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The article examines how outdated testing and static risk management in the U.S. delay the protection of human health, despite advancements in scientific knowledge. Topics discussed include the need for updated, sensitive testing methods, the importance of class-based regulation, and the challenge of evaluating chronic disease impacts from chemical exposures.

Background: Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. Objectives: This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price. Methods: We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview. Results: Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US. Conclusion: Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices. [ABSTRACT FROM AUTHOR]

Purpose: The rising number of food recalls has raised concerns about complexity, globalization and weak governance in the food supply chain. This paper aims to investigate the recall of plant-based products with data from the US Food and Drug Administration. Design/methodology/approach: Introducing the structural topic modeling method allowed us to test theories on recall in the context of sustainable food consumption, enhancing the understanding of food recall processes. This approach helps identify latent topics of product recalls and their interwoven relationships with various stakeholders. Findings: The results answer a standing research call for empirical investigation in a nascent food industry to identify stakeholders' engagements for food safety crisis management for corporate social responsibility practices. This finding provides novel insights on managing threats to food safety at an industry level to extend existing antecedents and consequences of product recall at a micro level. Practical implications: For practitioners, this empirical finding may provide insights into stakeholder management and develop evidence-based strategies to prevent threats to food safety. For public policymakers, this analysis may help identify patterns of recalls and assist guidelines and alarm systems (e.g. EU's Rapid Alert System for Food and Feed) on threats in the food supply chain. Originality/value: Two detected clusters, such as opportunisms of market actors in the plant-based food system and food culture, from the analysis help understand corporate social responsibility and food safety in the plant-based food industry. [ABSTRACT FROM AUTHOR]

This commentary is a call to action for a concerted commitment and effort to transform clinical trials and enable people with cancer to participate in clinical trials closer to home. Three key strategies are identified to address major barriers: confront challenges with the interpretation of US Food and Drug Administration Form 1572 requirements (Statement of Investigator); broaden acceptance of local laboratories and imaging centers; and invest in the creation of effective, sustainable partnerships between research centers and local providers. [ABSTRACT FROM AUTHOR]

The goal of this study was to analyze online marketing representations made by 300 US businesses selling allogeneic perinatal stem cell products. The study was conducted after a period of enforcement discretion by the US Food and Drug Administration (FDA). Data mining and content analysis were used to identify, analyze and categorize marketing claims made on the websites of 300 businesses selling perinatal stem cell interventions. The study identified types of perinatal interventions companies advertised, geographic locations of clinics selling such products, types of companies operating in this space, diseases and injuries such businesses claim to treat, prices companies charge for such interventions, brand names of advertised perinatal cell products and identities of suppliers. A substantial number of US businesses market unapproved perinatal stem cell products for various indications. This widespread commercial activity occurred following the conclusion of a period of enforcement discretion by the FDA and suggests the need for more robust and comprehensive regulatory responses to businesses selling unapproved perinatal stem cell products. [ABSTRACT FROM AUTHOR]

Background: Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA's Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs. Methods: Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010–2015 and 2016–2022) due to differences in available information. Results: From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes. Conclusion: Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA's Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting. [ABSTRACT FROM AUTHOR]

The accelerated approval (AA) program in the USA has succeeded in expediting the regulatory approval of new cancer drugs based on surrogate endpoint data. It is unclear whether the AA program promotes overall drug development, including verification of the clinical benefit, as the verification of drugs granted AA often takes long time. To determine the impact of the AA program on overall drug development, the time required for verification of clinical benefits was compared between anticancer drugs that initially received AA and those that received regular approval (RA). It was found that anticancer drugs that were approved under the AA program took longer time for verification, suggesting that the program may delay the start of a confirmatory study, and there may be room for speeding up the process. In addition, discordance was found in the pivotal study between the USA and the EU and the USA and Japan for obtaining the indication for which AA was granted in the USA and a delay in the start of the confirmatory study for the AA indication was considered to lead to a delay in approval in the EU and Japan. Early initiation of confirmatory studies for AA indications is recommended to reduce the time that patients receive drugs with unproven benefit in the USA, as well as to deliver innovative new drugs to patients earlier in the EU and Japan. [ABSTRACT FROM AUTHOR]

