The Problem of Limited-Supply Agreements for Medicare Price Negotiation.

This Viewpoint discusses how limited-supply agreements (introduction of generic products in reduced volumes) might thwart efforts to negotiate lower prices on prescription drugs in the US.

2020 in review: FDA approvals of new medicines.

Amid a global pandemic, the US Food and Drug Administration (FDA) remained relatively active, approving 55novel molecular entities (NMEs) in 2020, the third highest annual rate recorded. Orphan approvals also surged, capturing 60% of NMEs introduced during 2020, as did the number of NMEs approved using a priority review. The pandemic did appear to impact one recent trend, and in a paradoxically encouraging way. Escalating rates of consolidation slowed in 2020, with only 102 companies lost, down by two-thirds over the rate in 2019. This leaves 2000 extant clinical-stage pharmaceutical companies. When limiting this analysis to companies contributing to the research and development (R&D) of an approved drug, eight were lost, leaving 144 extant.

Compliance With Cannabis Act Regulations Regarding Online Promotion Among Canadian Commercial Cannabis-Licensed Firms.

Importance: As global jurisdictions shift toward cannabis legalization, 2 areas of public health importance relate to exposure to youth and to truthful promotion. Although Canada's Cannabis Act specifies many prohibitions related to cannabis promotion, no systematic monitoring or enforcement among licensed firms exists. Compliance with marketing regulations has effects beyond Canadian citizens because of the global outreach of websites and social media. Objectives: To evaluate compliance among licensed firms with the Cannabis Act and analyze trends among violations regarding promotional material. Design, Setting, and Participants: This cross-sectional study evaluated cannabis-licensed firms after cannabis legalization. Data were extracted from online public platforms, including company websites, Facebook, Instagram, and Twitter, from October 1, 2019, to March 31, 2020. Descriptive statistics, Poisson regression, and logistic regression were used to analyze the associations of covariates with promotion violations. Main Outcomes and Measures: The primary outcome was characterization of type and prevalence of promotion violations. Secondary outcomes were the role of various covariates (namely, licensed firm characteristics and online platforms) in the frequency and probability of violations. Hypotheses were formulated before data collection. Results: Among 261 licensed firms, 211 (80.8%) had an online platform, including 204 (96.7%) with websites, 128 (60.7%) with Facebook, 123 (58.3%) with Instagram, and 123 (58.3%) with Twitter. Of all licensed firms with an online platform, 182 (86.3%) had at least 1 violation. Compared with websites, the risk of violations was significantly higher on Facebook (rate ratio [RR], 1.24; 95% CI, 1.11-1.39) and Instagram (RR, 1.19; 95% CI, 1.05-1.34). The most common violations included lack of age restrictions, brand glamorization, and omission of risk information. With websites as the reference group, lack of age restrictions was approximately 15 times more likely to occur on Facebook (odds ratio [OR], 14.76; 95% CI, 8.06-27.05); the odds of an age restriction violation were also higher on Instagram (OR, 2.48; 95% CI, 1.43-4.32) and Twitter (OR, 4.03; 95% CI, 2.29-7.09). For unsubstantiated claims, the odds of violations were significantly decreased on Facebook (OR, 0.23; 95% CI, 0.11-0.48) and Instagram (OR, 0.28; 95% CI, 0.14-0.57). The odds of glamorization were associated with an increase on Instagram (OR, 2.90; 95% CI, 1.72-4.88). Conclusions and Relevance: In this cross-sectional study, widespread violations were observed in online Canadian cannabis promotion. To protect public health and safety amid legalization, decision-makers should make explicit federal regulation and enforcement regarding promotional activities of cannabis retailers. These results suggest that policy and enforcement of cannabis promotion in Canada would have an international impact, from ease of access to online media and downstream consequences of unregulated promotion.

R&D efficiency of leading pharmaceutical companies - A 20-year analysis.

Comparative analysis of the R&D efficiency of 14 leading pharmaceutical companies for the years 1999-2018 shows that there is a close positive correlation between R&D spending and the two investigated R&D output parameters, approved NMEs and the cumulative impact factor of their publications. In other words, higher R&D investments (input) were associated with higher R&D output. Second, our analyses indicate that there are 'economies of scale' (size) in pharmaceutical R&D.

The effect of generic market entry on antibiotic prescriptions in the United States.

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

Pharmaceutical company payments to authors of the Japanese guidelines for the management of hypertension.

