Payments to key opinion leader physicians and drug sales of top pharmaceutical companies during the COVID-19 pandemic

Background: The unprecedented context of the COVID-19 pandemic poses the opportunity to study several questions in circumstances that would probably not otherwise occur. We sought to determine the dynamics of pharmaceutical company drug sales revenue, market capitalization and payments to physicians during the pandemic, focusing on payments to so-called key opinion leaders (KOLs). Methods: We analyzed the CMS Open Payments data of 15 top pharmaceutical company general payments to US physicians. We calculated total payments per year for all physicians, KOLs and 2018 KOLs in subsequent years. Drug-related fold changes in payments, drug revenues and company market capitation were calculated using Q1-2018 as reference. Yearly differences in payments, drug sales revenue and market capitalization were tested using generalized estimation equations (GEE). A double-sided p<0.05 was considered significant. Results: The analyzed dataset comprised 8,563,872 payments to 382,779 physicians. In 2020, we observed a reduction in payments to physicians and KOLs compared to prior years. The total amount per KOL physician per company also decreased for each year for KOLs and the 2018 KOLs in the subsequent years. Payments per drug, but neither drug revenues nor pharmaceutical company market capitalization, followed a downward trend in 2020 compared to prior years. GEE analysis confirmed that, compared to 2018, the decrease in payments to KOLs overall and for the top drugs of each company was statistically significant. Yet, no significant differences in drug sales revenue and market capitalization was observed. Conclusions: A substantial and significant reduction in payments to KOLs during the first fiscal year of the COVID-19 pandemic was not associated with a reduction in drug sales revenue of blockbuster drug products and the market capitalization of 15 top pharmaceutical companies. Overall, these findings suggest that a substantial part of pharmaceutical payments to KOLs do not appear to impact top drug sales revenues.

Application of Mathematical Models to Determine the Feasibility of Amorphous Drug Layering in Pan Coaters

Oral solid dosage forms that contain APIs in the amorphous state have become commonplace because of many drug substances exhibiting poor water solubility, which negatively impacts their absorption in the human GI tract. While micronization, solvent spray-drying, and hot-melt extrusion can address solubility issues, spray coating of the APIs onto beads and tablets offers another option for producing amorphous drug products. High-level comparisons between bead and tablet coating technologies have the potential for simpler equipment and operation that can reduce the cost of development and manufacturing. However, spray coating directly onto tablets is not without challenges, especially with respect to meeting uniformity acceptance value (AV) criteria, comprising accuracy (mean) and precision (variance) objectives. The feasibility of meeting AV criteria is examined, based on mathematical models for accuracy and precision. The results indicate that the main difficulty in manufacturing satisfactory drug-layered tablets by spray coating is caused by the practical limitations of achieving the necessary coating precision. Despite this limitation, it is shown that AV criteria can be consistently met by appropriate materials monitoring and control as well as processing equipment setup, operation, and maintenance.

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Research and Education Needs for Complex Generics

Complex generics are generic versions of drug products that generally have complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, are complex drug-device combination products, or have other characteristics that can make it complex to demonstrate bioequivalence or to develop as generics. These complex products (i.e. complex generics) are an important element of the United States (U.S.) Food and Drug Administration’s (FDA’s) Generic Drug User Fee Amendments (GDUFA) II Commitment Letter. The Center for Research on Complex Generics (CRCG) was formed by a grant from the FDA to address challenges associated with the development of complex generics. To understand these challenges, the CRCG conducted a “Survey of Scientific Challenges in the Development of Complex Generics”. The three main areas of questioning were directed toward which (types of) complex products, which methods of analysis to support a demonstration of bioequivalence, and which educational topics the CRCG should prioritize. The survey was open to the public on a website maintained by the CRCG. Regarding complex products, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and inhalation and nasal products. Regarding methods of analysis, the top three selections were locally-acting physiologically-based pharmacokinetic modeling; oral absorption models and bioequivalence; and data analytics and machine learning. Regarding educational topics, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and data analytics, including quantitative methods and modeling & simulation. These survey results will help prioritize the CRCG’s initial research and educational initiatives.

