Food And Drug Administration Review Research Articles

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.

Analysis of US Food and Drug Administration new drug and biologic approvals, regulatory pathways, and review times, 1980–2022

U.S. laws enacted since 1983 have aimed to enhance the development and marketing of new pharmaceutical products. We thoroughly characterized all new molecular entities, therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA) during the period 1980–2022 in the context of these laws and regulations. Throughout the study period, the FDA approved 1355 new pharmaceutical products. The median FDA review time decreased from 26.6 months prior to the Prescription Drug User Fee Act (1992), which authorized the FDA to collect fees from drug companies to 9.9 months after the Food and Drug Administration Safety and Innovation Act (2012), which created new designations that eliminated the requirement for evidence of added therapeutic benefit for FDA expedited drug review. The greatest increase in approvals occurred in antineoplastic and immunomodulating drugs, biologics, and orphan drugs. More than half of new drug approvals benefited from regulatory designations and pathways that did not require addressing unmet medical needs or demonstrating therapeutic benefit over available alternatives. The legislative goal of bringing more drugs to the market faster has been achieved. Further studies are needed to determine the therapeutic value to patients of new drugs approved using expedited approval pathways.

Beyond the 510(k): The regulation of novel moderate-risk medical devices, intellectual property considerations, and innovation incentives in the FDA’s De Novo pathway

Moderate-risk medical devices constitute 99% of those that have been regulated by the U.S. Food and Drug Administration (FDA) since it gained authority to regulate medical technology nearly five decades ago. This article presents an analysis of the interaction between the 510(k) process —the historically dominant path to market for most medical devices— and the De Novo pathway, a more recent alternative that targets more novel devices, including those involving new technologies, diagnostics, hardware, and software. The De Novo pathway holds significant potential for innovators seeking to define new categories of medical devices, as it represents a less burdensome approach than would have otherwise been needed historically. Moreover, it supports the FDA in its effort to modernize the long-established 510(k) pathway by promoting the availability of up-to-date device “predicates” upon which subsequent device applications can be based, reflecting positive spillovers that are likely to encourage manufacturers to adopt current state-of-the-art technologies and modern standards of safety and effectiveness. We analyze the of characteristics all the De Novo classification requests to date, including the submission type, trends, FDA review times, and device types. After characterizing how the De Novo process has been used over time, we discuss its unique challenges and opportunities with respect to medical device software and AI-enabled devices, including considerations for intellectual property, innovation, and competition economics.

Assessment of the U.S. Food and Drug Administration's risk evaluation and mitigation strategy (REMS) for prasugrel (EFFIENT): A narrative review

BackgroundPrasugrel, first approved in 2009, was subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to mitigate the risk of bleeding associated with its use. MethodsWe performed a narrative review of FDA documents obtained through a Freedom of Information Act request. Document classification and primary evidence extraction was performed by three authors (TM, JC, and SL). ResultsThe prasugrel REMS consists of a medication guide and a communication plan. Assessment of the REMS was via patient and clinician surveys. 1560 patients were invited to participate and 212 individuals (13.6 %) completed the survey. Rates of awareness among respondents varied across key messages and were highest for those examining the risks of premature discontinuation (96 % and 88 % of respondents), while lower for those regarding the importance of perioperative discontinuation (66 %) and contraindications posed by a history of stroke (16 %) or transient ischemic attack (17 %). Of the 6000 clinicians invited to participate in the survey, 201 (3.4 %) agreed to take part. Four of 11 key risk messages did not meet prespecified acceptable levels of comprehension. No prespecified levels of patient or provider knowledge were required for the retirement of the REMS, which took place on March 23, 2012 based on the sponsor's request. ConclusionsThe prasugrel REMS consisted of passive educational materials whose adequacy was evaluated using highly limited, one-time, cross-sectional surveys. Our assessment adds to evidence suggesting the importance of improving the quality and impact of the FDA's post-approval activities to maximize drug safety.

