License Application Research Articles

Regulatory Prototype for Biological Products in the United States

Biological products are used for the treatment of many disease, so the biological application submitted for the approval of products are also increasing. The progress of a biosimilarproduct is more difficult and expensive than a small molecule generic product. Biosimilars are not true generic drugs, but demonstrate a high degree of similarity to the reference biological product. In order to improve access to costly biological treatments, a biosimilar pathway in the US was established under the Biologics Price Competition and Innovation Act of 2009. The study highlighted the “Regulatory prospective for the registration of Biological products in US” and a brief description about the development, Manufacturing and approval process of biosimilar products. This article is also focused on the regulatory framework, Biological License Application, Purple book, and Pharmacovigilance of biological products.

Повышение эффективности государственного управления в области обеспечения промышленной безопасности путем перехода на реестровую модель лицензирования отдельных видов деятельности

Licensing is one of the most important mechanisms in ensuring industrial safety in the Russian Federation. This tool of the state administration is a complex and energy-intensive process both for licensing authorities, and for license applicants, licensees. For the purpose to eliminate the excessive administrative barriers in planning and implementation of production activity, the issuance of licenses in paper form was canceled in favor of making a legally significant entry. In order to implement the register model, a number of new administrative regulations on the provision of state licensing services was developed, according to which, as a result of the provision of state services, from January 1, 2021, Rostechnadzor forms an entry in the register of licenses and sends a notification to the applicant about making the corresponding entry in the register of licenses. The information contained in the license register is open and publicly available, except in cases where access to such information is restricted in accordance with the legislation of the Russian Federation. Access to the information from the register of licenses is provided by Rostechnadzor by publishing it on the official website on the Internet. Also, the information about a specific license can be obtained by an interested person in the form of an extract from the license register in paper or electronic form, while the corresponding fee is charged for providing an extract from the license register in a hard copy. It is worth paying attention to the fact that the amount of the fee was set not for replenishing the budget of the Russian Federation, but in order to stimulate the transition of the interaction of applicants with licensing authorities to an electronic form. The innovations simplified the process of interaction between the licensing authorities and the license applicants and licensees, accelerated and simplified the procedure for obtaining a license, and increased the efficiency of state administration in the field of industrial safety.

Sanctioned licensing board violations for marriage and family therapists spanning a 10-year period.

Although disciplinary data on violations committed by licensed mental health professionals are important information for training programs, supervisors, and regulators, little disciplinary information is available on licensed marriage and family therapists (MFTs). This study collected data publicly available from state regulatory board websites and open records requests from 35 states for a total of 1241 separate cases, 889 of which were from CA. The findings indicated that the five most common violations for MFTs in 34 states (not including CA) were nonsexual dual relationships, failure to meet CE hour requirements, sexual dual relationships, unlicensed practice, and misrepresentation on licensing applications or renewals. For CA, the most common violations included criminal charges-misdemeanor, DUI/inappropriate substance use, unprofessional conduct, misrepresentation on licensure paperwork, and failure to meet CE hour requirements. MFTs licensed between 2 and 5years committed the majority of violations. Implications for training programs, supervisors, and regulators are discussed.

Patient-reported outcomes in breast cancer FDA drug labels and review documents

BackgroundPatient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions.MethodsWe included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted.ResultsOf 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods.ConclusionsDespite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Filing of DMF in the US, EU, and India, and its comparative review

A Drug Master File (DMF) covers all comprehensive, accurate, and precise information about Active Pharmaceutical Ingredient (API) or Finished Product Dosage Form (FP). It is a confidential document that contains complete, factual, and correct information about the active pharmaceutical ingredient and drug product's chemistry, manufacture, stability, purity, impurity profile, packaging, and the cGMP (Current Good Manufacturing Practices) status of any human drug product. When a DMF is filed, it allows a company to safeguard its intellectual property from its partner while complying with regulatory requirements when its process details are disclosed. There is no legalised or regulatory requirement to file a DMF. A DMF comprises of two parts: (a) the Applicant's Part (Open Part), which contains all the information to assess the quality that the license-holder requires and submit a license or amendment application; and (b) the Restricted Part (Closed Part), which contains confidential information about the manufacturing procedure which is only disclosed to the authorities.
 A DMF can be used by a holder who establishes the file or by one or more parties to support their files or applications.
 The present study is to brief an overview of DMF filing in different countries, which are the USA, Europe, and India. It also gives information on regulatory requirements of Drug Master Files by Food and Drug Administration (USA), European Medicines Agency (Europe), and Central Drug and Standard Control Organization (India) and their comparison.

A Comparative Study for License Application Regulations on Proprietary Chinese Medicines in Hong Kong and Canada.

