New Drug Application Research Articles

A Decade of Marketing Authorization Applications of Anticancer Drugs in the European Union: An Analysis of Procedural Timelines

BackgroundCancer is a serious global health problem and a major cause of death. The European Medicines Agency (EMA) has established several regulatory initiatives to expedite the development and authorization of drugs to ensure timely access of patients. In this study, we analyzed the procedural timelines of marketing authorization applications for anticancer drugs in the EU, with a specific focus to special regulatory programs, scientific advice and company size.MethodsAnticancer drugs that received an opinion from the EMA between January 2010 and December 2019 were included in the study. Public assessment reports were used to obtain publicly available information of the drugs.ResultsWe identified 96 applications for new anticancer drugs. 34 applications were granted access to at least one expedited program offered by the EMA. Total procedure time was reduced from average 370 to 200–215 days when accelerated assessment was granted. Granting of a conditional marketing authorization or an orphan designation, as well as having scientific advice, only mildly affected total procedure time. Average total procedure time of small companies was much longer compared with medium-sized and large companies (483 versus 356 days), which was caused by an increased clock stop time.ConclusionTotal procedure time for anticancer is mainly affected by the granting of accelerated assessment, which reduced the total procedure time, and company size, where total procedure time is much longer for small companies. Small companies are advised to have, and especially adhere to scientific advice to reduce procedure time and increase the chance of success.

Heterogeneity of Recent Phase 3 Complicated Urinary Tract Infection Clinical Trials.

BackgroundFor new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed.MethodsThis selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included.ResultsMicrobiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP.ConclusionsA study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics.

Exclude Alternative Causes before Attributing Exacerbation of Myasthenia to COVID-19

Myasthenia gravis (MG) may not only exacerbate by the infection but also by application of new drugs, which could worsen MG, it is crucial to know if any of the included patients received drugs known to deteriorate MG. Drugs commonly given to COVID-19 patients include chloroquine, remdesivir/lopinavir, azithromycin, steroids, tocilizumab, or muscle relaxants and opiates if intubated.

Ailanthus Altissima-derived Ailanthone enhances Gastric Cancer Cell Apoptosis by Inducing the Repression of Base Excision Repair by Downregulating p23 Expression.

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

The antitumor activity of cannabidiol on lung cancer cell lines A549 and H1299: the role of apoptosis

In the recent years, the application of new antitumor drugs has focused on the replacement of conventional chemotherapeutics with compounds derived from natural products. Cannabidiol (CBD) is one of the 113 cannabinoids derived from the plant Cannabis sativa and is characterized with complex and not entirely understood biological function. Unlike the other most abundant cannabinoid in Cannabis sativa – tetrahydrocannabinol, cannabidiol has low affinity to the endocannabinoid receptors and the manifestation of its activity does not appear to rely on the endocannabinoid system. Cannabidiol is used in the treatment of many diseases including some types of cancer. The aim of our study was to evaluate the cytotoxic activity of cannabidiol and its effect on the process of programmed cell death. This process is directly involved in the antitumor effect of many drugs. Two lung cancer cell lines, A549 expressing р53 and H1299-p53 negative, were used. Apoptosis was monitored by Anexin V assay and the activation of Caspase 3/7. We found that CBD treatment led to a dose-dependant apoptosis increase in p53 positive A549 cells. The level of apoptosis in p53 negative H1299 cells was much lower and did not seem to be dose dependent. However, the total cell viability was similar for the two cell lines, which was due to the increased necrosis observed in H1299 cells.

Pharmaceutical Lottery Stocks: Investors’ Reaction to FDA Announcements

We investigate return patterns of lottery-type-stocks around FDA announcements regarding New-Drug-Applications (NDAs), Biological-Licensing-Applications (BLAs), and New-Molecule-Entities (NMEs). Focusing on post-event returns, we document negative abnormal returns (‘bio-run-down’) for the 176 NDAs and BLAs, whether the FDA approved the firms’ applications or not. We document also negative abnormal returns for the 313 NMEs, mainly for small firms. We attribute these results to investors’ desire to participate in the ‘lotteries’ of FDA announcements and lack of interest in the firms’ stocks after the announcements. Employing Bloomberg’s Abnormal-Institutional-Attention (AIA) we suggest abovementioned pricing behavior is due to individual investors, rather than to professionals.