ABSTRACT: Antihypertensive drugs have been of significant interest to the pharmaceutical industry due to increasing sales opportunities in a global market. The financial relationships between pharmaceutical companies and the Japanese Society of Hypertension (JSH) have a possible influence on clinical practices in Japan. This study examined the distribution of pharmaceutical payments made to the authors of the revised Guidelines for the Management of Hypertension (JSH2019) and the transparency of the Conflict of Interest disclosure that each author made.We retrospectively obtained publicly available data regarding payments made by Japanese pharmaceutical companies to all authors of the JSH2019 in 2016. We also collected data on individual financial disclosure of JSH2019 authors to investigate whether their self-reported financial relationship with companies were compliant to the financial disclosure policy of JSH2019.The total and mean payment values reported by pharmaceutical companies were $4,246,436 and $21,447, respectively. Of the 198 authors, 171 (86.4%) authors received at least 1 payment. Of 74 authors required to disclose their conflict of interest (COI) the authors, one-third failed to follow the COI policy covering the clinical guidelines.Major pharmaceutical companies selling antihypertensive drug products in the Japanese market had a significant financial connection with the JSH2019 authors. Financial relationships between pharmaceutical companies and authors or Japanese medical societies are raising significant concerns about the credibility of clinical guidelines and the potentially biases and undue influences that they may cause, especially with respect to adverse prescription patterns.

Predictors of shortages of opioid analgesics in the US: Are the characteristics of the drug company the missing puzzle piece?

BACKGROUND: Shortages of opioid analgesics are increasingly common, interfere with patient care and increase healthcare cost. This study characterized the incidence of shortages of opioid analgesics in the period 2015-2019 and evaluated potential predictors to forecast the risk of shortages. METHODS: This was an observational retrospective study using the US Food and Drug Administration (FDA) drug shortages data. All FDA approved opioids were included in the study. Opioid analgesics were identified using the FDA National Drug Codes (NDC) and classified according to the Drug Enforcement Administration (DEA) schedule. We conducted Least Absolute Shrinkage and Selection Operator logistic regression analysis to assess direction of the association between risk of shortage and potential predictors. We used multivariable penalized logistic regression analysis to model predictors of shortages. We split the dataset into training and validation sets to evaluate the performance of the model. FINDINGS: The FDA approved 8,207 unique NDCs for opioid analgesics; 3,017 (36.8%) were in the market as of April 30, 2019 and 91(3.0%) of them were listed as in shortage by the FDA. All NDCs in shortage were schedule II opioids; 86 (94.5%) were injectable and 84 (92.3%) generics. There were 418 companies with at least one opioid NDC listed by the FDA. Three companies accounted for more than 4 in 5 of the schedule II active injectable opioids. For each unit increase in the number of prior instances of shortages of a company, the likelihood of an NDC shortage for that company increased by 3.4%. For each unit increase in number of NDCs marketed by a company, the odds of an NDC shortage for that company decreased by 1%. CONCLUSIONS: In the period 2015-2019, shortages of opioid analgesics disproportionally impacted schedule II and injectable opioids. The risk of shortage of opioid analgesics significantly increased with the incidence of previous instances of shortages of a manufacturing company and decreased with the number of NDCs marketed by a company. The characteristics of the manufacturing company, rather than the number of companies, might be the missing piece to the complex puzzle of drug shortages in the US.

The global procurement landscape of leishmaniasis medicines.

Ensuring access to essential medicines for leishmaniasis control is challenging, as leishmaniasis is a very small and unattractive market for pharmaceutical industry. Furthermore, control programmes are severely underfunded. We conducted an analysis of global procurement of leishmaniasis medicines for the past 5 years in order to shed light on the current leishmaniasis market landscape and supply and demand dynamics. We estimated global demand of each leishmaniasis medicines, the amount of each medicine required to treat all reported cases, based on the number of cases reported to WHO and the first-line treatment regimen used in each country. Procurement data were obtained from procurement agencies, international organizations, WHO, national leishmaniasis programmes and manufacturers. Expert interviews were conducted to have a better understanding of how medicines were procured and used. The comparison of estimated need and procurement data indicated discrepancies in supply and demand at global level as well as in the most endemic countries. The extent of the gap in supply was up to 80% of the needs for one of the leishmaniasis medicines. Mismatch between supply and demand was much wider for cutaneous leishmaniasis than visceral leishmaniasis. This study presents a current picture of procurement patterns and imbalance in global supply and demand. Addressing improved access and supply barriers requires concerted and coordinated efforts at the global and national levels. Priority actions include setting up a procurement coordination mechanism among major procurers, partners and national programmes where forecasting and supply planning is jointly developed and communicated with manufacturers. In addition, continuous engagement of manufacturers and advocacy is critical to diversify the supplier base and ensure quality-assured and affordable generic medicines for leishmaniasis.

Removal of the EMA orphan designation upon request of the sponsor: cui prodest?

