Investigation of Factors Associated With Immunogenicity Labeling Updates and Characteristics of Biologics License Applications.

Immunogenicity, the potential to elicit an antidrug immune response, is a critical concern in developing biological products, but its consequences are difficult to predict with animal studies. The aims of the present study are to investigate the evolution of immunogenicity information in labeling and to identify attributes associated with immunogenicity labeling updates. Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research, US Food and Drug Administration between 2008 and 2017 were studied. A majority of BLAs described the incidence/prevalence of antidrug antibodies (ADAs) (94.9%) and neutralizing antibodies (NAbs) (68.4%) in their original labeling documents. However, less than one third of the BLAs mentioned the impact of ADAs/NAbs in the original (20.3%) and most recent (29.1%) labeling documents. BLAs with a priority review status (57.4% vs. 33.3%), orphan designation (61.5% vs. 34.2%), or a mention of ADA impact in the latest label (69.6% vs. 38.9%) had higher percentages of applications with postmarketing requirements (PMRs) directly related to immunogenicity concerns in comparison with applications without those characteristics. Among the BLAs with updated immunogenicity information, the mean time to the first update was 1,077 days, while that for BLAs with accelerated approval was shorter (709.1 ± 492.2 days vs. 1173.8 ± 661.8 days). The results suggest that there is a substantial amount of critical information lacking in the original labeling documents and an overdependence on PMRs for more evidence. Additional efforts should be made to investigate the impact of ADAs to provide timely information for improved patient care.

A Multifaceted Perspective of Pharmaceutical Innovation: A Consideration of the Regulatory Role.

BACKGROUND: The pace of innovation, the creative engine of the pharmaceutical industry, has been variably described as stagnant, stable, or accelerating depending on the metric used for assessment or the quality of evidence. If the predominant perception holds that the speed of innovation is sluggish, pressure for changes in the regulatory environment intensifies. METHODS: A systematic evaluation of the course of innovation in this industry was performed by applying a formula derived from economic market share theory to estimate the innovative contribution of each new molecular entity approved since 1938. The total and average innovation scores per year are described based on the therapeutic class, mechanism, and drug target. These data are compared to the number and percent of first-in-class drugs per year. RESULTS: The average annual score based on therapeutic class novelty has been declining; however, the therapeutic class total innovation score has been stable since the mid-1970s with occasional significant peaks of activity. While the average score based on mechanism or target experienced a decline beginning in the 1950s and 1960s, it has begun to rise since the early 1990s. Notably, the total innovation score has steadily increased since the 1970s. These variations closely parallel the number of first-in-class drugs approved on an annual basis. CONCLUSIONS: While the reasons underlying these activities are likely complex, there is a temporal association between regulatory efforts to expedite drug development and approval. These findings should be considered when considering future incentivizing regulations and policies.

Correlates of time to approval and other clinical development periods.

The drug development cycle is classically divided into a clinical phase and review phase, with the clinical phase typically being further partitioned based on the planning and conduct of adequate and well controlled trials. Factors affecting the duration of the development intervals have not previously been systematically investigated. Here, we analyze a large population (N=825) of New Drug Applications (NDAs) approved between 2008 and 2017 to characterize the typical duration of these intervals and the development factors associated with their duration. These data and analyses will help those involved in pharmaceutical development by enabling data-driven planning and by providing insight into the effect of certain factors on the duration of drug development programs.

Identification of factors associated with first-cycle drug approval rates and regulatory outcomes for new drug applications.

The aims of this study were to identify types of deficiencies resulting in delay of approvals for drugs eventually approved by the US FDA and to search for factors associated with higher first-cycle approval rates. Review documents of New Drug Applications approved between 2008 and 2017 were retrieved from the Drugs@FDA database. Basic characteristics of the applications, regulatory actions, and reasons for non-approvals and/or major amendments after first review cycle were investigated. Of 825 applications studied, 446 (54.1%) applications received first-cycle approvals without a review extension resulting from a major amendment. Non-approvals (240, 29.1%) were based primarily on chemistry/manufacturing/controls and safety reasons. A higher first-cycle approval rate was associated with factors related to unmet medical needs or innovative development. The association between higher first-cycle approval rates and innovative drugs or those addressing unmet needs reveals the FDA's commitment in advancing innovation and protecting public health.