Aim: This study investigated whether US businesses engaged in direct-to-consumer online marketing of purported stem cell therapies and stem cell-derived exosome products made claims concerning the regulatory status of these interventions. Methods: We used data mining and content analysis of company websites to examine regulatory-related representations made by US businesses marketing stem cell treatments and exosome therapies. Results: More than two thirds of such businesses did not make explicit representations about the regulatory status of their marketed products. Businesses that made claims about the regulatory status of the stem cell and exosome products they sold used range of representations concerning the legal standing of these interventions. Conclusion: The absence of information addressing the regulatory status of stem cell interventions and exosome products and the use of what appeared to be inaccurate information concerning the regulatory status of numerous products likely complicates efforts by customers to make informed health-related decisions. Many US businesses engaged in direct-to-consumer marketing of purported stem cell and exosome therapies do not address the regulatory status of these products. [ABSTRACT FROM AUTHOR]

In this latest update we highlight: a publication from the US FDA regarding the definitions of real-world data (RWD) and real-world evidence (RWE); a publication from academic researchers on a demonstration project for target trial emulation; a publication from the National Institute of Health and Care Excellence (NICE) on the 1 year anniversary of their RWE framework; and a publication from NICE and Flatiron Health on the utility of US RWD for initial UK health technology assessment decision making.

This article examines the decades-long campaign to increase access to abortion pills in the United States, including advocates' work to win US Food and Drug Administration approval of mifepristone and misoprostol for abortion, the continuing restrictions on mifepristone, and the multiple strategies advocates have pursued to challenge these restrictions, including lobbying the FDA to remove the restrictions, obtaining a limited research exemption from FDA restrictions, and suing the FDA during the COVID-19 pandemic. The article pays particular attention to the influence of research conducted on the safety and efficacy of medication abortion as well as research on the impact of increased availability of abortion pills through telemedicine during the pandemic. The article also addresses self-managed abortion, wherein people obtain and use mifepristone and/or misoprostol outside the formal health care system, and it documents the growing network of organizations providing logistical, medical, and legal support to people self-managing abortion. The article concludes with reflections on the role abortion pills might play in the post-Roe era amid increasingly divergent abortion access trends across different regions of the United States. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration in 1983 and the European Union's European Medicines Agency in 2000 implemented the orphan drug development program for rare diseases. The study aimed to find the potential challenges encountered by generic companies in developing generics for rare diseases. We performed a thematic analysis, which consists of qualitative and quantitative research. For data analysis of approved orphan drugs, we used statistical methods, and for the industrial case study, we selected 14 generic companies and conducted semistructured interviews related to 10 critical areas of drug development. The orphan drug approvals were classified into 4 categories: the number of orphan approvals, pediatric claims, formulation, and therapeutic areas. We analyzed the approvals from 2001 to 2021; the Food and Drug Administration approved 815 drugs and European Medicines Agency approved 258 drugs. The pediatric orphan approvals were analyzed from 2010 to 2021; the average percentage of orphan drugs claim pediatric exclusivity during this period was found to be 31.8%. In formulation, we found the highest percentage of drugs belong to small molecules at 71%. In the therapeutic class, oncology drugs have a majority of approvals at 25%. The industrial case study responses revealed that the major challenge for drug development is the complexity of the disease at 21%, followed by the limited market at 17%. There is a high need for generic orphan drugs in the developing countries. The generic companies can use the opportunities provided by health authorities for the benefit of both the company and the patient perspective. • This study analyzed the types of rare diseases and their origin and development of small molecules and gene targeting drugs. • We found generic development challenges of small molecules and gene targeting drugs according to current health authority guidelines of the Food and Drug Administration and the European Medicines Agency. • The insights that this research provides for informing healthcare-related decision making are advantages and necessity of developing generic drugs for rare diseases, analyzing the developed countries' rare disease programs, and recommending to implement same in developing nations and describing the challenges and solutions for patients with rare diseases to overcome the pathetic conditions. [ABSTRACT FROM AUTHOR]

