times higher when compared to historical safety data of Polivy®. Using the HNSTD derived from repeat dose non-human primate toxicity study (24 mg/kg) and the MED calculated from single dose rodent efficacy studies (1 mg/kg) an impressive TI of 24 can be calculated for ARC-02 which is substantially higher than the TI of Polivy®. These encouraging results obtained so far indicate that ARC-02 a) has very favorable biophysical properties, b) shows a consistent and highly defined DAR, c) is highly stable in vitro and in vivo, d) is highly potent and efficacious in multiple tumor models and e) has improved tolerability in rodents and non-human primates and f) shows an impressive improvement in TI and ultimately warrant further development of ARC-02.

Pharmacokinetics, Efficacy and Safety Evaluation of FRSW107 in Previously Treated Hemophilia a Patients: A Multicentre, Open-Label, Non-Randomized Phase III Study

Background: FRSW 107, a novel homodimer recombinant factor VIII (rFVIII) Fc fusion protein, is the first domestic extended half-life (EHL) rFVIII under development in China，and is currently at stage of Biologics License Application (BLA) in NMPA for the prophylaxis and treatment of bleeding episodes in adolescent and adult (≥12 yr) with hemophilia A (HA). Aims: This phase III (NCT04456387, CTR20201212), open-label, non-randomized, multicenter trial aimed to evaluate the pharmacokinetics (PK), safety, and clinical efficacy of FRSW 107 for prophylaxis and treatment of bleeding in previously treated HA patients ≥12 yr. Methods: Eligible patients included male severe HA (FVIII:C< 1%) ≥12 yr, previous treatment with FVIII concentrates for ≥150 exposure days (EDs), and absence of FVIII inhibitors (＜0.6 Bethesda Units/mL). A total of 119 patients received FRSW 107 for prophylaxis treatment (n=83) or on-demand treatment (n=36). The patients in the prophylaxis group were administered one dose of 50 IU/kg of FRSW 107 every three days for at least 50 EDs for a minimum period of 6 months, and the primary efficacy endpoint was annualized bleeding rate (ABR). The patients in the on-demand treatment group received 30 to 50 IU/kg of FRSW 107 over 6 months, according to the severity and location of the bleeding, and the primary efficacy endpoint was hemostatic effect (excellent, good). The single-dose and repeat dose PK parameters of 15 patients in the prophylaxis group were analyzed at ED1 and ED35, respectively. Results: In the prophylaxis group, the mean and median annualized bleeding rate (ABR) were 1.61±3.74 and 0.00 (IQR, 0.00-2.02), decreased by 95.01% versus the baseline 32.24±23.98 and 26.00 (IQR, 16.00-46.00), and 56 (67.5%) patients had no bleeds during the trial. Detailed ABR data for prophylaxis group was included in the table below. In the on-demand treatment group, hemostatic efficacy was rated as "excellent” or "good” for 98.9% of bleeds. 97.9% of 721 reported bleeds were treated with ≤2 injections. No FVIII inhibitors have been reported in this study. Drug-related adverse events (AEs) occurred in 10.1% of the patients. No SAE was judged to be related to FRSW107 treatment. No thromboembolic events were reported, and there are no unexpected safety concerns. The terminal half-life of FRSW 107 ranged between 20 to 22 hours. The incremental recovery (IR) was approximately 2.14 (IU/dL)/(IU/kg). The PK parameters and profiles remained consistent between ED1 and the repeated dosing at ED35. Conclusions: The data indicate that FRSW 107 was safe and effective for prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult HA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Evidence (RWE) Studies Supported Hematologic Oncology United States Food and Drug Administration (US FDA) Approval: What Do They Look like?