PURPOSE: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. METHODS: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. RESULTS: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1-7 years). CONCLUSIONS: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome.

Evolving Landscape of New Drug Approval in Japan and Lags from International Birth Dates: Retrospective Regulatory Analysis.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

The Evidence REVEAL Study: Exploring the Use of Real-World Evidence and Complex Clinical Trial Design by the European Pharmaceutical Industry.

The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as to speed up patients' access to better diagnostics and treatment. Our study explored how two emerging approaches, the use of real-world evidence (RWE) and complex clinical trial (CCT) design, are currently being used by the pharmaceutical industry to support premarketing authorization of medical product development and reviewed the international landscape for regulatory acceptance of such novel approaches. Combining evidence from a literature review, company survey, and interviews with international regulators and experts, we found that 80% of Europe-based pharmaceutical companies have used RWE and 50% have used CCTs, in some capacity. Further, we present case examples of how companies are using these approaches and how international regulators are preparing for such developments. To conclude, we provide a set of recommendations for European industry and regulators to consider so that these novel approaches achieve their full potential within the EU regulatory system.

Current Challenges in Labelling for Generic Medicinal Products: Company Core Data Sheet (CCDS) Development and Maintenance.

Labelling of pharmaceutical products plays a vital role in the safe and effective use of approved medicinal products. This information may be provided to end-users including patients and/or prescribers, and it needs to be made available in multiple formats including printed forms (patient information leaflets, pack inserts, etc.) or web portals of the product, based on national authority guidelines. The Company Core Data Sheet (CCDS) serves as a key document representing the pharmaceutical company's position on the product and is used as a reference document for national labels. Content from national labels may differ from the CCDS for different reasons including implementation of national authority requirements in the serving market and findings from local markets. In the current article, we discuss the process, challenges and key concepts in creating and maintaining CCDS documents for generic products. We highlight key parameters that are worthy of process improvement in generic products' CCDS updates. In addition, we argue that labelling harmonisation across multiple regions, especially safety section-related information, plays a key role in promoting end-user safety and would help communicate risks. We also strongly believe that the topic is worthy of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) consideration, and propose that this is the key area that requires standardisation and harmonisation.

The NTD Supply Chain Forum-Strengthening the backbone of NTD programs.

Global programs targeting 5 preventive chemotherapy neglected tropical diseases (PC-NTDs) have scaled up rapidly in recent decades due, in large part, to the generous drug donations from 6 pharmaceutical companies-Eisai; Johnson & Johnson (J&J); GlaxoSmithKline (GSK); Merck & Co., Inc., Kenilworth, New Jersey, United States of America (MSD); Merck KgaA; and Pfizer. Today, the scale of the PC-NTD drug donation programs is staggering. Nearly 15 billion tablets have been manufactured, packaged, shipped, and distributed in order to reach the people in need. The supply chains established to support such massive operations are enormously complex. Here, we describe a unique public-private partnership that was formed to bring together supply chain expertise to overcome the critical challenges associated with such large-scale production and delivery of donated pharmaceutical products.

[Cost/benefit analysis of cancer drugs]. / Bénéfice clinique et coût des traitements anticancéreux.

A detailed analysis of the clinical benefit for 47 approved cancer drugs, using two internationally recognized assessment systems, shows essentially no correlation between clinical benefit and weekly treatment costs. This is true both in the USA and in four European countries, although prices are dramatically lower in Europe.

Importance of scientific collaboration in contemporary drug discovery and development: a detailed network analysis.

BACKGROUND: Growing evidence shows that scientific collaboration plays a crucial role in transformative innovation in the life sciences. For example, contemporary drug discovery and development reflects the work of teams of individuals from academic centers, the pharmaceutical industry, the regulatory science community, health care providers, and patients. However, public understanding of how collaborations between academia and industry catalyze novel target identification and first-in-class drug discovery is limited. RESULTS: We perform a comprehensive network analysis on a large scientific corpus of collaboration and citations (97,688 papers with 1,862,500 citations from 170 million scientific records) to quantify the success trajectory of innovative drug development. By focusing on four types of cardiovascular drugs, we demonstrate how knowledge flows between institutions to highlight the underlying contributions of many different institutions in the development of a new drug. We highlight how such network analysis could help to increase industrial and governmental support, and improve the efficiency or accelerate decision-making in drug discovery and development. CONCLUSION: We demonstrate that network analysis of large public databases can identify and quantify investigator and institutional relationships in drug discovery and development. If broadly applied, this type of network analysis may help to enhance public understanding of and support for biomedical research, and could identify factors that facilitate decision-making in first-in-class drug discovery among academia, the pharmaceutical industry, and healthcare systems.