Regulatory compliances in development of commercial scale process of Nanoparticles (Liposomes and Niosomes) in pharmaceutical industry : A review

The main objective of this review work was designed to explore the regulatory environments that govern the pharmaceutical industry. Main objective of regulatory department is to maintain the quality, safety and efficacy of the medical products it also ensures the standard of medicinal product for sales, importing and manufacturing. The biggest challenge faced by the pharma manufactures is Scaling up their production. Our review process focuses on regulatory requirements concerning Liposomes and Niosomes and their limitations in respect to industrial applicability. In detail explanation of what type of information should be submitted to FDA and EU in new drug applications (NDAs) or abbreviated new drug applications (ANDAs). By comparing these two developed regulatory markets we can build a strong regulation in Indian market on Liposomes and Niosomes. The review study deals with the sound knowledge about regulatory landscape that governs the pharmaceutical industry. Study describes in depth about liposomes and niosomes delivery systems and gives a critical overview of the current regulatory landscape surrounding commercialization efforts of higher-level complexity systems, the expected requirements and the hurdles faced by companies seeking to bring novel liposome and noisome based systems for clinical use to market.

68Ga-PSMA-11 NDA Approval: A Novel and Successful Academic Partnership.

The University of California Los Angeles (UCLA) and University of California San Francisco (UCSF) codeveloped 68Ga-PSMA-11 by conducting a bicentric pivotal phase 3 clinical trial for PET imaging for prostate cancer. On December 1, 2020, 2 separate new drug applications (NDAs) submitted by each institution (NDA 212642 for UCLA and NDA 212643 for UCSF) were approved by the Food and Drug Administration as the first drug for PET imaging of prostate-specific membrane antigen (PSMA)–positive lesions in men with prostate cancer. This article briefly describes the background, clinical development, regulatory approach, and regulatory process for NDA filing and approval. In the second part of this article, key chemistry, manufacturing, and controls (CMC) information is provided to facilitate abbreviated new drug application (ANDA) submission.

Verifying Death Reports in the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

Background:Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22–433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor.Study Question:Whether FDA death data in the PLATO trial matched the local site records.Study Design:The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA.Measures and Outcomes:Existence, precise time, and primary cause of deaths in PLATO.Results:Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to “vascular,” whereas 6 NDA ticagrelor “nonvascular” or “unknown” deaths were site-reported as of “vascular” origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint.Conclusions:Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.

Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications.

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.

Med Check: Unapproved, Misbranded Opioids; Treating Adults With ADHD; Improve Cognition in Patients With Schizophrenia

