Food And Drug Administration Approval Research Articles

Patent Portfolios Protecting 10 Top-Selling Prescription Drugs.

Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years. To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval. This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023. Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time). The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval. This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.

Abstract PO1-11-02: Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review

Abstract BACKGROUND As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term outcome. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC. METHODS We identified all initial and subsequent published trials supporting FDA approved indications for MBC between 1/2000-2/2023. Collected data included study design, patient characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated. FINDINGS A total of 41 indications for MBC were identified. Supporting studies comprised 20,152 patients. Data were evaluated from 241 publications or abstracts. Reporting of post progression therapy was available for 21 (51%) indications. Of these, post-progression therapy data were often partial and the appropriateness of the therapy could not be evaluated. At the time of FDA approval, data on overall survival (OS) were reported only in 17 (41%) studies. Of these, in 8 studies OS was significantly improved, in 7 studies OS was not improved and 2 studies were single arm. Differences between studies with and without data on post progression therapy are presented in the Table. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, while studies with both OS and progression free survival (PFS) as their primary endpoint had low reporting rate. There were no other statistically significant differences. Reporting post-protocol therapy has not changed over time with reported data in 50% and 52% studies between 2000-2010 and 2011-2023, respectively. CONCLUSIONS Data on post progression therapy in trials supporting FDA approval of drugs for MBC are available in fewer than half of indications. Reported data are often partial and may not include sequential therapies consistent with standard of care. As subsequent lines of therapy may have a crucial role in patients' outcome, post protocol reporting should be included in the regulatory submission and be made available publicly. Differences between studies with and without data on post progression therapy Citation Format: Shlomit Shachar, Yasmin Korzets, Daniel Shepshelovich, Noa Zlotchover, Eitan Amir, Ariadna Tibau, Hadar Goldvaser. Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-02.

Who Still Gets Ligated? Reasons for Persistence of Surgical Ligation of the Patent Ductus Arteriosus Following Availability of Transcatheter Device Occlusion for Premature Neonates

(1) Background: To identify reasons for the persistence of surgical ligation of the patent ductus arteriosus (PDA) in premature infants after the 2019 Food and Drug Administration (FDA) approval of transcatheter device closure; (2) Methods: We performed a 10-year (2014–2023) single-institution retrospective study of premature infants (<37 weeks) and compared clinical characteristics and neonatal morbidities between neonates that underwent surgical ligation before (epoch 1) and after (epoch 2) FDA approval of transcatheter closure; (3) Results: We identified 120 premature infants that underwent surgical ligation (n = 94 before, n = 26 after FDA approval). Unfavorable PDA morphology, active infection, and recent abdominal pathology were the most common reasons for surgical ligation over device occlusion in epoch 2. There were no differences in demographics, age at closure, or outcomes between infants who received surgical ligation in the two epochs; (4) Conclusions: Despite increasing trends for transcatheter PDA closure in premature infants, surgical ligation persists due to unfavorable ductal morphology, active infection, or abdominal pathology.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals. To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases. The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023. Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded. Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes. Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized. Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result. Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals : A Retrospective Cohort Study.

The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). Retrospective cohort. 619 U.S. hospitals. Adult inpatients. Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. Residual confounding. Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. U.S. Food and Drug Administration; NIH Intramural Research Program.

Demographic comparison of subjects in FDA approval trials in the United States to disorder specific demographics using Real World Data

The Food and Drug Administration (FDA) has recommended that clinical trial study populations accurately reflect the patients likely to use the product, if approved. The FDA has not provided specific guidance on how cohort sizes of clinically relevant demographic characteristics should be determined. Therefore, the present study was designed to compare demographic characteristics reported in US-only FDA approval trials to the demographic characteristics of the related medical disorders in an electronic health records database of >150 M patients in the United States (US). The results demonstrate that comparative disparities in demographic cohort proportions are common, yet inconsistent, and highlight the need to define disorder specific demographic cohort proportion goals in future clinical trials.

Reporting of Demographics & Subgroup Analyses in Premarketing Studies of FDA Approved High-Risk Cardiovascular Devices, 2014-2022.