Clinical Development of Biologics Approved by the US Food and Drug Administration, 2003-2016.

BACKGROUND: Biological therapies are increasingly common in the United States. Although their clinical development may deviate significantly from the classic paradigm used for small molecule drugs, there has been little systematic analysis of these programs. We describe the development programs and factors associated with approval in the first review cycle for biologics approved by the US Food and Drug Administration's Center for Drug Evaluation and Research (FDA CDER) between 2003 and 2016. METHODS: We conducted a retrospective analysis of publicly available approval packages including clinical pharmacology/biopharmaceutics, medical and summary reviews, and approval letters for biologics approved by FDA CDER. We evaluated characteristics of the development program (eg, use of expedited pathways, clinical pharmacology studies, number and type of pivotal trials) and the prevalence and correlates of first cycle approval, a key indicator of successful product development. RESULTS: We assessed 81 development programs for 75 unique therapies. Most programs (67%) made use of at least 1 expedited designation and about half (49%) were designated as orphan products. The clinical pharmacology programs were highly variable and one in four (25%) did not include an ascending dose study, where the tolerability of the therapeutic is typically determined before pivotal trials. Since 2003, an increasing proportion of biologics have been approved on first cycle approval and with fewer than 2 pivotal clinical trials (P < .001 for trend). Of the approximately three-fourths (76%) of products that were approved on the first review cycle, the likelihood of such approval was greater among development programs that performed an ascending dose study (84% vs 55%, P = .01) or held an End of Phase 2 meeting (85% vs 57%, P = .01). CONCLUSION: Considerable regulatory flexibility, with respect to the number of pivotal trials and data supporting dosing, coincides with a growing number of biologics approved on an annual basis.

A Critical Evaluation of Safety Signal Analysis Using Algorithmic Standardised MedDRA Queries.

INTRODUCTION: Algorithmic Standardised MedDRA® Queries (aSMQs) are increasingly used to enhance the efficiency of safety signal detection. The manner that aSMQs affect capture of potential safety cases is unclear. OBJECTIVES: Our objective was to characterise the performance of aSMQs with respect to their potential for double counting, the likelihood of events in aSMQ positive cases being clinically related, how frequently terms are used for algorithmically positive cases, and the face validity of positive cases based on the drug inducing events. We were also interested in what effect requiring symptoms to overlap temporally would have on performance. METHODS: We reviewed adverse event (AE) datasets of New Drug Applications and Biological License Applications and compiled a database including preferred terms and corresponding SMQs, SMQ term categories, AE start day, AE duration, drug name, and Anatomical Therapeutic Chemical class. Two reviewers independently determined if the algorithm was met and, if so, whether the broad terms overlapped temporally. RESULTS: A total of 107 marketing applications were reviewed, including 103,928 patients and 277,430 AEs. Use of algorithms condensed the number of AEs to between 5 and 8% and the incidence to about 1.5% relative to when the SMQs are used without the algorithm. Certain aSMQs exhibited a potential for overcounting. Requiring symptoms to temporally overlap helped to eliminate irrelevant cases. CONCLUSIONS: Our findings demonstrate that algorithmic and temporal assessment increased specificity of case retrieval, though the reduction in the number of terms or incidence seemed excessive for certain aSMQs. Evaluating the day of AE onset and duration improve specificity through identification of outlying events. Identification of drug classes known to cause the aSMQ's clinical condition provides face validity for this tool, yet detection of cases associated with novel classes may provide new understanding of these disorders. Improvements in some of the SMQ term lists may improve the performance of SMQs in general.

Informative graphing of continuous safety variables relative to normal reference limits.