A Systematic Literature Review and Network Meta-Analysis of Comparative Efficacy of Topical Fixed-Dose Combination Treatments for Moderate to Severe Acne Vulgaris

INTRODUCTION: Several topical and oral monotherapies/combination treatments are available for treating patients with moderate to severe acne vulgaris and a few are currently under review with the United States (US) Food and Drug Administration (FDA). Among these treatments, topical fixed-dose combinations (FDCs) are widely used in the US. No study has assessed the comparative efficacy of topical FDCs based on the treatment success endpoint of the proportion of patients achieving ≥2 grade reduction AND "Clear" or "Almost clear” status by week 12 on an Investigator's Global Assessment (IGA) or equivalent scales. The objective of this study was to conduct a systematic literature review (SLR) and network meta-analysis (NMA) to compare the efficacy of topical FDCs for the treatment of moderate to severe acne.
 STUDY DESCRIPTION: An SLR was conducted for identifying randomized controlled trials (RCTs), that included at least one topical FDC (currently approved/under review with FDA) arm, in academic (MEDLINE, Embase, Cochrane CENTRAL, PEDE, and NHS EED) and non-academic databases (HTA databases, conference abstracts databases, and trial registries). The search was conducted in May 2022, based on a pre-specified inclusion/exclusion criterion. RCTs included in the analysis evaluated acne severity using IGA or equivalent (Evaluator's Global Severity Score, Investigator’s Static Global Assessment) scales. A Bayesian network meta-regression was conducted, using the proportion of patients with moderate acne, inflammatory and non-inflammatory lesion counts at baseline as covariates to account for acne severity.
 RESULTS: Twelve Phase II/III/IV RCTs were identified from 5,159 citations comprising 8,349 patients across 8 treatment groups. The odds ratio for treatment success with topical FDC of clindamycin phosphate 1.2%, adapalene 0.15%, and benzoyl peroxide 3.1% (first triple agent FDC) gel was estimated to be 7.61 (95% Credible Interval: 4.44 –13.20) in comparison to Vehicle gel. Comparative effectiveness ranking demonstrated that the topical triple agent FDC gel was the most effective treatment with surface under cumulative ranking of 100%.
 CONCLUSION: Based on this SLR/NMA, the topical triple agent FDC of clindamycin phosphate 1.2%, adapalene 0.15%, and benzoyl peroxide 3.1% gel, which is currently under FDA review (PDUFA date 10/20/2023), was clinically superior to all other topical FDC treatments for moderate to severe acne vulgaris.

Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder.

To test for publication bias with alprazolam, the most widely prescribed benzodiazepine, by comparing its efficacy for panic disorder using trial results from (1) the published literature and (2) the US Food and Drug Administration (FDA). From FDA reviews, we included data from all phase 2/3 efficacy trials of alprazolam extended-release (Xanax XR) for the treatment of panic disorder. A search for matching publications was performed using PubMed and Google Scholar. Publication bias was examined by comparing: (1) overall trial results (positive or not) according to the FDA v. corresponding publications; (2) effect size (Hedges's g) based on FDA data v. published data. The FDA review showed that five trials were conducted, only one of which (20%) was positive. Of the four not-positive trials, two were published conveying a positive outcome; the other two were not published. Thus, according to the published literature, three trials were conducted and all (100%) were positive. Alprazolam's effect size calculated using FDA data was 0.33 (CI95% 0.07-0.60) v. 0.47 (CI95% 0.30-0.65) using published data, an increase of 0.14, or 42%. Publication bias substantially inflates the apparent efficacy of alprazolam XR.

Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis.

Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S. Food and Drug Administration (FDA). These findings were augmented with data from peer reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized following PRISMA guidelines. Meta-analysis was conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biologic were identified. Safety data including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00) across STPs, respectively. Immunogenicity data showed similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biologic and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients. This first systematic review using statistical methods to address the risk of switching patients between reference biologics and biosimilars finds no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or a biosimilar.

SURF: A Screening tool (for sponsors) to evaluate whether Using real-world data to support an effectiveness claim in an FDA application has Regulatory Feasibility.

Based on recent guidance and publicly available approvals, FDA has demonstrated its openness to considering evidence of effectiveness from real-world data (RWD) and non-randomized studies (or "real-world evidence (RWE)") in its decision-making. Through analysis of FDA approvals, several authors have identified methodologic issues commonly discussed by FDA reviewers. However, in our analysis of FDA guidance and use cases, acceptability of RWE also critically depends on whether the characteristics of the clinical development program align with circumstances in which FDA may have flexibility in considering evidence from real-world (RW) study designs relative to more robust designs. Successful use of RWD requires advance planning to allocate the necessary resources and time to undertake principled epidemiology approaches to study design, data selection, and implementation of analyses as well as address regulatory feedback. Thus, sponsors benefit from early identification of programs in which successful RWD use is more likely, to ensure efficient use of resources required for the next steps of scientific feasibility assessment. We developed SURF, a screening tool intended to help a sponsor decide whether to prioritize resources for further exploring the feasibility of using an RWD approach to meet FDA's effectiveness evidentiary standards for a particular clinical development program. Here we provide an analysis of FDA guidance, highlighting the circumstances in which RWD approaches may be most acceptable, and demonstrate the use of this screening tool, including the rationale for its construction, types of evidence needed, and application to publicly available approvals as support of concept.