Introduction/Background: Although randomized controlled trials are considered the gold standard of evidence for safety and efficacy of a drug, they are subject to several limitations such as difficulty in recruiting patients with rare diseases or randomization of patients to studies with treatments that lack an established standard of care owing to efficacy or toxicity concerns. RWE can help overcome these challenges. RWE collects patient data from historical trials or retrospective observational studies and compares or contextualizes these data to experimental treatments by using proper statistical adjustments. The 21st Century Cures Act inspired the framework for the US FDA to use RWE to assess product effectiveness of approved drugs to support regulatory decision-making. Consequently, RWE is increasingly used in New Drug Applications (NDAs) and Biologics License Applications (BLAs) for hematologic malignancies, and findings suggest that submissions using RWE may receive faster approval. However, data are lacking on adoption of RWE for regulatory submissions and its use in regulatory decision-making. Here, we outline RWE utilization and limitations of regulatory submissions for hematologic malignancy therapeutics, which received accelerated or full approval in the US. Methods: Between 2017 and 2021, all NDA and BLA approvals from the Division of Hematological Malignancies were reviewed for hematology/oncology drugs or indications. The FDA Oncology Drug Advisory Committee (ODAC) briefing and/or multidisciplinary review documents were evaluated to identify the drug approvals using RWE. This assessment was performed by 4 independent reviewers who evaluated FDA comments regarding RWE. RWE sources, study methodology, drug indications, pivotal trial information, statistical analyses, and results were summarized. Results: A total of 74 hematologic malignancy approvals were identified, of which 7 (9.4%) provided RWE that supported regulatory approval. Detailed analyses of the FDA ODAC briefing and/or multidisciplinary review documents for these 7 drug compounds including comparison of trial and RWE data source, patient population, clinical endpoints and outcomes, comparison strategy, and FDA comments are shown in the Table. The FDA identified several key considerations for RWE use for drug applications based on single-arm studies. These included pivotal trials that demonstrated a high response or large treatment effect, an improved drug toxicity profile, or a novel drug mechanism of action. The most common RWE sources included retrospective observational studies from medical records, data from other clinical trials, commercial electronic health record databases, and literature reviews. The most common hematologic indications for RWE submissions were relapsed/refractory (R/R) large B-cell lymphoma and R/R multiple myeloma. The most common endpoints for RWE included presence of measurable residual disease, complete response rate, and duration of response. In contrast, the most common endpoints in pivotal trials included survival endpoints (eg, progression-free survival). The most common statistical methods used to adjust for baseline imbalances included propensity-score matching and inverse-probability of treatment weighting. The FDA identified several areas that may compromise the reliability of RWE: lack of early engagement and discussion of the study design with the FDA, absence of a prespecified statistical analysis plan or protocol, lack of transparency in data collection methods, dissimilar inclusion/exclusion criteria, dissimilar study endpoints, and an inconsistent method or frequency of outcome assessments. Comparator arms often missed baseline covariates, had selection bias, and used different outcome assessment criteria. Conclusion: Good data quality, comparable patient populations, consistent endpoints, prespecified protocols, and the establishment of statistical analysis plans before the start of a study may be the most important factors in the FDA's approval of RWE regulatory submissions. Although the use of RWE to define a direct comparator was limited by flaws in study design and statistical analyses, RWE can be used to establish historical outcomes for patients with currently available treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety, Feasibility, and Efficacy of Upfront Daratumumab-Based Therapy in Blacks with Dysproteinemia

