The Pharmaceutical Industry in 2021. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

Similar to last year, 2021 will be remembered for the COVID-19 pandemic. Although five vaccines have been approved by the two most important drug regulatory agencies, namely the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the pandemic has still not been brought under control. However, despite the context of a global pandemic, 2021 has been an excellent year with respect to drug approvals by the FDA. In 2021, 50 drugs have been authorized, making it the fourth-best year after 2018 (59 drugs) and 1996 and 2020 (53 each). Regarding biologics, 2021 has been the third-best year to date, with 14 approvals, and it has also witnessed the authorization of 36 small molecules. Of note, nine peptides, eight monoclonal antibodies, two antibody-drug conjugates, and two oligonucleotides have been approved this year. From them, five of the molecules are pegylated and three of them highly pegylated. The presence of nitrogen aromatic heterocycles and/or fluorine atoms are once again predominant among the so-called small molecules. This report analyzes the 50 new drugs approved in 2021 from a chemical perspective, as it did for those authorized in the previous five years. On the basis of chemical structure alone, the drugs that received approval in 2021 are classified as the following: biologics (antibodies, antibody-drug conjugates, enzymes, and pegylated proteins); TIDES (peptide and oligonucleotides); combined drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

Clinical Pharmacology Studies Supporting Oligonucleotide Therapy Development: An Assessment of Therapies Approved and in Development Between 2012 and 2018.

Synthetic nucleotides that utilize RNA-centric pharmacology can target diseases at the RNA level, thus altering protein expression in ways previously inaccessible to small molecules and therapeutic biologics. Recognizing that the unique pharmacology of oligonucleotides may require specific considerations in pre-approval assessment, clinical and nonclinical pharmacology studies being conducted for a selected set of oligonucleotide therapies in a 6-year period were assessed. This investigation focused primarily on the four following areas: (i) drug-drug interaction (DDI) potential, (ii) organ impairment (i.e., renal and hepatic impairment), (iii) immunogenicity, and (iv) cardiac safety. Data were summarized and assessed from 14 Investigational New Drug programs and 7 New Drug Applications submitted to the US Food and Drug Administration (FDA) from the period of January 2012 to August 2018, encompassing 152 unique studies. The assessment of DDI potential was largely consistent with the recommendations of current DDI-relevant guidances. Limited data were available to provide recommendations across organ impairment categories. Limited data on immunogenicity indicate impact on pharmacokinetic, the impact on safety and efficacy, although not extensively evaluated, appeared negligible. Cardiac safety evaluation indicated a potential for discordant translation of risk from nonclinical studies to clinical findings. Continued experience with synthetic oligonucleotide therapies will help inform the development of best practices to support their development and regulatory approval.

The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules.

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

A Chronology for the Identification and Disclosure of Adverse Effects of Succinylcholine.

BACKGROUND: New therapies are created to address specific problems and enjoy popularity as they enter widespread clinical use. Broader use can reveal unknown adverse effects and impact the life cycle significantly. Succinylcholine, a depolarizing neuromuscular blocker, was the product of decades of research surrounding the ancient compound, curare. It was introduced into practice in the 1950s by Burroughs Wellcome and Company (BW Co) and was welcomed due to its rapidly acting muscle relaxation effects. Global clinical use revealed adverse effects, both minor and major, in particular, hyperkalemia and malignant hyperthermia. We investigated when practitioners and the manufacturer became aware of these adverse effects, how information about these side effects was disseminated, and whether the manufacturer met the regulatory requirements of the time, specifically regarding the timely reporting of adverse effects. SOURCES: Primary literature search using online and archived documents was conducted at the Wood Library-Museum of Anesthesiology, Schaumburg, IL. We consulted documents submitted by BW Co to federal authorities, through the Freedom of Information Act (FOIA), Food and Drug Administration (FDA) reports, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Initial clinical testing in humans in 1952 found no adverse effects on cardiovascular or respiratory systems. Fasciculations and myalgia were early side effects described in case reports in 1952. Large-scale clinical trials in 1953 found abnormally long recovery times among some patients; the discovery of abnormal pseudocholinesterase enzyme activity was not fully demonstrated until the early 1960s. Bradycardia was first reported in 1957 in children, and in 1959 in adults. In 1960, animal studies reported a transient increase in plasma potassium; further experiments in 1969 clearly demonstrated succinylcholine-induced hyperkalemia in burn patients. Malignant hyperthermia was first described in 1966. Similar cases of elevated temperatures and muscle rigidity were described globally but the underlying mechanism was not elucidated until the 1990s. Standard anesthesia textbooks did not report major side effects of succinylcholine until 1960 and included newly documented side effects with each edition. BW Co's packaging contained warnings as early as the 1950s but were later updated in 1962 and beyond to reflect the newly discovered hyperkalemia and malignant hyperthermia. CONCLUSION: Particularly given the regulatory environment of the time, BW Co appropriately reported the adverse effects of succinylcholine after market entry; it updated promotional and packaging material in a timely manner to reflect newly discovered adverse effects. The toxicity, though alarming and put clinicians on alert, did not seem to heavily impact succinylcholine's use, given its various desirable properties. It is still a choice muscle relaxant used today, although there are efforts to develop superior agents to replace succinylcholine.

