Assessment of black cumin (Nigella sativa L.) as a food ingredient and putative therapeutic agent.

The whole or ground seeds of the food ingredient Nigella sativa L., known in Western culture as "black cumin" or "black caraway", has a three-millennial history of use in Middle- and Far-Eastern cultures as a food ingredient. The seed and its extracts have also been increasingly reported as a successful therapeutic agent with efficacy often attributed to the presence of the powerful antioxidant, thymoquinone. However, quantitative analysis of the seed (especially the volatile fraction) yields widely variable results, which may be due to one or a combination of different crop origins or possible varietal differences, contamination/adulteration, method of extraction, stage of maturation of the extracted seed and other factors. Nonetheless, despite the reported wide variability in bioactive constituents, many publications cite quantifiable outcomes in in vitro and in vivo toxicity testing and in clinical trials. There are a few reports describing allergic reactions in humans when N. sativa extracts are applied to the skin. Notwithstanding the foregoing, N. sativa seeds, used as a food ingredient at historical levels of consumption and as traditionally practiced are safe and Generally Recognized As Safe.

The timing of 30-month stay expirations and generic entry: A cohort study of first generics, 2013-2020.

Before the first generic version of a drug is marketed, patent litigation often occurs. The process begins when generic manufacturers notify the US Food and Drug Administration (FDA) of their intent to market a generic copy of a brand-name drug protected by patents, which they allege to be invalid or not infringed (called a Paragraph IV certification). Assuming the brand-name manufacturer responds with litigation within 45 days, a 30-month stay period is triggered, which bars the FDA from authorizing generic entry until the stay period expires or litigation is resolved in favor of the generic manufacturer. To understand whether 30-month stays delay generic entry, we examined the timing of major legal events leading to generic entry for a cohort of 46 generic drugs, including the timing of Paragraph IV certification filings, stay period expirations, the FDA approvals of generics, and generic product launches. We found Paragraph IV certifications were filed a median of 5.2 years after the brand drug's FDA approval. There was a median of 3.2 years between the stay period expiration and subsequent generic launch. Because stay periods generally expire well in advance of when generic entry typically occurs, 30-month stays are unlikely to delay the timing of generic entry. Patent litigation could begin even earlier, however, if litigation was allowed to start immediately following a brand-name drug's FDA approval; but by law currently, the soonest this can begin is 4 years after the brand drug's FDA approval. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Before generic versions of new drugs reach the market, patent litigation often occurs. Once litigation has been initiated, a 30-month regulatory stay period is triggered that bars the US Food and Drug Administration (FDA) from approving the generic application until litigation resolves or the stay period expires. WHAT QUESTION DID THIS STUDY ADDRESS? What is the timing of key legal events in the regulatory approval process for generic drugs in relation to the eventual launch of the generic product? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? We identified the typical timing of the initiation of patent litigation and expiration of the 30-month stay period prior to the eventual launch of generic products. Litigation is often initiated as soon as legally possible (i.e., 4 years after the launch of the brand product), and stay periods typically expire well before generic entry occurs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Stay periods are unlikely to delay generic entry directly because stay expirations often occur well before the time of generic launch. Allowing the submission of generic drug applications immediately following a brand drug's FDA approval would facilitate earlier patent dispute resolution and prevent unnecessary delays in the anticipated generic product launch date.

3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration.