Background: Black patients (pts) with dysproteinemia are underrepresented in clinical trials included in new drug applications and biological license application submissions. Even after approval, access to novel therapies remains a challenge. Daratumumab (dara) is an anti-CD38 monoclonal antibody, which has revolutionized the care of patients with both multiple myeloma (MM) and light chain (AL) amyloidosis. The underrepresentation of black pts in clinical trials of dara in newly diagnosed patients with dysproteinemia raises concerns regarding the safety, tolerability and efficacy of dara in this population. We report the results from a cohort of pts treated with dara in the management of newly diagnosed MM (NDMM) and AL amyloidosis. Methods: The Cancer and Aging Resilience Evaluation in Hematologic Malignancies (CARE-Heme) registry is an ongoing prospective registry enrolling pts ≥50 years of age with a diagnosis of hematologic malignancy undergoing treatment at a single institution. For this analysis, we included pts with NDMM and AL amyloidosis treated with dara-based combination therapy between January 2020 and January 2022. We obtained baseline disease- and patient-related characteristics. Toxicity was evaluated by chart review up to the first 6 cycles and adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE v5.0). For patients receiving >1 cycle, response assessment was ascertained using International Myeloma Working Group (IMWG) uniform response criteria. All patients were followed until progression, death or last follow up and progression-free survival (PFS) and overall survival (OS) were measured using Kaplan Meier methods. Health-related quality of life (HRQoL) was measured using Patient-Reported Outcomes Measurement Information System (PROMIS) global 10 and quantified using physical health (PH) and mental health (MH) t-scores at baseline and 3 month follow up. Variables were compared in each race by using independent and paired sample t-tests as appropriate. Results: Over the study period, 36 black pts (NDMM=32; AL=4) and 50 white pts (NDMM=44; AL=6) received upfront dara-based combination therapy. There were no differences in age or sex, IGH translocations, but there was a higher incidence of cytogenetic high-risk disease among the black pts in our cohort (p=0.02). Black pts presented with more advanced disease at the time of presentation - hypercalcemia 33% vs. 14%, p=0.04; renal dysfunction 56% vs. 28%, p=0.01; anemia 67% vs. 38%, p=0.01). Incidence of bone disease was similar between the groups (p=0.69) (Table 1) Among blacks, the most utilized regimen was DaraVRd (56%), DaraRd (17%), DaraKRd (11%) and DaraVCd (11%). While for the white pts, it was DaraVRd (52%), DaraRd (12%), DaraKRd (8%) and DaraVCd (22%). Blacks had a similar incidence of ≥grade 3 non-hematologic AEs (p=0.21), with fatigue, diarrhea and leg edema being the most common. There is a trend towards higher ≥grade 3 hematologic AEs which did not reach statistical significance (p=0.05). After 6 cycles of therapy, overall response rate was comparable (100% vs. 94%, p=0.81) among the two groups (≥VGPR 47% vs. 62%, p=0.36). With 18 month median follow up, there was no difference in median PFS and OS, both not reached (Figure 1). Complete quality of life (QoL) t-scores were available at baseline for 55 pts (20 blacks and 35 whites). The baseline PH and MH related QoL scores were comparable between whites and blacks (p= 0.51; p=0.58, respectively). From baseline to 3 months follow up, PH t-scores improved in both whites as well as blacks although the difference was not statistically significant. Meanwhile, MH t-scores remained largely unchanged from baseline to follow up in both groups. Conclusions: We report the largest cohort to date of black pts with dysproteinemia systematically treated with frontline dara. Our data shows the feasibility of this strategy in a single institution setting with comparable safety, efficacy and HRQoL with the use of upfront dara-based combinations in black and white pts. Our data supports comparable clinical outcomes among black pts when treated with novel therapeutic combinations despite a higher proportion of high risk cytogenetic abnormalities in our cohort without an increase in AEs. Minority representation in cancer clinical trials as well as access to approved novel therapies can significantly help mitigate disparities in outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Recommendations from the Advisory Committee on Immunization Practices for the Use of Bivalent Booster Doses of COVID-19 Vaccines - United States, October 2022.

Four COVID-19 vaccines are currently approved for primary series vaccination in the United States under a Biologics License Application or authorized under an emergency use authorization (EUA) by the Food and Drug Administration (FDA), and recommended for primary series vaccination by the Advisory Committee on Immunization Practices (ACIP): 1) the 2- or 3-dose monovalent mRNA BNT162b2 (Pfizer-BioNTech, Comirnaty) COVID-19 vaccine; 2) the 2- or 3-dose monovalent mRNA mRNA-1273 (Moderna, Spikevax) COVID-19 vaccine; 3) the single-dose adenovirus vector-based Ad26.COV.S (Janssen [Johnson & Johnson]) COVID-19 vaccine; and 4) the 2-dose adjuvanted, protein subunit-based NVX-CoV2373 (Novavax) COVID-19 vaccine. The number of doses recommended is based on recipient age and immunocompromise status (1). For additional protection, FDA has amended EUAs to allow for COVID-19 booster doses in eligible persons (1). Because COVID-19 vaccines have demonstrated decreased effectiveness during the period when the Omicron variant (B.1.1.529) of SARS-CoV-2 predominated, bivalent booster doses (i.e., vaccine with equal components from the ancestral and Omicron strains) were considered for the express purpose of improving protection conferred by COVID-19 vaccine booster doses (2). During September-October 2022, FDA authorized bivalent mRNA vaccines for use as a booster dose in persons aged ≥5 years who completed any FDA-approved or FDA-authorized primary series and removed EUAs for monovalent COVID-19 booster doses (1). Pfizer-BioNTech and Moderna bivalent booster vaccines each contain equal amounts of spike mRNA from the ancestral and Omicron BA.4/BA.5 strains. After the EUA amendments, ACIP and CDC recommended that all persons aged ≥5 years receive 1 bivalent mRNA booster dose ≥2 months after completion of any FDA-approved or FDA-authorized monovalent primary series or monovalent booster doses.