Representation of diverse study populations in pivotal clinical trials for medical devices and subgroup analyses for demographic groups to explore differences in safety and effectiveness are essential to understanding the benefits and risks in diverse populations. The US Food and Drug Administration (FDA) has taken many steps to improve transparency and subgroup analyses over the past decade, but there has not been a recent evaluation of demographic reporting and subgroup analyses. We reviewed all FDA Premarket Approvals for high-risk cardiovascular devices from 2014 to 2022, focusing on pivotal studies supporting device approval. We abstracted detailed demographic data about the age, sex, race, ethnicity, and socioeconomic position of study participants. We also assessed the presence and results of subgroup analyses to understand the safety and effectiveness of devices across trial populations. Analysis of 92 pivotal studies revealed that age and sex were reported in 96.7% of the studies, while race and ethnicity were reported in 71.7% and 58.7%, respectively. However, only 7.9% of studies explicitly detailed the participation of older adults (≥65 years) and no studies reported patients' socioeconomic position. Subgroup analyses by sex were conducted in 70.7% of studies, with 12.3% reporting significant differences. In contrast, analyses by race and ethnicity were performed in only 12.0% of the studies, with 9.1% reporting significant differences. Approximately one-third of pivotal studies for high-risk cardiovascular devices approved by the FDA from 2014 to 2022 did not report the race of study participants, nearly 40% did not report ethnicity, and more than 90% did not report the participation of older adults (≥65 years). Subgroup analyses were infrequently conducted by age or race and ethnicity. There is a need for better trial demographic reporting and conduct of subgroup analyses in premarketing studies to ensure the safety and effectiveness of medical devices for all patients.

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population.

Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.

Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Objective Natural wingless-related integration site (Wnt) pathway antagonist sclerostin (SOST) has attracted much attention because unusual bone illnesses characterized by the increased bone mass result from its absence of action. The Wnt ligand is prevented from attaching to the Frizzled family receptor when SOST is present. In the active destruction complex, -catenin is phosphorylated. -Catenin molecules do not enter the nucleus and are broken down by a proteasome. As a result, Wnt-responsive genes are not activated, which lowers bone formation and raises bone resorption. A humanized monoclonal antibody called romosozumab binds to and inhibits SOST with significant cardiac side effects. As a result, the current study's objective is to find and screen Food and Drug Administration (FDA) medications that target SOST. Materials and Methods SOST's structure was retrieved from Protein Data Bank (PDB) (ID: 6l6r). Pharmacophore modeling and molecular operating environment-based virtual testing of FDA-approved medicines. Using the Desmond program, docking and molecular dynamics simulations were performed. Results Our findings revealed medications with FDA approval (ZINC000253387843) Amphotericin B. The stability and receptor–ligand interactions are pretty substantial, as demonstrated by the findings of docking and Molecular dynamics simulations, which have a docking score of −7.3 k/mol and root mean square deviation stability at 40 nanoseconds, respectively. Conclusion The suggested pharmacological therapy shows promise since it uses the Wnt pathway to target the primary bone formation mechanism. However, additional prospective studies are required to apply the available data to clinical practice.

Abstract 923: Biomarker use in oncology approvals in the US

Abstract Introduction: Precision medicine through the use of biomarkers has revolutionized the way we understand and combat cancer. We are summarizing the current state and challenges of biomarker use in the context of cancer therapeutic products approved by the United States Food and Drug Administration (FDA). Methods: We curated a dataset of oncology therapeutic products approved by the FDA through the regular and accelerated pathways from 2011 to 2022, based on publicly available FDA database, approval letters and reviews, prescribing information, publications, and clinicaltrial.gov. Results: During the period of 2011 to 2022, the FDA granted 132 accelerated and 331 regular approvals for 80 and 144 oncology therapeutic products with 133 and 340 new indications, respectively. The percentage of approvals for a biomarker-defined population was higher in accelerated approvals in comparison to regular approvals (i.e., 51% vs. 39%). The five disease sites with the highest number of approved indications were leukemia, lung, non-Hodgkin lymphoma, breast, and skin. The vast majority of lung and breast cancer indications were approved in a biomarker-defined population through a range of different biomarkers. Overall, HER2-, EGFR-, BRAF-, HR-, and ALK-defined populations received the highest numbers of approvals. The most common biomarkers linked to the approval of a specific cancer type include Philadelphia chromosome for leukemia, EGFR/ALK for lung cancer, HER2/HR for breast cancer, BRAF for skin cancer, and BRCA for ovarian cancer. Multiple myeloma, kidney cancer, and Hodgkin lymphoma did not have any approval with a biomarker-defined population. Non-Hodgkin lymphoma had a large number of approvals, but the percentage approved for a biomarker-defined population was small. dMMR, MSI-H or dMMR, BRAF mutation, NTRK fusions, TMB H, and RET fusions are biomarkers linked to tissue-agnostic indications approved for solid tumors only through the accelerated pathway. Conclusion: To the best our knowledge, the analysis represents the most comprehensive overview of the current landscape on integration of biomarker in oncology therapeutic products approved by the FDA through both the accelerated and regular pathways. Our analysis shows that the FDA has increasingly approved indications based on biomarkers, particularly through the accelerated approval pathway. Biomarkers are reshaping cancer therapy under an evolving regulatory landscape with a growing emphasis on precision medicine that promises continued progress in personalized cancer care. Citation Format: Yannan Nancy Dou, Christian Grimstein, Jian Wang, Jacques Mascaro. Biomarker use in oncology approvals in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 923.

