Fast-track Approval Research Articles

2023 in review: FDA approvals of new medicines

An analysis of all new entities approved by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) identified the approval of 69 new entities in the year 2023, 50 % more than in the previous year. Oncology drugs tied with congenital and infectious diseases drugs for the most approvals. Although orphan and priority approvals continued at a high pace, the rate of fast-track approvals continued to decline. The rate of industry consolidation also picked up again after decreasing slightly in 2022.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes: From Regulatory Status to Clinical Translation.

Cardiovascular diseases, considered the deadliest worldwide by the World Health Organization (WHO), lack effective therapies for regenerating cardiomyocytes. With their self-renewal and pluripotency capabilities, stem cell therapies are increasingly used in precision medicine. Induced pluripotent stem cells (iPSCs) are a promising alternative to embryonic stem cells. Good Manufacturing Practice (GMP) principles are not yet adapted for large-scale production of iPSCs. Additionally, the quality risk for iPSC products may not always be possible to eliminate, potentially jeopardizing the health of patients. This review aims to identify critical quality attributes (CQAs) for iPSC-derived cardiomyocytes (iPSC-CMs) for the development of cardiovascular therapy to ensure compliance with regulations and safety for patients. To attain these goals, the literature review was conducted with articles related to iPSCs and iPSC-CM therapies, legislation, and regulatory guidelines of the European Medicines Agency (EMA), Food and Drug Administration (FDA), and Pharmaceuticals and Medical Devices Agency (PMDA). In conclusion, additional regulations and guidelines are needed to monitor differentiation, maturation, and tumorigenicity. GMP-compliant cell banks and fast-track approval systems may increase accessibility for patients.

Use of Dulaglutide, Semaglutide, and Tirzepatide in Diabetes and Weight Management

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are effective therapies in lowering glycosylated hemoglobin (HbA1c), providing cardioprotective benefits, and lowering weight. The use of GLP1-RA solely for weight-loss has become commonplace in many practices, which in turn has made it difficult in some areas for those with type 2 diabetes (T2DM) to obtain these much-needed medications. Using recent published literature, along with clinical experience, it has become apparent that many GLP1-RAs have become difficult to obtain for patients with diabetes. Many clinicians started to prescribe the brand Ozempic® (semaglutide*) and dulaglutide for weight loss despite neither of them being Food and Drug Administration (FDA) approved for this indication. Ozempic, having outperformed dulaglutide in in both HbA1c reduction and weight loss, along with FDA approval of semaglutide for weight loss, has quickly become widely used off-label for weight loss. This off-label use may have increased, despite the approval of semaglutide,† because many insurances will not cover semaglutide solely for weight management. Most recently, Eli Lilly was able to develop tirzepatide,‡ which was FDA approved in May of 2022, and they are seeking fast-track FDA approval for weight loss and are projected to gain this approval within 2023. Insurance coverage for weight management remains sparse, and obtaining these therapies for diabetes has now become more burdensome, with insurance companies requiring a prior authorization proving FDA-approved diagnosis of T2DM. Hopefully, should more GLP1-Ras receive approval for weight loss, along with an increase in insurance coverage, the burden on patients with diabetes will be lessened as they are able to quickly obtain this highly effective therapy.

Fast-tracking drug development with biomarkers and companion diagnostics

To fully implement precision medicine, a deeper understanding of biomarkers, companion diagnostics, and their use in clinical trials is needed. Here, we describe key events in biomarker discovery and clinical trial design, and how those stages may be streamlined to fast-track approval of companion diagnostics (CDx). We discuss crucial qualities of a successful CDx that include understanding the prevalence of the marker in the intention to treat population, careful consideration of the scoring scheme that will be used in later clinical trial stages, and reliability of the performance of the CDx, in addition to other necessary features.

Delivering COVID-19 vaccine trials at speed: the implementation of a phase IV UK multi-centre randomised controlled trial to determine safety and immunogenicity of COVID-19 vaccines co-administered with seasonal influenza vaccines (ComFluCOV)

BackgroundIn February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response.MethodsComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites.ResultsComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published.ConclusionThe rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in ‘non-pandemic’ situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings.Trial registrationISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021.