Ethnopharmacological Relevance: Chinese Medicine plays a symbolic role among traditional medicines. As Chinese Medicine products are widely used around the globe, regulations for Chinese Medicine products are often used as models for the efficient regulation of natural products that are safe, and high-quality.Aim of the Study: We aimed to compare the regulatory registration requirements for Proprietary Chinese Medicines in Hong Kong and Canada.Materials and Methods: We compared registration requirements for Proprietary Chinese Medicine in Hong Kong and Canada based on publicly available information provided by the respective Regulators. A marketed product, Zhizhu Kuanzhong Capsule (SFDA approval number Z20020003; NPN approval number 80104354), was used as a case study to demonstrate the similarities and differences of the requirements in both Hong Kong and Canada.Results: There were similarities and differences between the two regulatory systems in terms of the quality, safety and efficacy requirements. Despite the superficial appearance of similar categories and groups/classes, Hong Kong requires significantly more primary test data compared to Canada's reliance on attestation to manufacturing according the standards outlined in approved reference pharmacopeias/texts.Conclusion: Improved understand of the similarity and differences will enable applicants to plan appropriate strategies for gaining product approval. Exploring ways to harmonize the regulatory process has the potential to benefit manufacturers, regulators, and patients by increasing efficiency and decreasing costs.

Do PA licensure questions violate the Americans with Disabilities Act?

Negative stigma related to mental health diagnoses is common in both clinicians and the public. Questions about physical and mental conditions on licensure applications often are overly broad and may violate the Americans with Disabilities Act (ADA). This study investigated state physician assistant (PA) licensing applications relating to physical and mental health, and their consistency with the ADA. We collected PA state licensure applications from all 50 states and the District of Columbia. To be considered consistent with the ADA about physical conditions, an application had to only contain questions about a current (within the past year) physical health condition that impaired the applicant's ability to practice as a PA, or not include any questions about physical health. Questions that asked for speculation about possible future situations were considered inconsistent with the ADA. Nearly 57% of state PA licensing applications were consistent with ADA guidelines on physical conditions; 51% were consistent for mental health conditions. Many state PA licensing boards include questions about physical and mental health conditions that are not limited to current impairment. These licensure questions could violate the ADA, and may reduce PAs' willingness to seek help for mental health issues. Balancing public safety with clinician health is a challenge. Further research and action are needed to optimize PA licensure questions on physical and mental health.

The Influence of Health Services Licenses to the Quality of Services at the Capital Investment and Integrated Services Office One Door of the City of Medan

The research objective was to analyze the effect of health service licensing policies on service quality at the Medan City Investment Service and One Stop Integrated Services. This research method is mixed methods, amounting to 27 people. The results of the research on the relationship of health service licensing policies with the satisfaction of the online licensing application for the SiCantik Cloud application, it is known that the licensing policy is good quality service with the relationship between physical evidence and satisfaction of the online licensing applicant for the SiCantik Cloud application, it is known that physical evidence of the applicant is satisfied, the relationship of reliability with the satisfaction of the online licensing applicant of the SiCantik application. Cloud, it is known the reliability of the applicant's clinical licensing officer, the relationship of responsiveness with the satisfaction of the online licensing applicant of the SiCantik Cloud application, it is known the responsiveness of the applicant's clinic licensing officer, the guarantee relationship with the satisfaction of the online licensing applicant for the SiCantik Cloud application, it is known that the clinical licensing guarantee of the applicant is satisfied, the relationship of empathy with the satisfaction of the licensing applicant online application SiCantik Cloud, it is known that the empathy of the applicant's clinical licensing officer is satisfied. Research suggestions are expected to the next researchers to prioritize research related to public services, especially health, because health services have a very important role in people's lives.

Correcting COVID-19 vaccine misinformation: Lancet Commission on COVID-19 Vaccines and Therapeutics Task Force Members.

Correcting COVID-19 vaccine misinformation: Lancet Commission on COVID-19 Vaccines and Therapeutics Task Force Members.

PRACTICAL GUIDANCE ON THE REGULATORY MANAGEMENT OF RADIOACTIVE LIQUID DISCHARGES FROM MEDICAL, EDUCATIONAL AND RESEARCH LABORATORIES.