A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022).

Mental health disorders are among the top leading causes of disease burden worldwide and many patients have high levels of treatment resistance. Even though medications offer improvement to some patients, antidepressants are only effective in about half of those treated, and schizophrenia is treatment-refractory in about one-third of patients. One way to combat this disparity is to improve medication development and discovery for psychiatric disorders through evidence-based research. Recently, most psychiatric medications approved by the United States Food and Drug Administration (FDA) are for increased tolerability or extended release. Because of the slow, incremental progress, there is a pressing need to explore novel medications with new indications or mechanisms of action to treat the expanding population with mental disorders, especially in those who are fully or partially recalcitrant to first-line medication options. This review aims to present the newest FDAmedications with new indications, establish the clinical need for each, and discuss future directions in drug development. We searched and reviewed novel psychiatric medications approved by the FDA from 2018 to 2022. We then analyzed each medication in the United States Clinical Trials Registry and gathered updated results for efficacy and safety information. We also searched PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, Web of Science, Elsevier, and Google Scholar to understand how these new indications met current clinical needs. Finally, we inquired about related technological implications that will lead the field of psychopharmacology now and in the years to come. We found 12 novel psychiatric medications approved by the FDA from 2018 to 2022, representing a very small percentage of the total FDA approvals during thatperiod. These psychiatric medications with novel mechanisms or improved efficacy and safety are expected to provide further options for treating mental health disorders; promising results will lead to new patterns of research.

Blood glucose monitoring devices for type 1 diabetes: a journey from the food and drug administration approval to market availability.

Blood glucose monitoring constitutes a pivotal element in the clinical management of Type 1 diabetes (T1D), a globally escalating metabolic disorder. Continuous glucose monitoring (CGM) devices have demonstrated efficacy in optimizing glycemic control, mitigating adverse health outcomes, and augmenting the overall quality of life for individuals afflicted with T1D. Recent progress in the field encompasses the refinement of electrochemical sensors, which enhances the effectiveness of blood glucose monitoring. This progress empowers patients to assume greater control over their health, alleviating the burdens associated with their condition, and contributing to the overall alleviation of the healthcare system. The introduction of novel medical devices, whether derived from existing prototypes or originating as innovative creations, necessitates adherence to a rigorous approval process regulated by the Food and Drug Administration (FDA). Diverse device classifications, stratified by their associated risks, dictate distinct approval pathways, each characterized by varying timelines. This review underscores recent advancements in blood glucose monitoring devices primarily based on electrochemical sensors and elucidates their regulatory journey towards FDA approval. The advent of innovative, non-invasive blood glucose monitoring devices holds promise for maintaining stringent glycemic control, thereby preventing T1D-associated comorbidities, and extending the life expectancy of affected individuals.

Assessing patient risk, benefit and outcomes in drug development: an observational study of regorafenib clinical trials

ObjectiveOur objective of this study was to analyse all oncological clinical trials using regorafenib to create a complete risk/benefit profile for the drug.BackgroundCreating a novel chemotherapy is costly both in...

How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public.

Fibrinolytic Agents in Thromboembolic Diseases: Historical Perspectives and Approved Indications.

Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was cloned using recombinant DNA methods to produce alteplase. Several additional derivatives of tPA, such as tenecteplase and reteplase, were developed to extend the plasma half-life of tPA. Over the past decades, fibrinolytic medications have been widely used to manage patients with venous and arterial thromboembolic events. Currently, alteplase is approved by the U.S. Food and Drug Administration (FDA) for use in patients with pulmonary embolism with hemodynamic compromise, ST-segment elevation myocardial infarction (STEMI), acute ischemic stroke, and central venous access device occlusion. Reteplase and tenecteplase have also received FDA approval for treating patients with STEMI. This review provides an overview of the historical background related to fibrinolytic agents and briefly summarizes their approved indications across various thromboembolic diseases.