Attitudes and perceptions about COVID-19 vaccination in the population with chronic HIV infection: A systematic review.

The coronavirus disease 2019 (COVID-19)-infected population has been increasing during the last 3 years worldwide. Moreover, simultaneously, COVID-19 vaccine clinical trials were launched. By the end of 2020, the Food and Drug Administration had authorized the emergency use of two messenger RNA vaccines against COVID-19. These fast-track vaccine approvals have produced controversy about their safety and efficacy. The purpose of this research wasto discover attitudes and perceptions regarding vaccination against COVID-19 disease among vulnerable groups such as human immunodeficiency virus(HIV)-infected patients. Between June 2, 2021and March 4, 2022, we conducted a cross-sectional study through a survey of high-risk patients with severe COVID-19, such as HIV-infected patients in the Infectious Diseases Unit (Hospital Clínico Universitario San Juan, Alicante). For the data collection strategy, a nonprobabilistic snowball sampling was adopted. A structured, anonymous, self-administered questionnaire was developed in which questions and statements were designed to evaluate their attitudes and perceptions about COVID-19 vaccination. Descriptive and bivariate analyses were performed for the obtained data. Forty-eight participants were recruited with a mean age of 51.5 ± 11.9 years. Thirty-nine of them (81.3%) were male. The acceptance rate of COVID-19 vaccination was extremely high (95.7%). Bivariate analysis showed older patients significantly received a higher proportion of vaccine doses at the time of the survey (p = 0.047). Older patients were more aware of the vaccine safety controversy (61.1%) compared to younger patients (p = 0.054). There were no other significant differences between groups among questions regarding safety, efficacy, or attitudes about COVID-19 vaccination. An extremely high degree of acceptance for COVID-19 vaccination was reported. Older patients were more aware of the vaccine safety controversy. Medical staff is the most trustworthy source of information, far above all other sources. Social networks and opinion leaders have not been shown to significantly influence our population.

Identification of the ideal recruitment situation in pandemic research: learning from the RECOVERY trial in Northern England: a qualitative study

BackgroundIn early 2020, little was known about treatments for COVID-19. The UK responded by initiating a call for research, leading to the formation of the National Institute for Health Research...

Sulbactam-durlobactam: A novel β-lactam-β-lactamase inhibitor combination targeting carbapenem-resistant Acinetobacter baumannii infections.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a difficult-to-treat nosocomial pathogen responsible for significant morbidity and mortality. Sulbactam-durlobactam (SUL-DUR), formerly ETX2514SUL, is a novel β-lactam-β-lactamase inhibitor designed specifically for the treatment of CRAB infections. The United States Food and Drug Administration (FDA) fast-track approval of SUL-DUR for the treatment of CRAB infections is currently pending after completion of the phase III ATTACK trial, which compared SUL-DUR to colistin, both in combination with imipenem-cilastatin (IMI) for patients with CRAB-associated hospital-acquired bacterial pneumonia, ventilator-associated pneumonia, and bacteremia. The results of this trial demonstrated that SUL-DUR was non-inferior to colistin for CRAB while also possessing a much more favorable safety profile. SUL-DUR was well-tolerated with the most common side effects being headache, nausea, and injection-site phlebitis. With the current landscape of limited effective treatment options for CRAB infections, SUL-DUR represents a promising therapeutic option for the treatment of these severe infections. This review will discuss the pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical studies, safety, dosing, administration, as well as the potential role in therapy for SUL-DUR.

Important Barriers to COVID-19 Vaccination Among African Americans in Black Belt Region.