Identification of areas of interest for radiological impact assessments in an evolving landscape context

Regulations concerning potential future health impacts of the final disposal of radioactive wastes in geological disposal facilities are written in terms of annual dose to individuals who are representative of small groups living in the landscape in the vicinity of the repository site. As disposal programmes in Sweden and Finland have progressed towards licensing and construction, so too has detail describing the state and evolution of surface biosphere and the landscape around the proposed disposal sites increased. Simple and generic biosphere dose assessment models in early iterations have grown in complexity with increasing site-specific detail that aims to capture the radiologically significant features of the landscape into which future releases of radionuclides might credibly occur. Current dose assessment models used in support of license applications for disposal programmes in Sweden and Finland are highly complex and their application consequently lacks transparency. An alternative simpler approach to characterising landscape objects for dose assessment models would be beneficial in that it would offer an additional line of reasoning and would add clarity, thereby supporting the decision-making process of the regulatory authorities.In the context of coastal Fennoscandia, landscape change is relatively rapid and dramatic with post-glacial landrise transforming areas of the coastal seabed into terrestrial ecosystems over a period of a few thousand years, global sea level rise notwithstanding. The locations of the geosphere-biosphere interfaces for deep geologic disposal can be estimated with some precision but the nature of the receiving ecosystems at the time of the release is less certain.The approach described here provides a statistical quantification of key morphological characteristics of areas in the landscape where doses could arise, so as to better express uncertainties in dose modelling. The proposed method assumes that the variation in the morphology of potential release locations can be described by the variation in landscape objects seen in the landscape on a wider scale, providing a statistical description of the possible landscape objects, so allowing a more comprehensive range of potential future evolutions to be addressed.Our understanding of the evolution of the landscape, based on the kinds of terrain and ecosystem development models used by POSIVA in Finland and SKB in Sweden, suggests that objects identified in present-day maps can be used as analogues for a statistical characterisation of objects in the future landscape; objects identified in the observed topography and bathymetry can therefore serve as the basis for the statistical description of landscape dose objects over the period during which doses are likely to arise. Using digital elevation models around a disposal site in Finland, we show that the statistical descriptions of landscape dose objects at three times over a period of 10 kyear of the evolved landscape are sufficiently similar to establish the suitability of the approach.The aim of this statistical analysis is to supplement current methods for defining radiological assessment models so as to provide additional numerical support to both the simpler and more complex methods employed by implementors and regulators. The method has been developed in the context of the Swedish and Finnish regulatory review process and is referred to in the IAEA's revised BIOMASS methodology. We briefly address how the method might be applied in other landscape contexts.

A Survey of Population Pharmacokinetic Reports Submitted to the USFDA: An Analysis of Common Issues in NDA and BLA from 2012 to 2021.

Population pharmacokinetic (PopPK) analysis is one of the important components of regulatory submission. The purpose of this study was to survey PopPK analysis reports in new drug applications (NDAs) and biological licensing applications (BLAs) submitted to the US Food and Drug Administration (FDA) and to retrieve the information regarding PopPK-related issues in the US FDA review reports. We surveyed NDAs and BLAs over the period from 2012 to 2022 from Drug@FDA databases and extracted the review reports from the website. We explored the issues identified in these reports and sorted them into four categories: (i) data used for PopPK analysis, (ii) base model development, (iii) final model development, and (iv) model evaluation. The percentage of the issues in each category and the total issues were calculated. Data from a total of 317 applications were analyzed. Of these, 122 applications had at least one PopPK-related issue, and the count went up to 168 issues. The proportion of issues for each category was ranked as follows: model evaluation (39%, 65 of 168), final model development (34%, 57 of 168), data used for PopPK analysis (14%, 24 of 168), and base model development (13%, 22 of 168). The most common issues were related to the goodness-of-fit plots, covariate selection, and high shrinkage of ETA, accounting for 17.9%, 15.5%, and 11.3% of the total issues, respectively. The findings from this study may help the applicant understand the FDA's thinking on the PopPK analysis.