License applicants are often faced with the need to perform a radiological impact assessment study for the liquid discharges in public sewers, even for practices with short-lived isotopes used in medical, educational or research laboratories. The present paper addresses the regulatory management challenges in performing such assessments and provides a practical calculation toolbox that enables more realistic derivation of doses to critical members, based on a simple calculation means. The proposed methodology is validated through comparisons with results from other models. The effectiveness of the method is illustrated by considering relevant examples of hospitals and education and research establishments in Greece. The results show that the proposed method is a sound tool that achieves a more realistic estimation of the induced doses. In most cases a reduction in the initial screening dose estimates by several orders of magnitude is attained, thus greatly facilitating the effort needed to ascertain regulatory compliance.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Indocyanine green beyond quantitative liver function tests – An adjuvant in pediatric imaging

Indocyanine green (ICG) is a nontoxic, inert, anionic water-soluble tricarbocyanine dye with ability to fluorescence when light of the near infrared spectrum is focused onto it with a customized camera. ICG has been known as a diagnostic agent for decades. As with many diagnostic modalities in the medicine, the use of ICG has slowly expanded to find varied and novel applications in the clinical practice. Its use as an imaging modality in pediatric surgery is only increasingly being recognized. The uses of ICG range from bile duct identification, biliary atresia surgery, bowel ischemia delineation, tumor detection, parathyroid identification, and lymph leak detection to name a few. Its safety profile, property to bind to plasma proteins, and be excreted exclusively in the bile make it ideal for intraoperative pediatric surgical imaging. Data on ICG use in children are limited to a handful of case reports and few case cohorts globally. A broad literature search on the history of ICG use, pharmacology, licensing applications, and clinical reports specifically for pediatric populations was carried out. This review was done with intent to analyze the safety profile and compile the various indications of ICG use in children. The dye finds ever expanding clinical uses in our large tertiary referral unit for children in NSW, Australia, and it was our intent to create a protocol that allows for its safe use in routine clinical practice. This protocol created will benefit not only our patients, but is one that can be adopted for other pediatric surgical services worldwide.

Application of Compulsory Licensing in the Context of the Covid-19 Coronavirus Pandemic

The article reveals the features and legal grounds for the application of the mechanism of restriction of patent rights through compulsory licensing of inventions. The analysis of the legislation on the regulation of these relations is carried out. The EU experience in the use of compulsory licensing is analyzed and prospects for Ukraine are considered. Theoretical positions on the subject of research are analyzed. It is substantiated that in emergency situations the state should defend the public interests to the detriment of the interests of the patent owner and may apply a compulsory license. Compulsory licensing is a common practice and an important legal institution. The conditions and features of granting a compulsory license for objects of patent law in accordance with the provisions of Ukrainian legislation are revealed. The terms of the compulsory license are not based on the mutual consent of the licensor and the licensee but are determined by the competent state body. The correlation of the Ukrainian legislation with the international obligations of Ukraine is investigated. Analysis of foreign sources shows that compulsory licensing is one of the effective mechanisms for reaching a compromise between the public interests and the patent owner. The paper confirms the expediency of shifting the balance of interests from the patent owner to society in the context of the COVID-19 pandemic. Recommendations for improving Ukrainian legislation are provided.

SEPs and automotive brake system: a study on horizontal application of patent licensing under FRAND terms in India

SEPs and automotive brake system: a study on horizontal application of patent licensing under FRAND terms in India

Cannabinoids: A new friend or just another pandemic?

Cannabinoids: A new friend or just another pandemic?

Research On Optimization Method of Fatigue Analysis for Nuclear Pipeline

The initial design life of nuclear power plant is 40 years. In 60 year life extending license application, the fatigue of component should be evaluated under the influence of the fatigue factors of the pressurized water reactor coolant environment. Because the original design used a more conservative analysis method, the result could not meet the requirement of Cumulative usage fatigue factor of RCC-M. An optimizing analysis method is studied, and as an example of application, optimizing fatigue analysis of Safety Injection Nozzle of Main Coolant Line is performed. The evaluation results show that the optimized fatigue analysis results meet the requirements of RCC-M.

U.S. Food and Drug Administration: Initial Experience with the Real-Time Oncology Review Program.

The FDA Oncology Center of Excellence commenced the Real-Time Oncology Review (RTOR) pilot project in February 2018 to facilitate earlier submission of topline results and datasets to support an earlier start to the FDA application review. RTOR was initially begun to support supplemental drug applications to add new indications, dosing regimens, or other clinical information to the prescribing information, but was later expanded to include original new drug applications and biological license applications for new molecular entities (NME). From February 2018 to April 2020, RTOR was used to support the submission and review of drug approvals for 20 oncology applications (11 for solid tumor and nine for hematologic malignancy indications). Two were NME drug approvals and 18 were supplemental approvals. All of the applications received priority review and nine (45%) applications had received breakthrough therapy designation status. FDA received the RTOR submissions a median of 5.7 weeks (range 1.7-16.2 weeks) prior to the full application submission. The median time from application submission to FDA approval was 3.3 months (range 0.4-5.9 months). RTOR was also integrated with other review programs including the Assessment Aid and Project Orbis programs. Innovative regulatory processes are critical to expedite the rigorous review of impactful products across the FDA.