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Unapproved, Misbranded Opioids; Treating Adults With ADHD; Improve Cognition in Patients With SchizophreniaTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:8 Oct 2020https://doi.org/10.1176/appi.pn.2020.10b1FDA Warns Websites Hawking Unapproved, Misbranded OpioidsIn September the U.S. Food and Drug Administration (FDA) sent warning letters to 17 website operators for illegally selling unapproved and misbranded opioids online. Misbranded opioids include those offered for sale without a prescription and opioids that lack adequate directions for use. Tramadol and oxycodone are among the opioids being offered for sale, and several of the websites offer opioids online without a prescription.“Those who illegally sell opioids online put consumers at risk and undermine the significant strides we have made to combat the opioid crisis,” said Donald D. Ashley, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, in a press release.The agency noted in the release that people who buy prescription drugs, including opioids, from illegal online pharmacies may put their health at risk because the products may be counterfeit, contaminated, expired, or otherwise unsafe. The agency added that illegal online pharmacies can also pose other risks to consumers, including credit card fraud, identity theft, and computer viruses.AR19 Shows Promise for Adults With ADHDIn September Arbor Pharmaceuticals LLC announced positive safety and efficacy results from a phase 3 study in adults of AR19, its investigational immediate-release, amphetamine sulfate capsule for the treatment of attention-deficit/hyperactivity disorder (ADHD). The drug is designed to resist manipulation for non-oral use such as snorting, smoking, or injecting and is currently under review by the FDA.In the study, 320 adults aged 18 to 55 years with ADHD were randomized to receive 20 mg of AR19, 40 mg of AR19, or placebo daily for five weeks. Researchers measured improvement according to the Adult ADHD Investigator Symptom Rating Scale. At the fifth week, patients in either group who took AR19 dropped roughly 7 more points on the scale than the placebo group dropped. The most common side effects, which were reported by more than 5% of patients who took AR19, were insomnia, dry mouth, lowered appetite, palpitations, and tachycardia.FDA Receives NDA for Parkinson’s Drug SPN-830Supernus submitted a New Drug Application (NDA) in September for SPN-830, its apomorphine infusion pump for the continuous treatment of on-off episodes in adults with Parkinson’s disease (PD) whose motor control is unsatisfactory with oral levodopa and at least one other noninvasive PD therapy. During off episodes, motor symptoms like stiffness or tremor return even though the patient is taking medication for PD.The company submitted the NDA based on the results of the phase 3 TOLEDO study (conducted in Europe) and an open-label study (conducted in the United States). Both 12-week studies included adults with average daily off episodes that lasted at least three hours. All patients kept diaries of their motor symptoms.In the TOLEDO study, 106 patients received either SPN-830 or placebo. The mean daily off time decreased a mean of 2.47 hours for those in the SPN-830 group compared with a mean decrease of 0.58 hours in the placebo group. In the U.S. study, all 94 patients took SPN-830 and their mean daily off episodes decreased by three hours. Most of the side effects reported by patients were mild or moderate and included problems at the infusion site, nausea, and dyskinesia.BI 425809 May Improve Cognition in Patients with SchizophreniaBoehringer Ingelheim’s investigational compound BI 425809 improved cognition in stable adult patients with schizophrenia in a phase 2 trial, the company announced in September.In the study, patients with schizophrenia in 11 countries were randomized to receive either 2 mg to 25 mg of BI 425809 or placebo daily for 12 weeks. All patients were medically stable with no hospitalization for worsening of schizophrenia in the three months before randomization. They were also psychiatrically stable with no exacerbations in their symptoms in the three months before randomization.At 12 weeks, cognitive function improved in patients who took BI 425809, as measured by the composite Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. This series of tests assesses patients’ speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. There were no differences in psychiatric adverse events or suicidality between groups. ■ ISSUES NewArchived

Real-world evidence for U.S. Food and Drug Administration-approved oncology products, 2015 to 2020.

280 Background: Since the 21st Century Cures Act, there has been growing interest in using real-world evidence (RWE) to support regulatory filings for new drugs and indications. The goal of this study was to provide a comprehensive source of RWE use cases of U.S. Food and Drug Administration (FDA) approvals for oncology products. Methods: A systematic review of FDA new drug applications (NDAs) and biologics license applications (BLAs) from 1/2015-2/2020 for approved oncology products was performed. Data on the RWE study were extracted (data source, study design, statistical methods, results), and corresponding FDA comments were synthesized to identify patterns of the FDA’s review. Results: We identified 102 NDAs and BLAs, 8 (8%) of which included RWE, all post-Cures Act (see Table). RWE supporting avelumab, axicabtagene ciloleucel, and avapritinib were received positively and used by the FDA in their approval decision. RWE results were used to provide contextualization to the pivotal trial, rather than statistical comparison. Common data sources included Flatiron (38%) and chart reviews (38%). FDA critiques included lack of a priori study protocol, incomparability with the pivotal trial population and endpoints, and uncontrolled confounding. Conclusions: There have been few examples of RWE in oncology submissions, and most served to complement clinical trial results. To meet FDA standards, RWE studies should be clearly designed and discussed with the FDA and include robust methods to minimize bias. [Table: see text]

An Overview of Drug Substance Manufacturing Processes.

To develop a comprehensive understanding of pharmaceutical drug substance manufacturing (DSM) processes, we conducted a data mining study to examine 50 new drug applications (NDAs) approved in 2010-2016. We analyzed the prevalence of several frequently deployed in-process control (IPC) techniques and postreaction workup procedures, as well as the operational conditions specified for reactions and workups. Our findings show that crystallization and high-performance liquid chromatography (HPLC) were the most commonly used workup steps and in-process controls, respectively, in drug substance manufacturing. On average, each NDA implemented 12.6 in-process controls and 11.3 workups. Operation time for reactions and workup procedures varied from a few minutes to multiple days, though 61% of these were between 1 and 10h.