Background: The 1983 US Orphan Drug Act provided impetus for the development of new therapies for rare diseases. Several studies focused on the number of orphan designations over time. However, very few focused on clinical trials that lead to their approval, particularly for infectious diseases. Materials and Methods: All new drug approvals (orphan and non-orphan) by the US Food and Drug Administration (FDA) from January 2010 to December 31, 2020, were identified and details of approvals were taken from the US-FDA labels and summary reports for each drug. The pivotal trials for each were characterized based on their design. We tested the association of the type of drug approval with respect to the characteristics of trial using Chi-square test and generated crude odds ratios with 95% confidence intervals. Results: From the total 1122 drugs approved, 84 were for infectious diseases, of which 18 were orphan drugs and 66 were nonorphan. A total of 35 pivotal trials supported 18 orphan drug approvals, while 115 pivotal trials supported 66 nonorphan drugs. The median number of participants enrolled/trial for orphan drugs was 89, while for nonorphan drugs, it was 452 (P < 0.0001). Blinding was done for 13/35 (37%) orphan drugs versus 69/115 (60%) nonorphan drugs (P = 0.029); randomization was done for 15/35 (42%) orphan drugs versus 100/115 (87%) nonorphan drugs (P < 0.0001) and 20/35 (57%) of the orphan drugs got approval in phase II versus 8/115 (6%) of nonorphan drugs (P < 0.00001). Conclusion: A significant number of orphan drugs get approval based on early phase, nonrandomized, and unblinded with a smaller sample size as compared to nonorphan drugs. [ABSTRACT FROM AUTHOR]

The US FDA Center for Biologics Evaluation and Research (CBER) is responsible for the regulation of biologically derived products. FDA has established Advisory Committees (AC) as vehicles to seek external expert advice on scientific and technical matters related to the development and evaluation of products regulated by the agency. We aimed to identify and evaluate common topics discussed in CBER AC meetings during the regulatory decision-making process for biological products and medical devices. We analyzed the content of 119 CBER-led AC meetings between 2009 and 2021 listed on the FDA AC webpage. We reviewed publicly available meeting materials such as briefing documents, summaries, and transcripts. Using a structured review codebook based on FDA benefit-risk guidance, we identified important considerations within the benefit-risk dimensions discussed at the AC meetings: therapeutic context, benefit, risk and risk management, and benefit-risk trade-off, where evidence and uncertainty are critical parts of the FDA benefit-risk framework. Based on a detailed review of 24 topics discussed in 23 selected AC meetings conducted between 2016 and 2021, the two most frequently discussed considerations were “Uncertainty about assessment of the safety profile” and “Uncertainty about assessment of the benefit based on clinical trial data” (16/24 times each) as defined in our codebook. Most of the reviewed meetings discussed Investigational New Drug or Biologics License Applications of products. This review could help sponsors better plan and design studies by contextualizing how the benefit-risk dimensions were embedded in the AC discussions and the considerations that went into the final AC recommendations. [ABSTRACT FROM AUTHOR]

The ACT Network was funded by NIH to provide investigators from across the Clinical and Translational Science Award (CTSA) Consortium the ability to directly query national federated electronic health record (EHR) data for cohort discovery and feasibility assessment of multi-site studies. NIH refunded the program for expanded research application to become “Evolve to Next-Gen ACT” (ENACT). In parallel, the US Food and Drug Administration has been evaluating the use of real-world data (RWD), including EHR data, as sources of real-world evidence (RWE) for its regulatory decisions involving drug and biological products. Using insights from implementation science, six lessons learned from ACT for developing and sustaining RWD/RWE infrastructures and networks across the CTSA Consortium are presented in order to inform ENACT’s development from the outset. Lessons include intentional institutional relationship management, end-user engagement, beta-testing, and customer-driven adaptation. The ENACT team is also conducting customer discovery interviews with CTSA hub and investigators using Innovation-Corps@NCATS (I-Corps™) methodology for biomedical entrepreneurs to uncover unmet RWD needs. Possible ENACT value proposition hypotheses are presented by stage of research. Developing evidence about methods for sustaining academically derived data infrastructures and support can advance the science of translation and support our nation’s RWD/RWE research capacity.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct. [ABSTRACT FROM AUTHOR]

During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents' combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure-response (E-R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011-2021 period and summarizes the main design features of clinical trials and the role of PK assessments. [ABSTRACT FROM AUTHOR]

BackgroundSurrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies.DiscussionIn this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm.ConclusionThe use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.