BACKGROUND: Interpreting graphs of continuous safety variables can be complicated because differences in age, gender, and testing site methodologies data may give rise to multiple reference limits. Furthermore, data below the lower limit of normal are compressed relative to those points above the upper limit of normal. The objective of this study is to develop a graphing technique that addresses these issues and is visually intuitive. METHODS: A mock dataset with multiple reference ranges is initially used to develop the graphing technique. Formulas are developed for conditions where data are above the upper limit of normal, normal, below the lower limit of normal, and below the lower limit of normal when the data value equals zero. After the formulae are developed, an anonymized dataset from an actual set of trials for an approved drug is evaluated comparing the technique developed in this study to standard graphical methods. RESULTS: Formulas are derived for the novel graphing method based on multiples of the normal limits. The formula for values scaled between the upper and lower limits of normal is a novel application of a readily available scaling formula. The formula for the lower limit of normal is novel and addresses the issue of this value potentially being indeterminate when the result to be scaled as a multiple is zero. CONCLUSIONS: The formulae and graphing method described in this study provides a visually intuitive method to graph continuous safety data including laboratory values, vital sign data.

Exposure- and Dose-response Analyses in Dose Selection and Labeling of FDA-approved Biologics.

PURPOSE: Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure-response and dose-response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016. METHODS: We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure-response/dose-response analyses. We also examined how exposure-response/dose-response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization. FINDINGS: A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose-response relationship. In support of doses that were described in labeling, exposure-response analyses for efficacy were performed more commonly (53%) than dose-response analyses (21%). This trend was apparent after 2012. IMPLICATIONS: This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose-response analyses have been often used as the rationale for dose selection of registrational studies, although exposure-response analyses are becoming more prevalent in support of the dosing guidelines in labeling.

Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications.

PURPOSE: Standardised MedDRA Queries (SMQs) have been developed since the early 2000's and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). METHODS: We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. RESULTS: A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with "narrow terms" to enhance specificity over strategies using "broad terms" to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process. CONCLUSIONS: SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions.

What's the Regulatory Value of a Target Product Profile?

Target product profiles (TPPs) are used as a regulatory tool for dialog on clinical development or manufacturing plans. Drugs and biologics approved by the FDA that mention TPPs are associated with more efficient regulatory review times, perhaps as a result of increased planning or because the TPP promotes well-organized regulatory dialog.

A Method for Retrieval of Adverse Event Terms in Clinical Trial Databases Using Standardised MedDRA Queries.

BACKGROUND: Standardized MedDRA Queries (SMQs) are sets of terms determined by experts that are used to identify adverse events (AEs) related to different disease processes. Their use can be challenging because most SMQs have 50 to 100 preferred terms and AE databases can have many thousands of events. AIM: The aim of this study is to develop a technique where AEs corresponding to preferred terms in SMQs may be easily detected. METHODOLOGY: The method I developed uses the Table Join function of the JMP® software program to quickly and easily probe clinical trial AE databases. The SMQ Severe cutaneous adverse reactions was used as a probe in a mock AE dataset. Potentially confounding demographic or study-specific factors were evaluated by combining these datasets with the dataset containing the AEs identified with the SMQs. RESULTS: AEs were successfully detected in an AE database using the method described. Cases with potential confounding factors, such as concomitant medications, were identified. CONCLUSIONS: The method developed allows for AEs to be found in clinical trial databases and evaluated using software programs that are readily available to clinical researchers.

A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease.

OBJECTIVE: To evaluate the efficacy and safety of aripiprazole treatment for psychotic symptoms associated with Alzheimer disease (AD). METHODS: In this parallel group, randomized, double-blind, placebo-controlled, flexible-dose trial, institutionalized subjects with AD and psychotic symptoms were randomized to aripiprazole (n = 131) or placebo (n = 125) for 10 weeks. The aripiprazole starting dose was 2 mg/day, and could be titrated to higher doses (5, 10, and 15 mg/day) based on efficacy and tolerability. RESULTS: No significant differences in mean change [2 x SD] from baseline between aripiprazole (mean dose approximately 9 mg/day at endpoint; range = 0.7-15.0 mg) and placebo were detected in the coprimary efficacy endpoints of Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Psychosis score (aripiprazole, -4.53 [9.23]; placebo, -4.62 [9.56]; F = 0.02, df = 1, 222, p = 0.883 [ANCOVA]) and Clinical Global Impression (CGI)-Severity score (aripiprazole, -0.57 [1.63]; placebo, -0.43 [1.65]; F = 1.67, df = 1, 220, p = 0.198 [ANCOVA]) at endpoint. However, improvements in several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI - improvement, Cohen-Mansfield Agitation Inventory and Cornell Depression Scale scores) indicated that aripiprazole may confer clinical benefits beyond the primary outcome measures. Treatment-emergent adverse events (AEs) were similar in both groups, except for somnolence (aripiprazole, 14%; placebo, 4%). Somnolence with aripiprazole was of mild or moderate intensity, and not associated with accidental injury. Incidence of AEs related to extrapyramidal symptoms was low with aripiprazole (5%) and placebo (4%). CONCLUSIONS: In nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs.