Key Evidence Supporting Prescription Opioids Approved by the U.S. Food and Drug Administration, 1997 to 2018.

Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics. To characterize the quality of safety and efficacy data in new drug applications (NDAs) for opioid analgesics approved by the FDA between 1997 and 2018. Cross-sectional analysis. Data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications. Patients with pain who participated in phase 3 pivotal trials. FDA-approved opioid analgesics. Key characteristics of each NDA, including the number, size, and duration of pivotal trials; trial control groups; the use of enriched trial populations; and systematically measured safety outcomes. Most of the 48 NDAs evaluated were for new dosage forms (n= 25 [52.1%]) or new formulations (n= 9 [18.8%]); only 1 (2.1%) was for a new molecular entity. Of 39 NDAs approved for treating chronic pain, only 21 products were supported by at least 1 pivotal trial; these trials (n= 28) had a median duration of 84 days (interquartile range [IQR], 25 to 84 days) and enrolled a median of 299 patients (IQR, 174 to 525 patients). Seventeen (81%) of these products were approved on the basis of designs that excluded patients who could not tolerate the drugs, had early adverse effects, or reported few immediate benefits. Among NDAs for chronic pain, 8 (20.5%) included pooled safety reviews that reported systematic assessment of diversion, 7 (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed development of tolerance. Eight of 9 products for acute pain were supported by at least 1 pivotal trial; the pivotal trials (n= 19) had a median duration of 1 day (IQR, 1 to 2 days) and enrolled a median of 329 patients (IQR, 199 to 456 patients). Although all but 1 of the 48 approved NDAs were for previously approved moieties, analysis of available NDAs for referent products yielded similar findings. The analysis was limited to approved opioids. Animal studies and nonpivotal trials were excluded. Evidence for safety in NDAs was presented for chronic pain only. Between 1997 and 2018, the FDA approved opioids on the basis of pivotal trials of short or intermediate duration, often in narrowly defined pain populations of patients who could tolerate the drug. Systematic collation of certain important safety outcomes was rare. None.

A Regulatory Perspective on Manufacturing Processes Pertaining to Lyophilized Injectable Products.

Freeze-drying, also known as lyophilization, is a dehydration process designed to prolong the shelf life of injectable drug products. Here, we provide regulatory considerations for manufacturing processes specific to lyophilized injectable products. Specifically, a general discussion on each unit operation, including compounding, filtration, filling, and lyophilization, is provided to help the pharmaceutical industry establish reliable manufacturing processes from a regulatory perspective. In addition, a list of manufacturing-related deficiencies identified from a total of 263 new drug applications (NDAs) and abbreviated new drug applications (ANDAs) submitted for lyophilized injectable products is provided. We hope that the information presented in this report may help applicants avoid some common manufacturing-related deficiencies in regulatory submissions, thereby making high-quality lyophilized pharmaceuticals expeditiously available to the American public.

Entecavir add-on Peg-interferon therapy plays a positive role in reversing hepatic fibrosis in treatment-naïve chronic hepatitis B patients: a prospective and randomized controlled trial.

BackgroundThe efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not.MethodsAll patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria.ResultsAt week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups.ConclusionsBoth therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy.Trial registrationClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132

Role of real-world evidence for oncology product registration in the United States: A review of approvals by the U.S. Food and Drug Administration from 2015 to 2019.