On June 24, 2022, the Supreme Court issued an opinion in which five justices voted to overturn Roe v Wade. Even before the final opinion issued, scholars and advocates had begun to consider legal strategies that might mitigate the decision's anticipated harmful consequences. One such strategy involves challenging state restrictions on Food and Drug Administration (FDA)-approved pregnancy termination drugs on preemption grounds. This article begins by exploring how these challenges might fare—considering both drug-specific restrictions and complete bans on abortion—arguing that there are compelling legal grounds on which courts should conclude that many state restrictions are preempted. Importantly, although these state restrictions have arisen within a larger debate about reproductive health care, this is far from the only area in which states seek to regulate prescription drugs. States have long regulated drugs in ways that diverge from FDA, arguably increasingly so in recent years. Accordingly, the article investigates the implications that preemption challenges in the abortion context may have for other areas of state drug regulation, making the case that the benefits of public health federalism need not be undermined by successful preemption challenges in the abortion arena. [ABSTRACT FROM AUTHOR]

Policy PointsOnly a small minority of new drugs in "nonprotected" classes are widely covered by Part D plans nationwide in the year after US Food and Drug Administration (FDA) approval.Part D plans frequently apply utilization management restrictions such as prior authorizations to newly approved drugs in both protected and nonprotected classes.Drug price influences both formulary inclusion (in nonprotected classes) and coverage restrictions (in both protected and nonprotected classes), while other drug characteristics such as therapeutic benefits are not consistently associated with formulary design. Plans do not seem to favor the minority of drugs that are determined to offer added therapeutic benefit over existing alternatives. Context: Medicare Part D is an outpatient prescription drug benefit for older Americans covering more than 46 million beneficiaries. Except for mandatory coverage for essentially all drugs in six protected classes, plans have substantial flexibility in how they design their formularies: which drugs are covered, which drugs are subject to restrictions, and what factors determine formulary placement. Our objective in this paper was to document the extent to which Part D plans limit coverage of newly approved drugs. Methods: We examined the formulary design of 4,582 Part D plans from 2014 through 2018 and measured (1) the decision to cover newly approved drugs in nonprotected classes, (2) use of utilization management tools in protected and nonprotected classes, and (3) the association between plan design and drug‐level characteristics such as 30‐day cost, therapeutic benefit, and the US Food and Drug Administration (FDA) expedited regulatory pathway. Findings: The FDA approved 109 new drugs predominantly used in outpatient settings between 2013 and 2017. Of these, 75 fell outside of the six protected drug classes. One‐fifth of drugs in nonprotected classes (15 out of 75) were covered by more than half of plans during the first year after approval. Coverage was often conditional on utilization management strategies in both protected and nonprotected classes: only seven drugs (6%) were covered without prior authorization requirements in more than half of plans. Higher 30‐day drug costs were associated with more widespread coverage in nonprotected classes: drugs that cost less than $150 for a 30‐day course were covered by fewer than 20% of plans while those that cost more than $30,000 per 30 days were covered by more than 50% of plans. Plans were also more likely to implement utilization management tools on high‐cost drugs in both protected and nonprotected classes. A higher proportion of plans implemented utilization management strategies on covered drugs with first‐in‐class status than drugs that were not first in class. Other drug characteristics, including availability of added therapeutic benefit and inclusion in FDA expedited regulatory approval, were not consistently associated with plan coverage or formulary restrictions. Conclusions: Newly approved drugs are frequently subject to formulary exclusions and restrictions in Medicare Part D. Ensuring that formulary design in Part D is linked closely to the therapeutic value of newly approved drugs would improve patients' welfare. [ABSTRACT FROM AUTHOR]

To promote the efficient review of oncology drug applications, the US Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) launched the Real-Time Oncology Review (RTOR) pilot program in 2018. RTOR allows FDA to review individual sections of eCTD modules of a drug application for oncology drugs in contrast to requiring the applicant to submit complete modules or the complete application before review is initiated. Initially, the program accepted only supplemental applications with simple study designs and easily interpretable endpoints, but the scope has since been expanded to include applications for New Molecular Entities (NME), and other applications with more complex features. Though many applicants experience faster approvals under RTOR, it is difficult to isolate the effect of the RTOR program on review timelines as its contribution is masked by other expedited programs like priority review and breakthrough therapy designation (BTD). This article discusses the expanded scope of RTOR, its interplay with other OCE initiatives to modernize regulatory review, summarizes Genentech's experiences in planning RTOR submissions from February 2019 to July 2021, and provides considerations for the future of the program. [ABSTRACT FROM AUTHOR]