Nonclinical testing has served as a foundation for evaluating potential risks and effectiveness of investigational new drugs in humans. However, the current two-dimensional (2D) in vitro cell culture systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, whereas animal studies present significant drawbacks with inherited species-specific differences and low throughput for increased demands. To improve the nonclinical prediction of drug safety and efficacy, researchers continue to develop novel models to evaluate and promote the use of improved cell- and organ-based assays for more accurate representation of human susceptibility to drug response. Among others, the three-dimensional (3D) cell culture models present physiologically relevant cellular microenvironment and offer great promise for assessing drug disposition and pharmacokinetics (PKs) that influence drug safety and efficacy from an early stage of drug development. Currently, there are numerous different types of 3D culture systems, from simple spheroids to more complicated organoids and organs-on-chips, and from single-cell type static 3D models to cell co-culture 3D models equipped with microfluidic flow control as well as hybrid 3D systems that combine 2D culture with biomedical microelectromechanical systems. This article reviews the current application and challenges of 3D culture systems in drug PKs, safety, and efficacy assessment, and provides a focused discussion and regulatory perspectives on the liver-, intestine-, kidney-, and neuron-based 3D cellular models.

Patient Participation in Clinical Trials of Oncology Drugs and Biologics Preceding Approval by the US Food and Drug Administration.

Importance: Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. Objective: To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. Design, Setting, and Participants: This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. Main Outcomes and Measure: The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. Results: A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). Conclusions and Relevance: The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.

Hispanic/Latinos and Skincare: Disparities in Product Development, Marketing, and Toxicity.

“Hispanic” and “Latino” (also known as Mestizo) describe a diverse racial and ethnic group, with a range of cultures, languages, and biological ancestry. It includes individuals of Mexican, Central-to-South American, and Spanish-Caribbean (eg, Cuban, Puerto Rican, and Dominican) descent.1 Individuals of Hispanic/Latino race and ethnicity represent a heterogenous group of people with different skin tones and Fitzpatrick phototypes. Hispanic/Latinos are the fastest growing population in the United States (US) - projected to increase from 55 million in 2014 to 119 million in 2060, an increase of 115%.2 By 2060, more than one-quarter (29%) of the US is projected to be Hispanic/Latino.2.

Assessment of Data Sources That Support US Food and Drug Administration Medical Devices Safety Communications.

Importance: Medical Device Safety Communications (MDSCs) are used by the US Food and Drug Administration (FDA) to convey important new safety information to patients and health care professionals. The sources of initial safety signals that trigger MDSCs have not been described previously. Objective: To assess the sources of initial safety signals that trigger publication of MDSCs and the potential associations among MDSC data source, type of safety issue, and subsequent FDA action. Design, Setting, and Participants: In this cross-sectional study, all MDSCs published on the FDA website between January 1, 2011, and December 31, 2019, were assessed. The MDSC characteristics, sources of initiating safety signals, regulatory approval or clearance pathways of the related medical devices, and subsequent FDA actions were collected from the FDA website. Main Outcomes and Measures: The main outcome was the distribution of sources of initial safety signals that led to publication of MDSCs. Secondary aims included exploration of potential associations among safety signal sources (direct reporting vs other), type of safety issue (death vs other), and FDA action (withdrawal vs other). Results: A total of 93 MDSCs were evaluated. Median time from device approval to MDSC posting was 10 years (interquartile range, 6-16 years). The most common data sources that triggered MDSCs were direct reports to the FDA through the Medical Device Reporting (MDR) program (44 of 93 [47%]) followed by regulator-initiated assessments (32 [34%]). Common safety issues included patient injury (25 [27%]), potential wrong diagnoses (19 [20%]), and death (18 [19%]). Frequent FDA action after MDSC posting included recommendation for increased vigilance and caution (47 [51%]), complete device withdrawal (12 [13%]), and warnings of specific lots or clinics (12 [13%]). There was a statistically significant correlation between direct reports of adverse events to the FDA through the MDR program and risk of death as a safety issue (14 of 44 [32%] for direct reporting vs 4 of 49 [8%] for any other data sources, P = .007). Conclusions and Relevance: In this cross-sectional study, the most common source of initial safety signals that triggered MDSCs was direct reports of real-world adverse events to the FDA through the MDR program. The delayed detection of postmarketing adverse events highlights the importance of proactive identification of emerging device-related safety issues.

A Call to Action to Track Generic Drug Quality Using Real-World Data and the FDA's Sentinel Initiative.

