Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists.

Importance: Glucagon-like peptide 1 (GLP-1) receptor agonists were first approved for the treatment of type 2 diabetes in 2005. Demand for these drugs has increased rapidly in recent years, as indications have expanded, but they remain expensive. Objective: To analyze how manufacturers of brand-name GLP-1 receptor agonists have used the patent and regulatory systems to extend periods of market exclusivity. Evidence Review: The annual US Food and Drug Administration's (FDA) Approved Drug Products With Therapeutic Equivalence Evaluations was used to identify GLP-1 receptor agonists approved from 2005 to 2021 and to record patents and nonpatent statutory exclusivities listed for each product. Google Patents was used to extract additional data on patents, including whether each was obtained on the delivery device or another aspect of the product. The primary outcome was the duration of expected protection from generic competition, defined as the time elapsed from FDA approval until expiration of the last-to-expire patent or regulatory exclusivity. Findings: On the 10 GLP-1 receptor agonists included in the cohort, drug manufacturers listed with the FDA a median of 19.5 patents (IQR, 9.0-25.8) per product, including a median of 17 patents (IQR, 8.3-22.8) filed before FDA approval and 1.5 (IQR, 0-2.8) filed after FDA approval. Fifty-four percent of all patents listed on GLP-1 receptor agonists were on the delivery devices rather than active ingredients. Manufacturers augmented patent protection with a median of 2 regulatory exclusivities (IQR, 0-3) obtained at approval and 1 (IQR, 0.3-4.3) added after approval. The median total duration of expected protection after FDA approval, when accounting for both preapproval and postapproval patents and regulatory exclusivities, was 18.3 years (IQR, 16.0-19.4). No generic firm has successfully challenged patents on GLP-1 receptor agonists to gain FDA approval. Conclusions and Relevance: Patent and regulatory reform is needed to ensure timely generic entry of GLP-1 receptor agonists to the market.

Regulatory performance of the East African Community joint assessment procedure: The way forward for regulatory systems strengthening.

BACKGROUND: Seven national medicines regulatory authorities in the East African Community (EAC) have embraced regulatory reliance, harmonization and work sharing through the EAC Medicines Regulatory Harmonization programme. Measuring the performance of regulatory systems provides key baseline information to build on regulatory system-strengthening strategies. Therefore, the aim of the study was to evaluate the regulatory performance of the EAC joint scientific assessment of applications approved between 2018 and 2021. METHODS: Utilising a data metrics tool, information was collected reflecting timelines for various milestones including submission to screening, scientific assessment and communication of regional recommendations for biologicals and pharmaceuticals that received a positive regional recommendation for product registration from 2018 to 2021. RESULTS: Several challenges as well as possible solutions were identified, including median overall approval times exceeding the EAC 465-day target and median times to issue marketing authorisation following EAC joint assessment recommendation that far exceeded the 116-day target. Recommendations included establishment of an integrated information management system and automation of the capture of regulatory timelines through the EAC metric tool. CONCLUSIONS: Despite initiative progress, work is required to improve the EAC joint regulatory procedure to achieve regulatory systems-strengthening and ensure patients' timely access to safe, efficacious and quality medicines.

Evaluación de los comparadores empleados en los estudios pivotales de nuevos medicamentos e indicaciones / Assessment of comparators used in pivotal studies of new medicines and indications

Objetivo: En algunos casos, los estudios pivotales para aprobar nuevos medicamentos no emplean el comparador más adecuado. El objetivo es cuantificar este problema analizando los Informes de Posicionamiento Terapéutico (IPT) publicados por el Ministerio de Sanidad español.Métodos: El comparador se clasificó en seis categorías según la adecuación del tratamiento, es decir, si coincidía con el estándar de tratamiento al ser autorizado: A-“inicialmente adecuado”, B-“sin comparador por causa ética”, C-“sin comparador excluyendo los clasificados en B”, D-“inadecuado” y E-“parcialmente subóptimo” (cuando era estándar solo para parte de los pacientes).La variable principal fue la proporción de nuevos fármacos/indicaciones con comparación suficiente (categorías A, B y C) o deficiente (el resto). La información sobre comparadores y tratamiento estándar se extrajo del IPT. Resultados: Se analizaron aleatoriamente 186 IPT con nuevos medicamentos/indicaciones, publicados entre 2013 y 2022. La comparación se consideró suficiente en un 73,7% (IC95 66,9-79,5) de los casos. El 26,3% restante (IC95 20,5-33,1) presentaba comparaciones deficientes en el ensayo pivotal, ya fuera por comparador inadecuado (11,3%), parcialmente subóptimo (5,4%) o ausencia de un estudio comparativo (9,7%). No hubo diferencias en relación con el año de aprobación.Conclusiones: Aproximadamente uno de cada cuatro nuevos medicamentos o indicaciones carece de una comparación suficiente en el momento de empezar a ser utilizado en la práctica clínica. La proporción no mejora a lo largo de los últimos 10 años. Las agencias reguladoras deben ser más exigentes en la selección del comparador para los ensayos clínicos pivotales, por cuestiones éticas y sanitarias. (AU)