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers.

Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)-approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions.

US Food and Drug Administration Approval Summary: Nivolumab Plus Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With Resectable Non-Small-Cell Lung Cancer.

On March 4, 2022, the US Food and Drug Administration (FDA) approved nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non-small-cell lung cancer (NSCLC). We discuss the FDA's review of the key data and regulatory considerations supporting this approval. The approval was based on the results of CheckMate 816, an international, multiregional, active-controlled trial that randomly assigned 358 patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American Joint Committee on Cancer seventh staging edition to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. The major efficacy end point that supported this approval was event-free survival (EFS). At the first planned interim analysis (IA), the hazard ratio (HR) for EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary = .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6 months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the time of a prespecified IA for overall survival (OS), 26% of patients had died, and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical significance boundary = .0033). Eighty-three percent of patients in the nivolumab-containing arm versus 75% in the chemotherapy-only arm received definitive surgery. This approval, the first for any regimen for the neoadjuvant treatment of NSCLC in the United States, was supported by a statistically significant and clinically meaningful improvement in EFS with no evidence of detriment in OS or negative impact on patients' receipt and timing of surgery or surgical outcomes.

Analysis of patient-reported outcomes in the approval of novel oncology drugs in the United States, 2017–2022

With the growing notion of patient-focused drug development, the quality of life and other patient-reported outcomes (PROs) of cancer patients are gaining considerable attention. Several drug regulatory agencies, including the U.S. Food and Drug Administration (FDA), are calling attention to PROs. This review aims to comprehensively characterise the application of PROs and regulatory considerations for PROs in the FDA-approved novel oncology drugs. The FDA review documents and labels for novel oncology drugs approved from July 2017 to July 2022 were retrieved. We collected and analysed drug approval information, types of endpoints for PROs, PRO measures, designs of trials including PROs, and regulatory comments on PRO-related contents. Results demonstrated that PROs were used more commonly for solid tumours than hematologic malignancies, which might be correlated with the disease characteristics. We further categorised and analysed existing PRO measures, providing insight for tool selection in future oncology trial design. Our findings also indicated that PROs currently do not play a significant role in oncology drug approvals. The major deficiencies related to PROs commented on by FDA reviewers were analysed, followed by recommendations for improvements. This review demonstrates that PROs currently do not play a significant role in oncology drug marketing review, and how they can be used to support the approval of new oncology drugs is still in the exploratory stage. This current situation is not only related to the deficiencies in the design and implementation of PRO-related contents in oncology trials, but more importantly, it is a reminder that we should pay more attention to patient experience in the development of oncology drugs. This study was not supported by any funding.

Progressive Multifocal Leukoencephalopathy (PML) With Anti-CD20 and Other Monoclonal Antibody (mAb) Therapies in Multiple Sclerosis (P8-3.016)