Abstract Background Until recently a typical rule that has often been used for the endorsement of new medications by the Food and Drug Administration has been the existence of at least two statistically significant clinical trials favoring the new medication. This rule has consequences for the true positive (endorsement of an effective treatment) and false positive rates (endorsement of an ineffective treatment). Methods In this paper, we compare true positive and false positive rates for different evaluation criteria through simulations that rely on (1) conventional p-values; (2) confidence intervals based on meta-analyses assuming fixed or random effects; and (3) Bayes factors. We varied threshold levels for statistical evidence, thresholds for what constitutes a clinically meaningful treatment effect, and number of trials conducted. Results Our results show that Bayes factors, meta-analytic confidence intervals, and p-values often have similar performance. Bayes factors may perform better when the number of trials conducted is high and when trials have small sample sizes and clinically meaningful effects are not small, particularly in fields where the number of non-zero effects is relatively large. Conclusions Thinking about realistic effect sizes in conjunction with desirable levels of statistical evidence, as well as quantifying statistical evidence with Bayes factors may help improve decision-making in some circumstances.

In this latest update we discuss real-world evidence (RWE) guidance from the leading oncology professional societies, the American Society of Clinical Oncology and the European Society for Medical Oncology, and the PRINCIPLED practical guide on the design and analysis of causal RWE studies.

In 2020, the US Food and Drug Administration approved 53 novel drugs. Thirty-six of the 53 (68%) drugs were reviewed and approved through an expedited review pathway, and 31 of the 53 (58%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the US Food and Drug Administration in 2020. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) established the Real-Time Oncology Review (RTOR) pilot program in 2017 to streamline the review process for oncology drug applications with the applicant and the Agency agreeing upon a piecemeal strategy and timeline for module components. The Prescription Drug User Fee Act (PDUFA) review clock does not officially start until the final component is submitted. Participation requires careful planning of time and resources due to the multiple submissions and interactions with the FDA. Applicants must also meet certain criteria regarding the clinical trial design and development program to be eligible for RTOR. Publicly available databases (Drugs@FDA) and documents were searched for all RTOR applications, which revealed a total of 28 approved applications that participated from February 2018 to August 2020. Initial marketing applications were further reviewed to identify any potential advantages or limitations from participation in the pilot program. These four case studies demonstrated an individualized RTOR process reflecting the program's pilot status. The FDA approved 3 out of the 4 applications approximately three to four months before the PDUFA goal date. The time savings is not guaranteed as other parts of the review may influence the overall timeline. However, the optional biweekly teleconferences increased communication and collaboration between the applicant and the FDA. The full impact of RTOR on applications remains undetermined as the number of approved applications that have participated in the pilot program is still relatively small. [ABSTRACT FROM AUTHOR]

More than 25 years have passed since the Dietary Supplement Health and Education Act of 1994 classified dietary supplements as a subcategory of food, thereby exempting manufacturers from providing premarket evidence of product safety and efficacy. In this commentary, I discuss problems in the supplement industry through an examination of cases introduced or decided in US federal courts between 2010 and 2019. More than half the cases located involved defendants charged with introducing misbranded food or drugs into interstate commerce. Contaminants included anabolic steroids, erectile dysfunction medications, weight-loss drugs, workout stimulants and mind-altering substances. As the article points out, raw powders obtained in bulk quantities facilitate the practice of 'home brewing' and the introduction of prescription drugs into dietary supplements. [ABSTRACT FROM AUTHOR]

Background: Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a "broad disease" categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.Results: Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.Conclusions: Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades. [ABSTRACT FROM AUTHOR]