Anticancer drugs approved by the Food and Drug Administration for gastrointestinal malignancies: Clinical benefit and price considerations.

BACKGROUND: The cost of new anticancer drugs is rising. We aimed to assess the clinical benefit and price of anti-cancer drugs approved by the US Food and Drug Administration (FDA) for advanced gastrointestinal cancers. METHODS: Drugs approved between 2006 and 2017 for advanced GI malignancies were identified from FDA.gov, and their updated supporting trial data were searched. Incremental clinical benefit was quantified by using ESMO Magnitude of Clinical Benefit Scale version 1.1 (grade 0-5) and ASCO Value Framework version 2 (score range -20 to 180). Higher scores indicate larger net benefit, and substantial benefit was defined as score 4 or 5 by the European Society for Medical Oncology (ESMO). The Micromedex REDBOOK was used to estimate the monthly average wholesale price (AWP) and total drug price (TDP) over the median treatment duration per patient. Clinical benefit, AWP and TDP of each drug class were assessed. RESULTS: In total, 16 GI cancer drugs received FDA approval for 24 indications, including five monoclonal antibodies (mAbs), five oral targeted therapies (TT), two immunotherapeutics (IO), three cytotoxic chemotherapies (CT), and one recombinant fusion protein (aflibercept). Most supporting trials (82%) reported overall survival benefit of less than 3 months and no significant improvement in quality of life. Only five agents (including one TT and one IO) with 21% the of approved indications met the ESMO's threshold of substantial clinical benefit. Median incremental benefit scores of TT and IO were comparable to other drug classes. However their median TDP was much higher at $153 402 and $98 208, respectively, compared to $30 330 USD per patient for CT. The estimated TDP did not correlate with clinical benefit scores. CONCLUSION: Most FDA-approved gastrointestinal cancer drugs do not meet the ESMO threshold of substantial clinical benefit. TT and IO are estimated to carry significant drug costs, and further cost analysis of these drugs is urgently needed.

Biosimilars: Exploring the History, Science, and Progress.

BACKGROUND: Biosimilars provide opportunities for improving healthcare access and outcomes and reducing overall healthcare costs for patients with cancer. OBJECTIVES: The purpose of this article is to explore the history of biosimilars, regulatory pathways, and barriers to biosimilar approval. This article also aims to describe the patient and clinician barriers to biosimilars use and the progress that has been achieved since the first biosimilar approval in Europe in 2006 and in the United States in 2015. METHODS: A literature search was conducted to retrieve articles that are highly relevant to the history of biosimilars development and regulatory pathways in the United States, Europe, Asia, and Canada. Patient and clinician perspectives on safety issues and concerns regarding immunogenicity and bioequivalence that limit use of biosimilars are also included. FINDINGS: Patient and provider concerns regarding immunologic patient safety issues, such as immunogenicity, lack of comparability, and low biosimilarity, still exist. The clinical safety, efficacy, and tolerability of biosimilars are among the top concerns in patients, prescribers, and clinicians.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

Data Integrity: History, Issues, and Remediation of Issues.