<h3>Objective:</h3> To review the incidence of progressive multifocal leukoencephalopathy (PML) associated with monoclonal antibody (mAb) therapies, specifically anti-CD20 medications used in multiple sclerosis (MS). <h3>Background:</h3> PML is an opportunistic and fatal inflammatory disease of the central nervous system, which occurs almost exclusively in immunocompromised hosts; therefore, patients receiving mAb immunotherapy become an at-risk population. B cell-depleting mAbs targeting CD20+ cells have become widely used in MS. Although their efficacy is well-known, their associated risk of PML, especially among those without previous disease-modifying therapy (DMT) exposure, has been insufficiently studied. <h3>Design/Methods:</h3> A systematic literature review of PubMed, Google Scholar, EMBASE, and Scopus was conducted by two independent researchers from June 1, 1997, to July 10, 2022. Further data was obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and individual pharmaceutical companies (Genentech, Novartis, and TG Therapeutics). Carryover cases from prior exposure to other immunosuppressants were excluded. <h3>Results:</h3> Between 2015 and 2017, 10 cases of PML were reported in the FAERS database among 334 MS patients taking rituximab; two had previously received natalizumab, leaving eight cases in total. Rituximab-associated PML was also seen in lymphoproliferative disorders (n=52), rheumatoid arthritis (n=9), and granulomatosis with polyangiitis (n=2). Two fatal PML cases were found in MS patients taking ocrelizumab. No cases of PML were reported with ofatumumab in MS; however, 5 cases were reported in chronic lymphocytic leukemia. PML has not been observed with ublituximab, which is currently under FDA review. Among other DMTs, PML was frequently reported with natalizumab (n=884), fingolimod (n=30), dimethyl fumarate (n=12), and alemtuzumab (n=1). <h3>Conclusions:</h3> Anti-CD20 therapies are a safe class of medications with a low infectious risk for PML, especially compared to other mAbs used in MS, such as natalizumab. Nonetheless, risk stratification in susceptible individuals, as done with natalizumab, could prove beneficial with all mAb treatments. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. JENA has nothing to disclose. Dr. Kakara has nothing to disclose. Dr. Sriwastava has nothing to disclose. Maha Daimee has nothing to disclose. Dr. Xu has nothing to disclose.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

An insider's perspective on FDA approval of aducanumab.

Aducanumab was approved in 2021 by the US Food and Drug Administration (FDA) under the accelerated approval pathway. Since then, there have been many misconceptions about the approval decision despite multiple publications from the FDA to explain the rationale. Even though the FDA's final decision was accelerated approval, the Office of Clinical Pharmacology recommended regular/full approval based on its own analyses. Exposure-response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for amyloid beta and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint change across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective. Positive exposure-response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure-amyloid reduction relationship was established. Consistent amyloid reduction-clinical endpoint change relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely unlikely we would observe the overall positive findings in the aducanumab program. These results provided convincing evidence to support aducanumab's effectiveness. In addition, the observed effect size in the studied patient population represents a clinically meaningful benefit given the magnitude of disease progression within the trial duration. Totality of evidence supports the Food and Drug Administration (FDA)'s approval decision for aducanumab.Different opinions were clearly explained in the FDA's public reviews from different disciplines.Readers are encouraged to read the FDA's reviews to understand the FDA's rationale to approve aducanumab.

US Food and Drug Administration regulatory reviewer disagreements and postmarket safety actions among new therapeutics

ObjectivesTo examine the association between regulatory reviewer disagreements and postmarket safety actions among novel therapeutics approved by the US Food and Drug Administration (FDA) between 2011 and 2015. Disagreements among...