Product Development within the National Institutes of Health Radiation and Nuclear Countermeasures Program.

The Radiation and Nuclear Countermeasures Program (RNCP) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) was established to facilitate the development of medical countermeasures (MCMs) and diagnostic approaches for use in a radiation public health emergency. Approvals for MCMs can be very challenging but are made possible under the United States Food and Drug Administration (FDA) Animal Rule, which is designed to enable licensure of drugs or biologics when clinical efficacy studies are unethical or unfeasible. The NIAID portfolio includes grants, contracts, and inter-agency agreements designed to span all aspects of drug development and encompasses basic research through FDA approval. In addition, NIAID manages an active portfolio of biodosimetry approaches to assess injuries and absorbed radiation levels to guide triage and treatment decisions. NIAID, together with grantees, contractors, and other stakeholders with promising products, works to advance candidate MCMs and biodosimetry tools through an established product development pipeline. In addition to managing grants and contracts, NIAID tests promising candidates in our established preclinical animal models, and the NIAID Program Officers work closely with sponsors as product managers to guide them through the process. In addition, a valuable benefit for stakeholders is working with the NIAID Office of Regulatory Affairs, where NIAID coordinates with the FDA to facilitate interactions between sponsors and the agency. Activities funded by NIAID include basic research (e.g., library screens to discover new products, determine early efficacy, and delineate mechanism of action) and the development of small and large animal models of radiation-induced hematopoietic, gastrointestinal, lung, kidney, and skin injury, radiation combined injury, and radionuclide decorporation. NIAID also sponsors Good Laboratory Practice product safety, pharmacokinetic, pharmacodynamic, and toxicology studies, as well as efficacy and dose-ranging studies to optimize product regimens. For later-stage candidates, NIAID funds large-scale manufacturing and formulation development of products. The program also supports Phase 1 human clinical studies to ensure human safety and to bridge pharmacokinetic, pharmacodynamic, and efficacy data from animals to humans. To date, NIAID has supported >900 animal studies and one clinical study, evaluating >500 new/repurposed radiation MCMs and biodosimetric approaches. NIAID sponsorship led to the approval of three of the six drugs for acute radiation syndrome under the FDA Animal Rule, five Investigational New Drug applications, and 18 additional submissions for Investigational Device Exemptions, while advancing 38 projects to the Biomedical Advanced Research and Development Authority for follow-on research and development.

Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms.

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides.

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.

Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone. The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals. Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates. The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure. Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.

Estimated Spending on Beremagene Geperpavec for Dystrophic Epidermolysis Bullosa

New gene therapies can offer substantial benefits to patients, particularly those with rare diseases who have few therapeutic options. In May 2023, the US Food and Drug Administration (FDA) approved the first topical gene therapy, beremagene geperpavec (B-VEC), for treating both autosomal recessive and autosomal dominant dystrophic epidermolysis bullosa (DEB). However, FDA approval was based on limited data in patients with autosomal dominant disease, even though they comprise approximately 50% of all DEB cases. To estimate projected spending in the US on B-VEC therapy for treating autosomal recessive and autosomal dominant DEB. This economic evaluation used data from the National Epidermolysis Bullosa Registry to estimate the current population of US patients with autosomal dominant and autosomal recessive DEB, with the aim of estimating US spending on B-VEC therapy from an all-payers perspective during 1- and 3-year periods after FDA approval. A base-case cost of $300 000 per patient per year was assumed based on a report from the manufacturer (Krystal Biotech). Treatment with B-VEC. Estimated overall spending on B-VEC in the first year and over a 3-year period after FDA approval. Several prespecified sensitivity analyses with different assumptions about the eligible patient population and the cost of therapy were performed, and lifetime total costs of treatment per patient were estimated. The estimated number of US patients with DEB who were eligible for treatment with B-VEC in the first year after FDA approval was 894. The estimated total expenditure for B-VEC therapy was $268 million (range, $179 million-$357 million). Over a 3-year period, estimated spending was $805 million (range, $537 million-$1.1 billion). Estimated lifetime total costs per patient were $15 million (range, $10 million-$20 million) per patient with autosomal recessive DEB and $17 million (range, $11 million-$22 million) for patients with autosomal dominant DEB. Results of this economic evaluation suggest that the FDA's broad indication for the use of B-VEC in treating both autosomal recessive and autosomal dominant DEB will have significant implications for payers.