SENSORY STIMULATION THERAPY BY LISTENING TO MUSIC IN THE ELDERLY

Group Activity Therapy given to the elderly using the Sound Sensory Stimulation method by listening to music for the elderly at UPT PMKS Mojopahit Mojokerto is a form of community service in the form of Activity Therapy activities that are expected to reduce social interaction problems that occur in the elderly. This activity was carried out on April 16, 2022 at UPT PMKS Mojopahit Mojokerto. The target of this activity is all the elderly who are in UPT PMKS Mojopahit Mojokerto. Before the activity was carried out, the implementers of this community service activity made preparations approximately 3 weeks before the implementation of the activity in order to prepare the implementation method, determine the type of therapy to be carried out up to the application of licensing for the implementation of the activity to the parties concerned. As a form of evaluation, the activity was attended by 25 elderly people, the participants participated in the activity very enthusiastically, the Group Activity Therapy activity went well, on time, and smoothly.

Participation of Older Adults in Clinical Trials for New Drug Applications and Biologics License Applications From 2010 Through 2019

Older age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles. To assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs). This cross-sectional study analyzed US Food and Drug Administration (FDA) data for NDAs and BLAs approved from 2010 through 2019. Age distribution of clinical trial participants was compared with age distribution of the US population with the disease or disorder (prevalent population). Data were from adults enrolled in registration trials for depression, heart failure, insomnia, non-small cell lung cancer (NSCLC), nonvalvular atrial fibrillation (NVAF) stroke prevention, osteoporosis, and type 2 diabetes or adults sampled from US prevalent population in community-dwelling health data. Data were analyzed from November 2020 to February 2021. Trial enrollment. Representativeness of trial populations was assessed by the participation to prevalence ratio (PPR) defined as the percentage of patients by age group among clinical trial participants to the percentage of patients by age group among US prevalent population. Data from 166 clinical trials (229 558 participants) for 44 NDAs and BLAs were analyzed. The most consistent finding was the limited enrollment of the oldest age groups, namely those 75 years and above for type 2 diabetes and NSCLC, and 80 years and above for NVAF stroke prevention, insomnia, heart failure, and osteoporosis. Adults aged 60 to 74 years were enrolled in equal or greater proportion than the US prevalent population. In this cross-sectional study, underrepresentation of the oldest adults existed during evaluation of new drugs and biologics, yet the older adults may represent significant proportions of the treatment population. Closing the representation gap between clinical trial enrollment and potential treatment populations is essential for safe and effective use of new drugs and biologics.

Carbon capture utilization and storage (CCUS) – it’s happening now! However, are there still any challenges?

These days we see a growing interest and more concrete project plans for CCUS in many European countries but with a pathway to “Net Zero”, we are fare from on-track! This definitely implies a stronger push for CCUS in Europe.Although we can show 26 years of permanently stored CO2 in deep geological formations offshore Norway, heavily studied and monitored, there are still many questions about whether CCS is a safe and viable technology. Based on this experience and many years of research and development, we can conclude that this is a viable and safe technology.We know that we have a large storage resources for CO2 on land and offshore in Europe, and we have large CO2 emissions that need to be captured. If CCUS is to achieve the economies of scale necessary to reduce costs and develop technology, cooperation is needed. Like other technologies that are expensive at the start, CO2capture needs to be more efficient and by that less expensive and we need an effort to speed up the mapping and characterization of safe CO2 storage capacity. However, CCUS is the lowest cost, or only, option for many industries to decarbonize, and these industries will be fully exposed to the carbon price by 2023, so CCUS is essential to deliver large-scale and permanent removal of CO2.To contribute to the development of technology for capture, transport, and storage of CO2, with the ambition of achieving a cost-effective solution, the Norwegian government decided in 2020 to develop a full-scale carbon capture and storage project, called Longship.As a result of this decision, we now see that the next phase for CCS is already underway with a growing interest in new areas for CO2storage and more industrial demonstration projects for emission reductions. On the Norwegian continental shelf, three licenses for offshore storage of CO2have been awarded in recent years, these involve 5 companies, and new license applications and new companies are on the way. These companies have presented clear projects involving the entire business chain.We have the knowledge and the technology is ready, so why isn't the CCUS flying? Perhaps it is about setting clear political goals, transporting CO2across national borders, removing potential regulatory barriers and developing new business models. Easy? Let's talk about it and cooperate.