DISCLOSURES: The author reports funding from the U.S. Food and Drug Administration to study real-world data approaches to detect generic drug quality issues. There are no further conflicts or disclosures.

Vaccine Policy in the United States.

In an era when the success of the US vaccination policies to date is threatened by vaccine hesitancy, it is important for clinicians to have a working understanding of how vaccines are developed and recommended for use in the United States and how federal and state governments are coordinated to ensure a safe and effective vaccine supply. This article discusses the federal agencies involved in vaccine development and recommendation, other organizations involved in vaccine policy, and the role of vaccine-related public health law in promoting universal vaccination.

Breast Implant Imaging Surveillance among U.S. Plastic Surgeons: U.S. Food and Drug Administration Recommendations versus Clinical Reality.

BACKGROUND: Device rupture is considered a major complication associated with breast implants. The U.S. Food and Drug Administration recommends magnetic resonance imaging (MRI) surveillance 3 years after implantation and then every 2 years, but adherence to these recommendations is poor. The authors identified current practice management for breast implant rupture surveillance by surveying practicing U.S. plastic surgeons. METHODS: An online survey of all active members of the American Society of Plastic Surgeons was performed. Questions analyzed imaging practice patterns related to breast implants. Logistic regression models were used to analyze determinants for radiographic imaging in breast implant patients. RESULTS: The survey had a response rate of 16.5 percent. For patients with breast implants, 37.7 percent of respondents recommended MRI at the recommended intervals. Fifty-five percent perform imaging only if there is a problem with the implant. Academic surgeons more frequently recommended MRI (56.3 percent and 39.3 percent; p = 0.0002). Surgeons with less than 5 years of experience are four times more likely to order MRI than surgeons with over 25 years' experience (60.8 percent and 28.1 percent; p < 0.0001). Furthermore, lower volume surgeons recommend significantly more MRI (45.2 percent and 27.3 percent; p = 0.001). Respondents are almost two times more likely to recommend MRI in reconstructive versus cosmetic patients (51.2 percent and 35.6 percent; p = 0.0004). CONCLUSIONS: MRI limitations include high costs, time commitments, and equipment constraints. Fewer than 40 percent of survey respondents suggest the recommended screening frequency to their patients; however, academic, low-volume, early-career surgeons are more likely to recommend MRI implant monitoring. Screening recommendations need to be evidence based and align with common practices to prevent undue system, provider, and patient burden.

Reflections of the Angiotensin Receptor Blocker Recall by the FDA and Repercussions on Healthcare.

PURPOSE: Beginning in July of 2018, the FDA issued a voluntary recall regarding the presence of a contaminant found in the manufacturing of valsartan. What would ensue has become a largely unprecedented sequence of alarming events since the FDA began reporting public recalls, withdrawals and safety alerts on their website in 2016. Since then, the United States has been significantly impacted by drug recalls affecting angiotensin receptor blockers. This report arms clinicians with additional guidance and provides a framework for responding appropriately to future similar incidents and includes an overview of the angiotensin receptor blockers, and their effects and safety profiles. METHODS: This report includes a review of data from all pertinent clinical and scientific sources including information from the FDA's inspection documents and recall website. Additional information is provided on the specific bottles including all lot numbers, expiration dates, etc. RESULTS: The recalls/withdrawals are attributable to the presence of cancer-causing contaminants identified during the manufacturing process from drug manufacturers abroad. The root causes behind the recalls and subsequent shortage appear multifactorial, and stem to a certain extent from the outsourcing of medication manufacturing overseas and lack of quality checks and appropriate oversight. CONCLUSIONS: This inherent issue is not likely to resolve soon and has eroded the public trust of/in the healthcare system and the pharmaceutical industry. Patients and healthcare providers are significantly affected and should have a full understanding of the matter in order to guide appropriate response and actions.

Some thoughts on the QR method for analytical similarity evaluation.