Med Check: No Accelerated Pathway for Donanemab and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: No Accelerated Pathway for Donanemab and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:24 Feb 2023https://doi.org/10.1176/appi.pn.2023.03.3.2FDA Declines Accelerated Approval for DonanemabThe U.S. Food and Drug Administration (FDA) has declined to accept Eli Lilly’s Alzheimer’s biologic donanemab into the accelerated approval pathway, the company announced in January. Donanemab is a monoclonal antibody that targets beta amyloid buildup in the brain, which is thought to contribute to Alzheimer’s disease.In its complete response letter to the accelerated approval application, the FDA specifically requested that Eli Lilly provide data from at least 100 patients who received a minimum of 12 months of continued treatment on donanemab.The FDA had previously granted Breakthrough Therapy designation for donanemab based on the results of a phase 2 clinical trial called TRAILBLAZER-ALZ that evaluated the safety and efficacy of donanemab in patients with Alzheimer’s disease. In the trial, 257 patients with early symptomatic Alzheimer’s disease received either donanemab or placebo intravenously every four weeks for up to 72 weeks. Compared with those who received placebo, those who received donanemab experienced less cognitive and functional decline over the course of the trial, as measured by the change from baseline on the Integrated Alzheimer’s Disease Rating Scale.Although the TRAILBLAZER-ALZ trial included more than 100 patients treated with donanemab, due to the speed of plaque reduction, many patients were able to stop dosing as early as six months of treatment, resulting in fewer than 100 patients receiving 12 months of donanemab. FDA Reviews Nasal Nalmefene for Treating Opioid OverdoseThe FDA has accepted for Priority Review a New Drug Application (NDA) for OPNT003 (nasal nalmefene) for the treatment of opioid overdose, Opiant Pharmaceuticals announced in January. Priority Review is granted to therapies that the FDA determines have the potential to provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. OPNT003 was previously granted Breakthrough Therapy designation when a confirmatory pharmacokinetic study comparing a 3 mg spray of the drug with a 1 mg intramuscular nalmefene hydrochloride injection in 68 healthy patients revealed that OPNT003 achieved higher plasma concentrations compared with the intramuscular injection.The NDA also included data from a second study that found similar plasma concentrations of OPNT003 whether the treatment was administered as a single dose in each nostril or as two doses in a single nostril. A third study found the drug to be noninferior to intranasal naloxone and found that nasal nalmefene produced a greater reversal of remifentanil-induced respiratory depression that was nearly twice that produced by nasal naloxone at five minutes. Brexpiprazole Gets Priority Review for Treating Alzheimer’s Agitation In January Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S announced that the FDA has granted Priority Review for its supplemental NDA (sNDA) for brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia.The sNDA submission includes data from two positive clinical phase 3 studies that investigated the treatment of brexpiprazole in patients with agitation related to Alzheimer’s dementia. In Study 331-12-283, 433 patients with agitation associated with Alzheimer’s took either 1 or 2 mg of brexpiprazole or placebo daily for 12 weeks. Those who took 2 mg of brexpiprazole had greater improvements in their Cohen-Mansfield Agitation Inventory (CMAI) Total Score from baseline to week 12 compared with placebo. In Study 331-14-213, which included 345 patients, patients were randomized to either 2 or 3 mg of brexpiprazole or placebo daily for 2 weeks. Those who took either dose of brexpiprazole had greater improvements in their CMAI Total Score from baseline to week 12 compared with placebo. ■ ISSUES NewArchived

Med Check: Lecanemab; ANEB-001; Azstarys; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Lecanemab; ANEB-001; Azstarys; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:27 Oct 2022https://doi.org/10.1176/appi.pn.2022.11.11.2Lecanemab May Slow Decline in Alzheimer’sLecanemab, an investigational anti-amyloid beta protofibril antibody, may slow cognitive decline in Alzheimer’s disease, Biogen Inc. and Esai Co. Ltd. announced in September. Lecanemab is being developed for the treatment of mild cognitive impairment from Alzheimer’s disease and mild or early Alzheimer’s disease with confirmed presence of amyloid pathology in the brain.In the phase 3 Clarity AD trial, 1,795 patients with early Alzheimer’s disease were randomized to receive either placebo or biweekly doses of 10 mg of lecanemab per kilogram of body weight. The primary endpoint was reduced clinical decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At the end of 18 months, CDR-SB scores had declined by 27% less in patients who received lecanemab compared with those who received placebo. The CDR-SB scores were a mean 0.45 points lower for those who received lecanemab compared with those who received placebo.Last year the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to lecanemab based on the results of a phase 2b clinical trial, which examined the impact of treatment with lecanemab on reducing amyloid beta and clinical decline, as measured by changes on the Alzheimer’s Disease Composite Score (ADCOMS). Breakthrough Therapy designation expedites the development and review of drugs for serious conditions.In the trial, 856 patients who had mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia were randomized to receive 2.5 mg/kg, 5 mg/kg, or 10 mg/kg of lecanemab once every two weeks; 5 mg/kg or 10 mg/kg of lecanemab once every four weeks; or placebo for 18 months. Patients who took 10 mg/kg biweekly lecanemab had a 76% probability of achieving 25% less decline on ADCOMS compared with those who took placebo. ANEB-001 May Reverse Cannabinoid IntoxicationA phase 2 trial of the investigational cannabinoid receptor agonist ANEB-001 suggests that the medication may reverse cannabinoid intoxication, Anebulo Pharmaceuticals Inc. announced in September.The trial involved approximately 60 participants, who were given 21 mg of delta-9-tetrahydrocannabinol (THC). They were then given 10 mg of ANEB-001, 30 mg of ANEB-001, or placebo.Those who received placebo reported a substantial increase in feeling high and body sway, decreased alertness, and a slightly increased heart rate from baseline. Participants who received either 10 mg or 30 mg of ANEB-001 experienced significant reductions in the visual analog scale (VAS) score for feeling high, improvement in the VAS alertness scale, and a reduction in THC-induced body sway compared with those who received placebo. Azstarys May Improve Sleep for Children with ADHDAzstarys (serdexmethylphenidate and dexmethylphenidate) may help improve sleep in children with attention-deficit/hyperactivity disorder (ADHD), Corium Inc. announced in September. Azstarys is approved for the treatment of ADHD in patients aged six years and older.In a one-year open-label study, 238 children with ADHD aged six to 12 years received Aztarys for one year. After one month of treatment with Azstarys, the children’s total average sleep disturbance score on the Children’s Sleep Habits Questionnaire (CSHQ) decreased significantly from a mean of 53.4 points to 50.5 points. Furthermore their total mean CSHQ scores remained between 48.9 to 50.1 points for up to 12 months, indicating that the improvements in their sleep were sustained.The results of the study were presented in a poster at the Psych Congress 2022 in New Orleans. FDA Reviews Two-Month Aripiprazole Injection for SchizophreniaIn September, Otsuka America Pharmaceutical Inc. and H. Lundbeck A/S announced that the FDA has accepted for review a New Drug Application (NDA) for aripiprazole two-month, long-acting injectable for the treatment of schizophrenia in adults and for maintenance monotherapy of bipolar I disorder in adults. The NDA is for a formulation designed to be administered via intramuscular injection in the gluteal muscle.The NDA is based on data from a clinical trial involving 266 patients who were randomized to receive either four 920 mg injections of aripiprazole two-month long-acting injectable or eight 400 mg injections of aripiprazole one-month depot. Plasma concentrations of aripiprazole were similar between both groups of patients, and the two-month injectable was well-tolerated and showed no safety concerns compared with the once-monthly injectable. ■ ISSUES NewArchived