To identify important barriers to COVID-19 vaccination among African Americans living in the Black Belt region. A cross-sectional, web-based questionnaire survey was conducted using best-worst scaling case 1 (the object case). Thirty-two potential barriers to COVID-19 vaccination were identified from the literature and confirmed by an expert. A nested balanced incomplete block design was used to generate 62 sets of 16 choice tasks. Each choice task included six barriers. Participants were asked to choose the most and least important barriers to their COVID-19 vaccination in each choice task of one set. The natural logarithm of the square root of best counts divided by the worst counts of each barrier was calculated to rank the importance of barriers. Responses from a total of 808 participants were included. Among 32 barriers to COVID-19 vaccination, the five most important barriers were "safety concern of COVID-19 vaccines," "rapid mutation of COVID-19," "ingredients of COVID-19 vaccines," "Emergency Use Authorization (Fast-track approval) of COVID-19 vaccines," and "inconsistent information of COVID-19 vaccines." On the other hand, the five least important barriers were "religious reasons," "lack of time to get COVID-19 vaccine," "no support from my family and friends," "political reasons," and "fear of the needle." Important barriers to the COVID-19 vaccination for African Americans living in the Black Belt region centered around the issues that could be resolved by communication strategies.

Expensive Drug Prices for Rare Cancers: Are Patients Truly Benefitting?

Cancer medicines comprise the largest proportion of expensive drugs for rare diseases (EDRDs). The US Orphan Drug Act (ODA) (Office of Inspector General, Department of Health and Human Services 2001) encourages pharmaceutical manufacturers to develop medicines for rare diseases through a range of financial incentives, which has shifted the development of cancer medicines to rare cancer subtypes. Although certain medicines approved through the ODA have revolutionized cancer treatment, only half demonstrate added therapeutic benefit compared to existing alternatives. Canadian regulators should ensure that cancer medicines that receive fast-track approval through the Health Canada Notice of Compliance with conditions offer benefit to Canadian patients. Furthermore, payers might engage in methods for reassessment and renegotiations over the medicines' lifespan.

Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity

Bedaquiline (BDQ) is a new class of anti-tubercular (anti-TB) drugs and is currently reserved for multiple drug resistance (MDR-TB). However, after receiving fast-track approval, its clinical studies demonstrate that its treatment is associated with hepatotoxicity and labeled as ‘boxed warning’ by the USFDA. No data is available on BDQ to understand the mechanism for drug-induced liver injury (DILI), a severe concern for therapeutic failure/unbearable tolerated toxicities leading to drug resistance. Therefore, we performed mechanistic studies to decipher the potential of BDQ at three dose levels (80 to 320 mg/kg) upon the repeated dose administration orally using a widely used mice model for TB. Results of BDQ treatment at the highest dose level showed that substantial increase of hepatic marker enzymes (SGPT and SGOT) in serum, oxidative stress marker levels (MDA and GSH) in hepatic tissue, and pro-inflammatory cytokine levels (TNF-α, IL-6, and IL-1β) in serum compared to control animals. Induction of liver injury situation was further evaluated by Western blotting for various protein expressions linked to oxidative stress (SOD, Nrf2, and Keap1), inflammation (NF-ĸB and IKKβ), apoptosis (BAX, Bcl-2, and Caspase-3) and drug metabolism enzymes (CYP3A4 and CYP2E1). The elevated plasma level of BDQ and its metabolite (N-desmethyl BDQ) were observed, corresponding to BDQ doses. Histopathological examination and SEM analysis of the liver tissue corroborate the above-mentioned findings. Overall results suggest that BDQ treatment-associated generation of its cytotoxic metabolite could act on CYP2E1/NF-kB pathway to aggravate the condition of oxidative stress, inflammation, and apoptosis in the liver and precipitating hepatotoxicity.

A Comparative study of Regulations of Cell and Gene therapy in US, EU and India

Cell and Gene therapy products were a field that is growing fast inventive therapies. The United States (US) and the European Union (EU) are encouraging their evolution and India is in its nascent stage. For three regions, CGTs fall beneath the biological merchandise regulatory framework of it requires the legal foundation for their evolution. In the EU, there is a defined trend between cell- and gene-based products concerning their classification as advanced therapies or coverage by the legal frameworks, while in the United States there is a wide classification as to classified as organic products. In EU, USA and India, to allocate a cell or an gene product’s as innovative therapy, care has to be taken for therapy of cells involves manoeuvres that amend their characters which are organic, as the term tactic in the USA is difference between systemic and non- systemic cells and gene therapy products. A descriptive analysis was carried out. Till now in USA 20 CGTPs are approved, out of 20 GTMP consists of 7 and CTMP consists of 13 products. Many products are under clinical trials, I searched clinical trials website to know the status of clinical trials in USA. I found 355 clinical trials under ATMPs, out of 355 GTMP consist of 225, SCTMP consists of 105, and CATMP consists of 25. In India the procedures are of two types which are to speed up the drug approval process for the betterment of everyone. They are 1) Conditional Approval, 2). Fast Track Approval. There are only 4 products were approved namely Apceden, Stempeucel, Ossgrow and Cartigrow. The problems related to clinical has been degenerate as the unproven stem cell clinics numbers in the USA reportedly were increased to approximately 715 by 2017. Therefore, the unproven industry of sanatorium is a moving intention essential in method examine and regulatory lapse.