In vitro tools for orally inhaled drug products—state of the art for their application in pharmaceutical research and industry and regulatory challenges

The drug development process is a lengthy and expensive challenge for all involved players. Experience with the COVID-19 pandemic underlines the need for a rapid and effective approval for treatment options. As essential prerequisites for successful drug approval, a combination of high-quality studies and reliable research must be included. To this day, mainly in vivo data are requested and collected for assessing safety and efficacy and are therefore decisive for the pre-clinical evaluation of the respective drug. This review aims to summarize the current state of the art for safety and efficacy studies in pharmaceutical research and industry to address the relevant regulatory challenges and to provide an outlook on implementing more in vitro methods as alternative to animal testing. While the public demand for alternative methods is becoming louder, first examples have meanwhile found acceptance in relevant guidelines, e.g. the OECD guidelines for skin sensitizer. Besides ethically driven developments, also the rather low throughput and relatively high costs of animal experiments are forcing the industry towards the implementation of alternative methods. In this context, the development of orally inhaled drug products is particularly challenging due to the complexity of the lung as biological barrier and route of administration. The replacement of animal experiments with focus on the lungs requires special designed tools to achieve predictive data. New in vitro test systems of increasing complexity are presented in this review. Limits and advantages are discussed to provide some perspective for a future in vitro testing strategy for orally inhaled drug products. Graphical abstract

Micromorphological and Pharmacognostic Studies of Leaf and Stem of Solenostemon monostachyus P. Beauv (Lamiaceae)

Solenostemon monostachyus P. Beauv (Lamiaceae), it’s ethnomedical uses include anti-plasmodial, anti-pyretic, antiulcerogenic, antioxidant, anti-inflammatory and anti-nociceptive activities. The aim of this study was to employ the quality control parameters in the evaluation of the leaf and stem of Solenostemon monostachyus to aid in the identification and standardization of the medicinal plant. The plant leaves and stems were collected, identified, air-dried, pulverized and stored in separate glass containers. Standard procedures were employed to obtain the microscopic features of the fresh and powdered samples, micromeritic, chemomicroscopy, fluorescence properties, moisture contents, ash values and soluble extractive values. The results of the microscopic studies using fresh and powdered leaf samples revealed the presence of diacytic stomata on both the abaxial and adaxial surfaces (amphistomatic), with stomatal index of 27.9% and 14.8% respectively. The result of the micromeritics properties of the powdered leaf and stem samples showed angles of repose of 38.0o and 46.0o, Carr’s index of 23.7% and 32.5% and Hausner’s ratios of 1.3 and 1.5 respectively. Results for the moisture content, total, acid-insoluble and water-soluble ash values were 11.7%w/w, 13.7%w/w, 1.8%w/w and 9.4%w/w for the leaf and 13.3%w/w, 17.3%w/w, 1.8%w/w and 9.2%w/w for the stem respectively. Extractive values for water-soluble, methanol-soluble and ethanol-soluble were 26.5%w/w, 32.3%w/w, 14.5%w/w and 15.5%w/w, 15.8%w/w and 14.5%w/w for the leaf and stem respectively. Chemomicroscopy indicated the presence of lignin, calcium oxalate crystals and protein in the leaf and stem. The results obtained therefore could be used to establish pharmacopoeial standard for the fresh and powdered drug products of Solenostemon monostachyus, thus preventing adulteration.

Development and validation of standardization methods of aqueous sapropel extract

Methodological bases and uniform standardization criteria of humic compounds as substances for drug products have not been developed yet. This is due to the structural complexity of humic compounds, the variety of ways to extract them from natural objects, the impossibility of using many classical methods of analytical chemistry to identify and quantify humic substances (HS), the lack of standard samples. The identification of humic acids (HA) in the aqueous sapropel extract (ASE) is identified after extracting from ASE by alkaline hydrolysis by the quantification method. After further precipitation with a concentrated sulfuric acid solution characteristic dark brown color is appeared. It was carried out the HA extraction from the sample of ASE, the precipitation of HA, the oxidation of HA and Mohr’s salt titration in accordance with the methodology developed on the basis of SSTU 7083:2009. It was determined that the total mass fraction of HA in the ASE sample was 83.8 mg/g± 0.12%. The methods of identification and quantification of the total mass of HA in ASE have been developed and validated. The ASE has been standardized.

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.