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

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

Single-patient expanded access: A primer for pharmacists.

The process of providing treatment with investigational drugs through expanded access is explained. Roles and informational resources for pharmacists are discussed. Expanded access is a regulatory pathway for the treatment of serious or life-threatening diseases or conditions with investigational agents outside of clinical trials. In the setting of no available therapies or ineligibility for clinical trials, a patient and their treating physician may pursue therapies that are not approved by the Food and Drug Administration (FDA). The drug manufacturer, FDA, and institutional review boards are required stakeholders in the expanded access process. Other pathways for obtaining investigational agents outside of clinical trials, including federal Right to Try and emergency use authorization, exist but differ in their level of involvement of these key stakeholders. Pharmacists are equipped to be involved in therapy identification, risk vs benefit evaluations, therapy preparation and administration, supportive care, transitions of care, and regulatory compliance. Specific websites, publications, and organizations can aid in navigating expanded access. Combining elements of traditional clinical care and research, expanded access involves direct treatment with non-FDA-approved agents outside of a clinical trial. Healthcare providers should be aware of the possibility of providing investigational treatments after all approved options have been exhausted.

The road to the first FDA-approved genetically engineered pig heart transplantation into human.

We have been testing genetically engineered (GE) pig hearts and optimizing immunosuppression (IS) in non-human primates (NHPs) since 2005. We demonstrate how we translated this preclinical investigation into a US Food and Drug Administration (FDA)-approved clinical cardiac xenotransplantation. First, genetically engineered (GE) pig hearts were transplanted into the abdomen of NHP along with IS, which included anti-CD20 and anti-CD40-based co-stimulation blockade antibodies. We reported 945 days of survival of three gene GE pig hearts in NHPs. Building on this proof-of-concept, we tested 3-10 gene-modified GE pig hearts (in order to improve the immunocompatibility of the xenograft further) in a life-supporting orthotopic model, but had limited success due to perioperative cardiac xenograft dysfunction (PCXD). With novel non-ischemic continuous perfusion preservation (NICP), using the XVIVO Heart solution (XHS), life-supporting survival was extended to 9 months. We approached the FDA under an application for "Expanded Access" (EA), to transplant a GE pig heart in a patient with end-stage non-ischemic cardiomyopathy. He was without other therapeutic options and dependent on VA-ECMO. A team of FDA reviewers reviewed our preclinical research experience and data and allowed us to proceed. This clinical cardiac xenotransplantation was performed, and the patient survived for 60 days, demonstrating the translational preclinical investigation of cardiac xenotransplantation from bench to bedside. The ultimate etiology of graft failure is currently a topic of investigation and lessons learned will progress the field forward.