As indicated in a recent published draft guidance on comparative analytical assessment, the United States (US) Food and Drug Administration (FDA) seems to suggest the use of quality range (QR) method for analytical similarity evaluation. It is a concern that the use of QR method for analytical similarity evaluation could potentially approve biological products which are not deemed biosimilar to the reference biological products. In this article, the limitations and potential risk for the use of the QR method for analytical similarity evaluation are discussed. Alternatively, two modified versions of the QR method, which are referred to as effect size (ES) mQR and plausibility interval (PI) mQR methods are suggested. The performance and statistical properties of the mQR methods are evaluated via extensive clinical trial simulation under various scenarios. The results indicate that the modified versions of the QR method not only overcome the limitations of the QR method for analytical similarity evaluation, but also can potentially help in detecting reference product changes during manufacturing process.

Patterns of care for older patients with stage IV non-small cell lung cancer in the immunotherapy era.

BACKGROUND: Historically, older patients with advanced lung cancer have often received no systemic treatment. Immunotherapy has improved outcomes in clinical trials, but its dissemination and implementation at the population level is not well-understood. METHODS: A retrospective cohort study of patients with stage IV non-small cell lung cancer (NSCLC) diagnosed age 66 or older from 2012 to 2015 was conducted using SEER-Medicare. Treatment patterns within one year of diagnosis were ascertained. Outcomes included delivery of (a) any systemic therapy; (b) any second-line infusional therapy, following first-line infusional therapy; and (c) any second-line immunotherapy, following first-line infusional therapy. Trends in care patterns associated with second-line immunotherapy approvals in 2015 were assessed using generalized additive models. Sociodemographic and clinical predictors of treatment were explored using logistic regression. RESULTS: Among 10 303 patients, 5173 (50.2%) received first-line systemic therapy, with little change between the years 2012 (47.5%) and 2015 (50.3%). Among 3943 patients completing first-line infusional therapy, the proportion starting second-line infusional treatment remained stable from 2012 (30.5%) through 2014 (32.9%), before increasing in 2015 (42.4%) concurrent with second-line immunotherapy approvals. Factors associated with decreased utilization of any therapy included age, black race, Medicaid eligibility, residence in a high-poverty area, nonadenocarcinoma histology, and comorbidity; factors associated with increased utilization of any therapy included Asian race and Hispanic ethnicity. Among patients who received first-line infusional therapy, factors associated with decreased utilization of second-line infusional therapy included age, Medicaid eligibility, nonadenocarcinoma histology, and comorbidity; Asian race was associated with increased utilization of second-line infusional therapy. CONCLUSION: United States Food and Drug Administration (FDA) approvals of immunotherapy for the second-line treatment of advanced NSCLC in 2015 were associated with increased rates of any second-line treatment, but disparities based on social determinants of health persisted.

Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

Is Bioequivalence a Sufficient Measure of Equivalence?

This article reviews the U.S. Food and Drug Administration (FDA) regulation of generic medications-specifically, the use of bioequivalence to compare generic and brand prescriptions. New or "brand" drugs are subjected to extensive review by the FDA before they can be marketed to the public. Generics, which are posited to be identical to brands, are subject to a less extensive review process and must prove only that the generic is the "bioequivalent" (BE) of the brand drug. Generic medications are important because they comprise almost 80% of prescriptions filled in the United States and cost 80% to 85% less than brand drugs, playing a crucial role in patients' access to cost-effective treatments. However, there is dissension about whether they can be interchanged with brand drugs without any consequences for the patient, especially for Narrow Therapeutic Index (NTI) drugs, which have precise dosage requirements. The regulatory designation of bioequivalence also has implications for doctor-patient relationships, patient outcomes, and patient legal rights. This article aims to establish that there is insufficient evidence to conclude whether using bioequivalence is adequate to determine whether two drugs can be considered equivalent given the medical and legal implications that flow from deeming two drugs equivalent.