Objective: Pivotal studies to approve new medicines often do not use the most appropriate comparator. The objective is to quantify this problem by analysing the Therapeutic Positioning Reports (IPT for its acronym in Spanish) published by the Spanish Health Ministry.Methods: The comparator was classified into six categories, based on the appropriateness of the treatment, i.e. whether it matched the standard of treatment when authorised: A-«initially adequate» (at the start of the study), B-«no comparator for ethical reasons», C-«no comparator -excluding B-«, D-«inadequate» and E-«partially suboptimal» (when it was standard for part of the included patients but not for all of them).The primary endpoint was the proportion of new drugs/indications with sufficient (categories A, B and C) or poor comparator (the rest). Information on comparators and standard treatment was extracted from the IPT. Results: We randomly analysed 186 IPTs with new drugs or indications, published between 2013 and March 2022. Comparability was assessed as sufficient in 73.7% (95%CI 66.9-79.5) of cases. The remaining 26.3% (95%CI 20.5-33.1) had poor comparisons in the pivotal trial, either due to inadequate comparator (11.3%), partially suboptimal (5.4%) or absence of a comparative study excluding ethical justification (9.7%). Conclusions: Approximately one in four new medicines or indications lacks sufficient comparability at the time of entry into clinical practice. The proportion has not improved over the last 10 years. Regulatory agencies need to be more stringent in comparator selection for pivotal clinical trials, for ethical and health reasons. (AU)

Immune checkpoint inhibitors for the treatment of non-small cell lung cancer: A comparison of the regulatory approvals in Europe and the United States.

Regulatory authorization of oncology drugs, including immune-checkpoint inhibitors, is often based on enhanced efficacy and acceptable toxicity profiles, investigated in randomized, open-label clinical trials. Regulatory approval decisions of the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are frequently compared and contrasted, specifically based on review requirements, and time to approval or refusal decisions. We reviewed databases of the US FDA, the EMA and Clinicaltrials.gov, from January 1, 2015 until December 31, 2021, and analyzed regulatory approvals for immune-checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC). We specifically focused on time to approval duration of each immune-checkpoint inhibitor, and considerations of patient-reported outcomes (PROs) by each regulatory agency. Despite similarities in the regulatory pathways and methods used for immune-checkpoint inhibitor approvals, NSCLC indications that stood out in terms of outcome divergence were mainly first-line drugs for treatment naïve patients. The US FDA was quicker to reach approval decisions, when compared with the EMA. The US FDA and the EMA both recognize the value of PROs as important patient-centered endpoints. Policy statement: There are several regulatory structures in the US and Europe that aim to leverage the latest clinical trial evidence and speed up the regulatory approval processes. In our study, the preponderance of outcome differences in approvals were not influenced by the expedited drug development and access programs. Increased harmonization and collaboration on the PRO measurement and validation are encouraged among these agencies to improve the efficiency of regulatory decisions in the future.

The Importance of and Challenges with Adopting Life-Cycle Regulation and Reimbursement in Canada.

Regulatory and reimbursement decisions for drugs and vaccines are increasingly based on limited safety and efficacy evidence. In this environment, life-cycle approaches to evaluation are needed. A life-cycle approach grants market approval and/or positive reimbursement decisions based on an undertaking to conduct post-market clinical trials that address evidentiary uncertainties, relying on the collection and analysis of post-market data. In practice, however, both conditional regulatory and reimbursement decisions have proven problematic. Here we discuss some of the regulatory implications and unsettled ethical and pragmatic issues, taking lessons from the recent experiences of Israel in rapidly approving the Pfizer-BioNTech COVID-19 vaccine.

[Administrative delays of temporary recommendation for use: Impact on access to innovation in melanoma]. / Délais administratifs des RTU, effet sur l'accès à l'innovation dans le mélanome.

INTRODUCTION: Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). METHOD: We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. RESULTS: On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. CONCLUSION: Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

Recent Developments in the Use of Kinase Inhibitors for Management of Viral Infections.

Kinases are a group of therapeutic targets involved in the progression of numerous diseases, including cancer, rheumatoid arthritis, Alzheimer's disease, and viral infections. The majority of approved antiviral agents are inhibitors of virus-specific targets that are encoded by individual viruses. These inhibitors are narrow-spectrum agents that can cause resistance development. Viruses are dependent on host cellular proteins, including kinases, for progression of their life-cycle. Thus, targeting kinases is an important therapeutic approach to discovering broad-spectrum antiviral agents. As there are a large number of FDA approved kinase inhibitors for various indications, their repurposing for viral infections is an attractive and time-sparing strategy. Many kinase inhibitors, including baricitinib, ruxolitinib, imatinib, tofacitinib, pacritinib, zanubrutinib, and ibrutinib, are under clinical investigation for COVID-19. Herein, we discuss FDA approved kinase inhibitors, along with a repertoire of clinical/preclinical stage kinase inhibitors that possess antiviral activity or are useful in the management of viral infections.

Japan's Special Approval for Emergency System During the COVID-19 Pandemic.

The development of drugs for coronavirus disease 2019 (COVID-19) is a global challenge. In Japan, remdesivir was approved in May 2020 for COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In February 2021, a vaccine against COVID-19 was approved. These two approvals were made using the Special Approval for Emergency system in Japan. This Japanese system was started in 2010 and has been used to approve four drugs to date, including remdesivir and the Pfizer COVID-19 vaccine. This paper discusses future challenges for Japan's Special Approval for Emergency system and organizes what can be learned from experiences to date. As a result, I would like to point Out the following issues. (i) Special Approval for Emergency is a system for approving drugs approved overseas, not a system for approving drugs originally developed in Japan. A system to approve drugs that have not been approved in foreign countries needs to be considered. (ii) In the Special Approval for Emergency system, it is necessary to ensure that postmarketing activities are conducted in accordance with the Risk Management Plan and the conditions of approval, to disclose the results in a timely and speedy manner, and to judge the appropriateness of continued approval based on the results of postmarketing activities.