e14130 Background: There are few concrete examples of real world evidence (RWE) used to support clinical development in regulatory filings despite growing interest in this field. This study systematically reviewed FDA oncology approvals to identify use cases of RWE. Methods: FDA’s new drug application (NDA) and biologics license application (BLA) approvals for oncology products from 2015-2019 were systematically reviewed. Among cases with RWE, data characterizing the submission and RWE details (data source, study design, FDA comments) were synthesized. Results: 93 approved NDAs and BLAs were identified; 6 included RWE in support of efficacy (see Table), approved on or after 2017, and were largely retrospective studies that contextualized results to pivotal trial, with primary endpoints overall survival (OS), overall response rate (ORR), and time to treatment discontinuation (TTD). Flatiron data were used in 3 of these as database analyses, 1 was an expanded access program (EAP), 1 was a meta-analysis, and 1 was a retrospective chart review. Conclusions: In the past 5 years, few FDA decisions incorporated RWE in oncology drug approvals. When used, RWE has been a complement rather than a supplement for clinical trial data. Early engagement, a priori protocol development, and robust research design (adjusting for bias, comparability to clinical trial population) remain key determinants for successful use of RWE in FDA decision making. [Table: see text]

PDG38 ASSESSMENT OF GENERIC COMPETITION FOR ORPHAN DRUGS MARKETED IN THE US (1993-2019)

The Orphan Drug Act of 1982 created the orphan designation for drugs for the treatment of rare diseases that affect less than 200 thousand patients in the US. This study evaluated generic competition of orphan and non-orphan new molecular entities approved by the US US FDA in the period 1983-2019. Data for all new molecular entities (NME) and orphan drugs approved by the FDA in the period 1983-2019 were compiled from the USFDA website. The study compared orphan and non-orphan drugs as a percentage of drugs without patent or market exclusivity and generic competition, the number of abbreviated new drug applications (ANDA), and the difference between the approval of a new drug application (NDA) and the first ANDA. Descriptive analysis, linear and logistic regression were conducted using IBM SPSS vs.25. The FDA approved 628 NME in the period 1983-2019 that did not have patent or exclusivity protection as of December 31, 2019. The analysis included 506 (80.1%) that were marketed by December 31, 2019, of which 104 (20.1) were orphan drugs. Generic competition occurred for 65 (62.5%) orphan drugs and 352 (87.6%) non-orphan drugs (p<0.0001). The period from the NDA to the first ANDA approval was 12.7+4.6 years for non-oprhan drugs and 12.2+- 5.6 years for orphan drugs (NS). The number of ANDAs was lower for orphan (7.2+-6.6, median 7) than for non-orphan drugs (15.5+-12, median=11). After controlling for other factors, orphan designation was significantly and negatively associated with generic entry, and the number of ANDAs approved by the FDA. No significant differences in time from NDA to ANDA approval were observed between orphan and non-orphan drugs. Orphan drugs experience less generic competition and have a lower number of generic drugs than non-orphan drugs reducing affordability to essential therapeutic alternatives.

PNS81 UTILIZATION AND EXPENDITURES FOR MEDICATIONS DISPENSED TO MEDICAID ENROLLEES IN 2017 BY YEAR OF DRUG APPROVAL

We assessed the relationship between the number of years since the initial approval date of medications and the utilization and expenditures represented by those medications in state Medicaid programs in 2017 based on publicly available data. Prescription drug and expenditure data for 2017 was extracted from Centers for Medicare & Medicaid Services state drug utilization files for all states. Approval dates at the active ingredient level were collected from various historical submission, application, and product files available from the FDA. Our assessment determined the initial approval date for an active ingredient using New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), or Biologics License Applications (BLAs). We linked each marketed generic product to its innovator product and its associated initial approval date. Reported expenditures did not include rebates. Descriptive analyses were conducted to summarize the distributions of approval dates weighted by overall utilization and expenditures for Medicaid prescriptions in 2017. We linked approval dates to nearly 723 million prescriptions accounting for $63.9 billion in expenditures across Medicaid enrollees in 2017. Drugs with an active ingredient approved between 2007 and 2017 accounted for 2.8% of all claims and 32.3% of all expenditures. Drugs approved since 1997 accounted for 19.1% of claims and 67.1% of expenditures, while drugs approved since 1987 accounted for 52.5% of claims and 80.5% of expenditures. For the top 100 drugs in 2017 weighted by claim volume and expenditures, the median weighted approval years were 1989 and 2002, respectively. This study provides insight into the overall “age” of innovation represented across the medications used in the Medicaid population. While a third of all expenditures are represented by drugs approved in the last 10 years, nearly half of all prescriptions dispensed in 2017 had approval dates of 1987 or older.

The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: An Update From the US Food and Drug Administration.

Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.