Fluoride varnish is widely used in dentistry as a caries preventive measure with recommendations for its use even in infants. In addition, nondental providers are also applying varnish on children's teeth in various settings. However, there are questions from these nondental providers as to the safety of fluoride varnish. To evaluate and describe the adverse events (AEs) related to fluoride varnish, the US Food and Drug Administration's Manufacturer and User Facility Device Experience database was used. AEs reported for the dental product code for "varnish, cavity," "varnish," and "fluoride" were evaluated. The identified AEs were then reviewed and categorized using appropriate key words for the various signs and symptoms, outcomes, and treatment. Over the 10-year period, only 65 AEs were reported for fluoride varnish products. Swelling (33.8%); burning, itching, or soreness (23.1%); and rash (16.9%) were the most common signs and symptoms reported. The most common site reported was the lips (27.7%). The most common outcome was that the patient was taken to the hospital (18.5%) or emergency department (15.4%). No deaths were reported. The patients were treated primarily using diphenhydramine (Benadryl, Johnson & Johnson Consumer) (26.1%), followed by an epinephrine autoinjector (EpiPen, Mylan) and other forms of epinephrine (15.4%), and prednisolone (9.2%). In 16.9% of the cases with AEs there was a history of allergies. The rate of AEs is estimated to be between 0.099 and 0.105 per million for fluoride varnish. A concern is the likelihood of underreporting AEs in the Manufacturer and User Facility Device Experience database. Given the widespread use of fluoride varnish in the United States, the number of AEs reported to the US Food and Drug Administration were few. Thus fluoride varnish can be considered a safe dental product. Provides data on the safety of fluoride varnish that can be used by the dental profession to allay concerns by nondental providers and patients on this important caries preventive measure. [ABSTRACT FROM AUTHOR]

Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.

Background: According to 21 Code of Federal Regulation (CFR) Part 211, Over-the-Counter (OTC) drug manufacturers must establish and follow current good manufacturing practices (cGMP) to produce quality products while meeting regulatory standards. The warning letters issued by the U.S. Food and Drug Administration (FDA) reveal quality inadequacies that may impact the safety and effectiveness of these products. This study provides an analysis of warning letters and cited violations to identify the most common areas of quality issues and to understand the FDA's current thinking on regulatory expectations. Methods: Warning letters between U.S. fiscal years (FY) 2015–2019 were analyzed by the following steps: extraction of CFR violations, categorization of violations, trend analysis of data, and interpretation of results. Results: A total of 116 OTC warning letters and for comparison purposes 561 prescription (Rx) warning letters were analyzed in this study. OTC drug violations relating to product and process controls significantly increased, while violations relating to labeling decreased over the years. Despite these changes in violation numbers, the number of violations increased in most categories, highlighting a continual increase of quality inadequacies. Conclusion: The quality issues are mostly seen in cGMP violations specifically in the drug product, process, and laboratory controls. Most significant violation changes are also seen in drug product and process controls. The overall number of violations in OTC drugs has been increasing in the past 5 years and the analysis results provide a projection for continued increases in violations. Although this study provides an overall quality analysis of OTC warning letters and cited violations, more studies are required to understand the risk to consumers using OTC drug products due to the trends associated with these observations. [ABSTRACT FROM AUTHOR]

Cases of discordance between the US Food and Drug Administration (FDA) and its advisory committees are uncommon. Due to the importance of oncology therapies, we sought to identify and discuss instances of disagreement between the regulatory decision made by FDA, and the recommendation made by its Oncologic Drugs Advisory Committee (ODAC) via committee vote. Public databases (Oncologic Drugs Advisory Committee Meeting Materials, Drugs@FDA) as well as publicly available documents from ODAC meetings were reviewed to discern cases of disagreement between the two bodies. This review of public data yielded six (6) instances in which FDA's ultimate regulatory decision went against the recommendation of the ODAC. The six cases are briefly discussed and key drivers for or against an approval decision are outlined. In cases where FDA's decision was less conservative than that of the ODAC, the value of therapies with novel mechanisms of action which provide new options for patients, as well as regulatory precedent were observed as key drivers for regulatory decision-making. In cases where FDA took a more conservative approach than the ODAC, the importance of appropriate clinical trial design, clinically relevant trial endpoints, and the integrity of the data collected were stressed as driving the ultimate regulatory decision. [ABSTRACT FROM AUTHOR]

In the United States, all newly developed drugs undergo a lengthy review process conducted by the US Food and Drug Administration (FDA). These regulatory delays have direct immediate costs for drug manufacturers and patients waiting for treatment. Under certain market conditions, regulatory delays may also affect future research and development (R&D) strategies of pharmaceutical companies. To estimate the magnitude of this effect, we match data on drugs in the development pipeline in 2006 to data that we collect on FDA review times for all drugs approved between 1999 and 2005. Employing a rich and novel set of controls that affect drug R&D decisions and, potentially, regulatory review lags, we find that on average, three additional months of delay result in one fewer drug in development in that drug category. Our results suggest that the length of the regulatory delay matters for pharmaceutical firms' R&D decisions and that the firms are likely unable to pass on these costs onto consumers. [ABSTRACT FROM AUTHOR]