Data integrity is critical to regulatory compliance, and the fundamental reason for 21 CFR Part 11 published by the U.S. Food and Drug Administration (FDA). FDA published the first guideline in 1963, and since then FDA and European Union (EU) have published numerous guidelines on various topics related to data integrity for the pharmaceutical industry. Regulators wanted to make certain that industry capture accurate data during the drug development lifecycle and through commercialization-consider the number of warning letters issued lately by inspectors across the globe on data integrity. This article discusses the history of regulations put forward by various regulatory bodies, the term ALCOA Plus adopted by regulators, the impact of not following regulations, and some prevention methods by using some simple checklists, self-audit, and self-inspection techniques. FDA uses the acronym ALCOA to define its expectations of electronic data. ALCOA stands for Attributable, Legible, Contemporaneous, Original, and Accurate. ALCOA was further expanded to ALCOA Plus, and the Plus means Enduring, Available and Accessible, Complete, Consistent, Credible, and Corroborated. If we do not follow the regulations as written, then there is a huge risk. This article covers some of the risk aspects. To prevent data integrity, various solutions can be implemented such as a simple checklist for various systems, self-audit, and self-inspections. To do that we have to develop strategy, people, implement better business processes, and gain a better understanding of data lifecycle as well as technology.LAY ABSTRACT: If one does a Google search on "What is data integrity?" the first page will give the definition of data integrity, how to learn more about data integrity, the history of data integrity, risk management of data integrity, and at the top about various U.S. Food and Drug Administration (FDA) and European Union (EU) regulations. Data integrity is nothing but about accuracy of data. When someone searches Google for some words, we expect accurate results that we can rely on. The same principle applies during the drug development lifecycle. Pharmaceutical industry ensures that data entered for various steps of drug development is accurate so that we can have confidence that the drugs produced by the industry are within some parameters. The regulations put forward by FDA and EU are not new. The first regulation was published in 1963, and after that regulators published multiple guidelines. Inspectors from both regulatory bodies inspected the industry, and they found that the data was not accurate. If pharmaceutical industry produces drugs within the stated parameters, then it is approved and available in the market for patients. If inspectors find that the data is modified, then the drug is not approved. That means revenue loss for industry and drugs not available for patients. In this article, I explain some of the remediation plans for the industry that can be applied during the drug development lifecycle pathway.

Food and Drug Administration Drug Approval Process: A History and Overview.

In this article, the processing of investigational and new drug applications is described and the standard and expedited review processes are examined. The efforts of the US Food and Drug Administration to ensure greater agency transparency and fiscal responsibility and intensify oversight during the drug development and approval process are reviewed. Often attributed to a decrease in the number of uninsured adults, both the increase in prescription drug sales and the high costs associated with bringing a new drug to market highlight the necessity for a streamlined and cost-effective process to deliver these drugs safely and effectively.

Hatch-Waxman Turns 30: Do We Need a Re-Designed Approach for the Modern Era?

In 1984, Congress passed the Hatch-Waxman Act, which catalyzed the creation of the modem generic drug industry. Generic drugs today account for eighty-four percent of all prescriptions dispensed, but less than twenty percent of drug costs. Despite this success, numerous problems in the generic drug market have emerged. Some involve the deliberate manipulation of the Hatch-Waxman system, while others have arisen more unexpectedly, such as the Supreme Court's 2011 decision in Pliva v. Mensing that could undermine consumer confidence in generic drugs. We discuss these emerging challenges and propose updates to the Hatch-Waxman Act to continue support for the timely emergence of safe generic drugs.

The discovery of first-in-class drugs: origins and evolution.

Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.

The complications of controlling agency time discretion: FDA review deadlines and postmarket drug safety.

Public agencies have discretion on the time domain, and politicians deploy numerous policy instruments to constrain it. Yet little is known about how administrative procedures that affect timing also affect the quality of agency decisions. We examine whether administrative deadlines shape decision timing and the observed quality of decisions. Using a unique and rich dataset of FDA drug approvals that allows us to examine decision timing and quality, we find that this administrative tool induces a piling of decisions before deadlines, and that these "just-before-deadline" approvals are linked with higher rates of postmarket safety problems (market withdrawals, severe safety warnings, safety alerts). Examination of data from FDA advisory committees suggests that the deadlines may impede quality by impairing late-stage deliberation and agency risk communication. Our results both support and challenge reigning theories about administrative procedures, suggesting they embody expected control-expertise trade-offs, but may also create unanticipated constituency losses.