RWD33 Analysis of COVID-19 Vaccine-Related Adverse Events in Adults, Geriatrics and Pediatrics – A Retrospective Study

Normally, drug discovery (including vaccines) is a long process that may take up to 10 to 15 years. Due to the mortality and contagious nature of the SARS-CoV2 virus, there was a need for the fast-track development and approval of the vaccine. The clinical trials conducted for the development of a vaccine for COVID-19 were of short duration. Therefore, there is a need to evaluate the safety of the vaccine through the analysis of real-world data.Analysis of selected adverse events after COVID-19 vaccination in adults (18 to 64 years), geriatrics (≥65 years), and pediatrics (<18 years). Optum’s de-identified Clinformatics® Data Mart database was used to identify the adults, geriatrics, and pediatrics patients who had received vaccination for COVID-19 from 1 Nov 2020 to 30 June 2021. The occurrence of the ICD-10 code for COVID-19 vaccination in the claims database was defined as the index event. These patients were then followed for 10 days to check for the adverse events (listed by the CDC). Patients with a confirmed diagnosis of COVID-19 before vaccination and during the follow-up period were excluded from the study. Patients having the ICD-10 for diseases listed in adverse events were also excluded from the study. Out of the 845,357 unique patients who received vaccination for COVID-19, 644,707 (76.3%) were adults, 160,799 (∼19.0%) were geriatrics, and 39,851 (∼5%) were pediatrics. The rate of thrombocytopenia was higher in geriatrics (628 and 721 cases per million after 1st and 2nd dose, respectively) as compared with adults (172 and 192 cases per million after 1st and 2nd dose, respectively). Cases for Guillain-Barré Syndrome (GBS), myocarditis, and pericarditis were rare. Further statistical tests will be applied to analyze the level of significance. Severe reactions after COVID-19 vaccination are rare. A long-term analysis of adverse events should be performed to support these findings.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Fast-track development of vaccines for SARS-CoV-2: The shots that saved the world.

In December 2019, an outbreak emerged of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which leads to coronavirus disease 2019 (COVID-19). The World Health Organisation announced the outbreak a global health emergency on 30 January 2020 and by 11 March 2020 it was declared a pandemic. The spread and severity of the outbreak took a heavy toll and overburdening of the global health system, particularly since there were no available drugs against SARS-CoV-2. With an immediate worldwide effort, communication, and sharing of data, large amounts of funding, researchers and pharmaceutical companies immediately fast-tracked vaccine development in order to prevent severe disease, hospitalizations and death. A number of vaccines were quickly approved for emergency use, and worldwide vaccination rollouts were immediately put in place. However, due to several individuals being hesitant to vaccinations and many poorer countries not having access to vaccines, multiple SARS-CoV-2 variants quickly emerged that were distinct from the original variant. Uncertainties related to the effectiveness of the various vaccines against the new variants as well as vaccine specific-side effects have remained a concern. Despite these uncertainties, fast-track vaccine approval, manufacturing at large scale, and the effective distribution of COVID-19 vaccines remain the topmost priorities around the world. Unprecedented efforts made by vaccine developers/researchers as well as healthcare staff, played a major role in distributing vaccine shots that provided protection and/or reduced disease severity, and deaths, even with the delta and omicron variants. Fortunately, even for those who become infected, vaccination appears to protect against major disease, hospitalisation, and fatality from COVID-19. Herein, we analyse ongoing vaccination studies and vaccine platforms that have saved many deaths from the pandemic.