Measuring How Public Health Stakeholders Seek to Influence Alcohol Premises Licensing in England and Scotland: The Public Health Engagement In Alcohol Licensing (PHIAL) Measure.

In the United Kingdom, some public health teams (PHTs) routinely engage with local alcohol premises licensing systems, through which licenses to sell alcohol are granted. We aimed to categorize PHT efforts and to develop and apply a measure of their efforts over time. Preliminary categories of PHT activity were developed based on prior literature and were used to guide data collection with PHTs in 39 local government areas (27 in England; 12 in Scotland), sampled purposively. Relevant activity from April 2012 to March 2019 was identified through structured interviews (N = 62), documentation analysis, and follow-up checks, and a grading system was developed. The measure was refined based on expert consultation and used to grade relevant PHT activity for the 39 areas in 6-month periods. The Public Health engagement In Alcohol Licensing (PHIAL) Measure includes 19 activities in six categories: (a) staffing; (b) reviewing license applications; (c) responding to license applications; (d) data usage; (e) influencing licensing stakeholders or policy; and (f) public involvement. PHIAL scores for each area demonstrate fluctuation in type and level of activity between and within areas over time. Participating PHTs in Scotland were more active on average, particularly on senior leadership, policy development, and working with the public. In England, activity to influence license applications before decision was more common, and a clear increase in activity is apparent from 2014 onward. The novel PHIAL Measure successfully assessed diverse and fluctuating PHT engagement in alcohol licensing systems over time and will have practice, policy, and research applications.

Facing Challenges while Creating a Stronger Community of Medical Regulators

Avedas Donabedian, recognized as one of the thought leaders of the modern quality movement, characterized a quality system as one that has alignment of structures, processes, and outcomes.1 Without such alignment, a healthcare system is destined to have both untoward variation and undesired outcomes.In the current issue of JMR, Giddings and colleagues2 report the results of their literature review regarding how medical licensing systems query physicians regarding their health and potential impact on patient safety to determine whether that impairs reporting the health issue on licensure applications. The manuscript is timely and impactful in both its results and as an example of misalignment of structures to desired outcomes.Surprisingly, or perhaps not, only 9 published and peer-reviewed articles addressed the subject according to the authors. As they note, there are published evidence-based guidelines about how to ask questions about self-reported health issues and their (again self-reported) potential impact on safe clinical practices. The review highlights often significant medical licensing system variation from these guidelines. As a result, the authors cite evidence that physicians are hesitant to self-report or seek therapeutic care. From a quality system perspective, the structure (questions that query health conditions) and processes (providers to seek help or recognizing a patient safety issue) are misaligned to the outcome desired, which is physician well-being and patient safety. A system that shows misalignment needs to be adjusted, but a system that may also unintentionally promote bad outcomes needs to be changed.Approximately 57% of physicians are reporting symptoms of burnout2; physician suicide, substance abuse, and divorce rates are alarming. Feeding the stress fire have been all the burdens and strains of the current medical system that have been discussed without resolution ad nauseum. While the COVID-19 pandemic has highlighted these issues, the pandemic has also highlighted and accentuated an issue that has been brewing but still relatively taboo as a discussion for decades.The authors conclude that there should be a review and rewording of how the health conditions are self-reported on license applications. This should be more than an exercise in wordsmithing. Those who suffer mental health and other forms of psychological strain are prevalent and pervasive. If not addressed early and thoroughly, physical and mental strains can only worsen and negatively impact outcomes. Would any physician hesitate to refer a patient for mental health or counseling if that patient presented to them?Physicians are patients also. The licensing system should look at novel approaches that support and encourage not just physician reporting of physical and mental health issues that may have already affected patient care but rather promote and align the application structures, so the early recognition, support, and treatment, if appropriate, occur without hesitancy. Desired outcomes can then occur. Waiting until impairment becomes flagrant, as may be occurring with current licensure questions, does no good for anyone.