A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine.

OBJECTIVE: Major mental disorders are associated with an increased risk for obesity-related cardiovascular mortality, leading to interest in risk-reduction approaches that target weight and risk-related plasma lipids, including use of antipsychotic agents with low metabolic risk. This multicenter, randomized, double-blind study compared the metabolic effects of aripiprazole versus olanzapine in overweight persons with schizophrenia or schizoaffective disorder who were previously on olanzapine treatment. METHOD: In total, 173 subjects with DSM-IV-TR-defined schizophrenia or schizoaffective disorder were randomly assigned to receive aripiprazole (N = 88) or olanzapine (N = 85) for 16 weeks in a study conducted from March 30, 2004, to August 8, 2006. Primary and secondary endpoints were mean weight change from baseline and percentage change from baseline in fasting triglyceride levels, respectively. RESULTS: At week 16, weight decreased significantly with aripiprazole versus olanzapine (-1.8 vs. +1.41 kg; p < .001). Significant differences in percentage change in triglyceride levels were observed with aripiprazole (decreases) versus olanzapine (increases) at all time-points. In addition, significantly more subjects receiving aripiprazole had clinically relevant (> or = 7%) weight loss versus olanzapine (11.1% vs. 2.6%; p = .038), and a lower percentage of subjects receiving aripiprazole had clinically relevant weight gain (2.5% vs. 9.1%; p = .082). Mean percentage changes in fasting total cholesterol and high-density lipoprotein cholesterol at week 16 were significantly different with aripiprazole versus olanzapine, with no significant effects on glycemic laboratory measures. Mean Clinical Global Impressions-Improvement (CGI-I) scores for both groups were in the range of "no change" to "minimal improvement." CGI-I endpoint scores were statistically significantly better with olanzapine (mean +/- SE = 3.09 +/- 0.16) versus aripiprazole (mean +/- SE = 3.74 +/- 0.15; p < .001), and more subjects discontinued aripiprazole (N = 32/88; 36%) than olanzapine (N = 22/85; 26%). CONCLUSION: Significant improvements in weight and lipids observed during discontinuation of olanzapine and switch to aripiprazole treatment occurred with limited evidence of negative psychiatric effects, relative to uninterrupted continuation of olanzapine treatment. The results suggest that the potential value of therapeutic substitutions involving specific antipsychotic medications should be considered in overall efforts to reduce cardiovascular risk in this population.

A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence.

The purpose of this study was to compare the efficacy and safety of aripiprazole with placebo in the treatment of alcoholics. In this 12-week multicenter, double-blind study, 295 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence were randomized to treatment with aripiprazole (initiated at 2 mg/d, titrated to a maximum dose of 30 mg/d at day 28) or placebo after screening, wherein patients maintained alcohol abstinence for 3 days or more. The primary efficacy measure was the percentage of days abstinent over 12 weeks. Discontinuations (40.3% vs 26.7%) and treatment-related adverse events (82.8% vs 63.6%) were higher with aripiprazole than with placebo. Mean percentage of days abstinent was similar between aripiprazole and placebo (58.7% vs 63.3%; P = 0.227). Percentage of subjects without a heavy drinking day and the time to first drinking day were also comparable between groups, although the aripiprazole group had fewer drinks per drinking day (4.4 vs 5.5 drinks; P < 0.001). The aripiprazole group showed a larger decrease in percent carbohydrate-deficient transferrin, a biomarker of heavy alcohol consumption at weeks 4 (-14.91% vs -2.23%; P = 0.020) and 8 (-16.92% vs -5.33%; P = 0.021), although not at week 12 (-9.06% vs -4.12%; P = 0.298). At study end point, aripiprazole-treated subjects reported more positive subjective treatment effects and less overall severity of alcohol dependence than placebo-treated subjects. Although there was no difference between aripiprazole and placebo on the primary end point, possibly because of dose-related attrition, effects on the secondary outcomes suggest that further study of aripiprazole for treatment of alcohol dependence may be warranted at lower doses.

Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses.

OBJECTIVE: To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD). METHODS: In this double-blind, multicenter study, 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version Psychosis Subscale score. Secondary measures included NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores. RESULTS: Aripiprazole 10 mg/day showed significantly greater improvements (mean change [2 x SD]) than placebo on the NPI-NH Psychosis Subscale (-6.87 [8.6] versus -5.13 [10.0]; F = 6.29, df = 1, 422, p = 0.013 by analysis of covariance [ANCOVA]); CGI-S (-0.72 [1.8] versus -0.46 [1.6]; F = 4.68, df = 1, 419, p = 0.031 [ANCOVA]); BPRS Total (-7.12 [18.4] versus -4.17 [21.6]; F = 4.72, df = 1, 399, p = 0.030 [ANCOVA]); BPRS Core (-3.07 [6.9] versus -1.74 [7.8]; F = 7.30, df = 1, 407, p = 0.007 [ANCOVA]); CMAI (-10.96 [22.6] versus -6.64 [28.6]; F = 5.23, df = 1, 410, p = 0.023 [ANCOVA]), and NPI-NH Psychosis response rate (65 versus 50%; chi(2) = 5.52, df = 1, p = 0.019 [CMH]). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and CMAI scores. Aripiprazole 2 mg/day was not efficacious. Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. No deaths in any group (aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%) were considered to be treatment-related. CONCLUSION: Aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression. However, clinicians should be aware of the safety considerations of atypical antipsychotic uses in this population.

Aripiprazole for the treatment of psychosis in patients with Alzheimer's disease: a randomized, placebo-controlled study.

This study compared the efficacy, safety, and tolerability of aripiprazole, a novel antipsychotic, with placebo in patients with psychosis associated with Alzheimer's Disease (AD). This 10-week, double-blind, multicenter study randomized 208 outpatients (mean age, 81.5 years) with AD-associated psychosis to aripiprazole (n = 106) or placebo (n = 102). The initial aripiprazole dose of 2 mg/d was titrated upwards (5, 10, or 15 mg/d) according to efficacy and tolerability. Evaluations included Neuropsychiatric Inventory (NPI) Psychosis subscale and Brief Psychiatric Rating Scale (BPRS), adverse event (AE) reports, extrapyramidal symptoms (EPS) rating scales, and body weight. Overall, 172 patients (83%) completed the study. Mean aripiprazole dose at end point was 10.0 mg/d. The NPI Psychosis subscale score showed improvements in both groups (aripiprazole, -6.55; placebo, -5.52; P = 0.17 at end point). Aripiprazole-treated patients showed significantly greater improvements from baseline in BPRS Psychosis and BPRS Core subscale scores at end point compared with placebo. AEs were generally mild to moderate in severity and included (aripiprazole vs. placebo): urinary tract infection (8% vs. 12%), accidental injury (8% vs. 5%), somnolence (8% vs. 1%), and bronchitis (6% vs. 3%). Somnolence was mild and not associated with falls or accidental injury. There were no significant differences from placebo in EPS scores, or clinically significant ECG abnormalities, vital signs, or weight. In conclusion, aripiprazole showed similar improvements to placebo in psychotic symptoms as assessed by NPI Psychosis subscale scores, but significantly greater effects on BPRS Core and Psychosis assessments in community-living AD patients with psychosis. Aripiprazole was safe and well tolerated in this patient population.