Detection of targetable fusion alterations in gastric cancer in the Chinese population.

e16061 Background: Despite a decreasing incidence and mortality globally, gastric cancer (GC) remains a main threat to public health, especially in China. Consistently, drug therapy is a big challenge for gastric cancer. Although HER2-directed therapy and immune checkpoint inhibitors have achieved great success, other valid targeted drugs are required to develop. Targeted drugs of NTRK gene fusion have been approved in solid tumors including GC by FDA. Moreover, FDA has granted Zenocutuzumab fast-track approval for patients with NRG1 gene fusion in solid tumors. However, in China, gene fusion and functional characterization have not been reported to date in detail. Methods: In order to estimate the fraction of patients who may benefit from targeted drugs, we retrospectively analyzed the fusion alterations in gastric cancer tissue samples from 955 Chinese patients. Remarkably, as fusion partners, all genes included fusion analysis possess experimental or approved drugs. The clinicopathological characteristics were retrieved from the medical records in hospital. Chi-square analysis was used to investigate the relationship of gene fusions with drivers mutations, MSI, TMB and MMR. Results: We found 2.82% (27/955) of patients harboring fusion genes, including MET, ROS1, ALK, FGFR1/2, NTRK, BRAF, EGFR and so on. Among them, EML4-ALK, EWSR1-FLI1 and EGFR-SEPTIN14 have been described in other studies, but 88.9% (24/27) fusion genes are previously unreported. Sequencing results indicate that fusion genes are significantly enriched in patients with ERBB2 gene amplification. In addition, there is no obvious correlation between the positive rate of gene fusion and clinical features including age and gender. Similarly, MSI status, TMB and MMR are included for correlation analysis with gene fusion. Unfortunately, the results are not statistically significant. Conclusions: Our work characterizes the landscape of targetable fusion alterations in gastric cancer in the Chinese population and investigates that targetable fusion testing should be advised to patients with disease progression after receiving standard therapy.

The economics of moonshots: Value in rare disease drug development.

The economics of moonshots: Value in rare disease drug development.

ADAURA: The Splash of Osimertinib in Adjuvant EGFR-Mutant Non-small Cell Lung Cancer.

The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB–IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib’s fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.

From COVID-19 Treatment to Miracle Cure

From COVID-19 Treatment to Miracle Cure

Global consequences of the US FDA's accelerated approval of cancer drugs.

The accelerated approval system is a fast-track drug approval pathway created by the US Food and Drug Administration (FDA) in 1992 in response to the HIV-AIDS crisis to allow expedited access to life-saving drugs and fulfil an unmet medical need. Nowadays, this pathway is most commonly used for cancer drug approval. 1 Sachs RE Gavulic KA Donohue JM Dusetzina SB Recent trends in Medicaid spending and use of drugs with US Food and Drug Administration accelerated approval. JAMA Health Forum. 2021; 2e213177 Google Scholar In theory, the accelerated approval pathway strikes a balance between early access to therapies and the need for robust evidence generation. This pathway allows drugs to be approved early on the basis of improvement in surrogate outcomes that are reasonably likely to translate to clinical benefit. This approval is conditional, with a mandate that drugs are tested in a post-approval confirmatory trial to substantiate the presumed clinical benefit, in the absence of which approval will be withdrawn. Several challenges and limitations of this pathway for the US regulatory and clinical environment have been previously described. 2 Gyawali B Ross JS Kesselheim AS Fulfilling the mandate of the US Food and Drug Administration's accelerated approval pathway: the need for reforms. JAMA Intern Med. 2021; 181: 1275-1276 Google Scholar Here, we discuss the often-overlooked consequences of the accelerated approval pathway for global oncology. Consequences of US FDA approval decisions in high-income countriesAkhade and colleagues1 highlight the global consequences of approving cancer medicines on the basis of uncertain evidence through the US Food and Drug Administration (FDA)'s accelerated approval pathway. Traditionally, the concern for US regulatory standards has remained inside the USA. However, Akhade and colleagues show that the consequences can be far reaching. Their Comment has substantial implications, especially considering the nomination of a new FDA commissioner and the opportunity that this nomination brings to enforce a suitable efficacy standard. Full-Text PDF