Evaluation of sleep apnea prevalance among driving license applicants

Aim: This study aimed at evaluating the PSG results of the applicants of driving license by reference to the BMI, and investigating the accuracy of this cutoff value of BMI (33) on detecting the patients with OSAS among the applicants of driving licenseMaterials and Methods: Driving license applicants with a BMI 36 constituted the group B. The AHI levels of the groups were compared, and ROC analyzes were performed to detect accurate BMI values. Results: Median AHI values did significantly differ among three groups (p0.001). median AHI was statistically significantly higher in group A (median AHI: 12.5) and in group B (median AHI: 12.9) compared to the control group (median AHI: 2.4) (p0.001). However, there was no significant difference between the median AHI of the group A and B (median AHI: 12.5 vs. 12.9) (p= 0.336). Additionally, 34 was found to be the cut-off value for BMI suggesting that AHI could be 15 and/or above; and 34.8 was found to be the cut-off value for BMI suggesting that AHI could be 30 and/or above. Conclusion: Patients with a BMI over 33 had a greater AHI compared to the patients. Additionally, 34.8 value was found to be the cut-off value for BMI suggesting that AHI could be 30 and/or above.

1243. Semi-Quantitative Benefit-Risk Assessment for a New Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Individuals 2 Years of Age and Older

BackgroundMenACYW-TT is a new quadrivalent meningococcal conjugate vaccine approved by the US FDA for use in individuals 2 years and older. We present the structured benefit-risk assessment conducted by Sanofi Pasteur in support of the initial biological license application for MenACYW-TT.MethodsThe safety and immunogenicity of MenACYW-TT in subjects ≥ 2 years was evaluated in 5 pivotal randomized, active-controlled clinical trials. Collectively, 4,919 subjects received either a single primary dose (n=4517) or a booster dose (n=402) of MenACYW-TT. A semi-quantitative framework was used to establish favorable and unfavorable effects of MenACYW-TT relative to comparators: MenACWY-CRM in children 2-9 years and adolescents 10-17 years, MenACWY-D in adolescents 10-17 years and adults 18-55 years, and MPSV4 in older adults ≥ 56 years. Benefit outcome measures included vaccine seroresponse and seroprotection (titers ≥ 1:8) at D30 evaluated by serum bactericidal assay using human complement, for each serogroup. Risk outcome measures included rates of solicited injection site and systemic reactions (including grade 3 reactions) within 7 days after vaccination, and rates of serious adverse events within 6 months after vaccination. The differences in rates for MenACWY-TT vs comparator vaccines were calculated along with 95% confidence intervals.ResultsFor all benefit criteria, and in all age groups, rate differences favored MenACYW-TT in meningococcal vaccine-naïve individuals. Immune response differences were more pronounced for serogroup C. Differences showed favorable (seroresponse criteria) or comparable (seroprotection criteria) effects for MenACYW-TT in adolescents and adults previously primed with MenACWY-D or MenACWY-CRM. For the risk criteria, rate differences generally showed comparable effects between MenACYW-TT and MenACWY-D or MenACWY-CRM in children, adolescents and adults, while the rate differences for both solicited injection site and systemic reactions favored MPSV4 in older adults. The latter was possibly due to the use of a protein carrier in MenACYW-TT.ConclusionThe benefit risk-profile of MenACYW-TT in individuals ≥ 2 years is considered favorable relative to comparator licensed vaccines.DisclosuresDavid Neveu, MPharm, Sanofi Pasteur (Employee) Marie-Laure Kürzinger, MSc, Sanofi (Employee) Aiying Chen, PhD, Sanofi Pasteur (Employee) Mandeep S. Dhingra, MD, Sanofi Pasteur (Employee)

An exploratory study about the Challenges with Pilot Training and Recruitment in Europe

Pilot training and recruitment is of fundamental importance for the aviation industry. Yet, a number of Commercial Pilot’s License (CPL) applicants trained by Approved Training Organizations (ATOs) fail their airline assessments. To provide some clarity on why this is happening, we conducted in-depth interviews with twelve industry professionals and a detailed documentary analysis was undertaken. We found that the main reasons are: (1) Lack of preparation or technical knowledge; (2) Poor communication skills; and (3) Poor display of teamwork and leadership. The paper suggests that regulation should be implemented for ATO’s to use screening processes on potential students to increase quality or Airline Pilot Standard Multi Crew-Cooperation (APS MCC) system, as an additional training system on top of what is being taught in ATOs. Regulations should further be linked with regular audits in place for smaller airlines to increase the effectiveness of their pilot assessments and recruitment processes in order to increase safety. Areas of further research as also identified.