Harnessing policy to promote inclusive medical product evidence: development of a reference standard and structured audit of clinical trial diversity policies.

Objective: To develop a reference standard based on US Food and Drug Administration and stakeholder guidance for pharmaceutical companies' policies on diversity in clinical trials and to assess these policies. Design: Development of a reference standard and structured audit for clinical trial diversity policies. Setting: 50 pharmaceutical companies selected from the top 500 by their market capitalizations in 2021 (the 25 largest companies and 25 non-large companies, randomly selected from the remaining 475 companies). Population: Data from pharmaceutical company websites and annual reports. Policy guidance from the Pharmaceutical Research and Manufacturers of America, International Federation of Pharmaceutical Manufacturers and Associations, Biotechnology Industry Organization, International Committee of Medical Journal Editors, the US Food and Drug Administration, European Medicines Agency, and World Health Organization, up to 15 May 2023. Main outcome measures: Multicomponent measure based on distinct themes derived from FDA and stakeholder guidance. Results: Reviewing FDA and stakeholder guidance identified 14 distinct themes recommended for improving diversity in clinical trials, which were built into a reference standard: (1) enrollment targets that reflect the prevalence of targeted conditions in populations, (2) broad eligibility criteria for trials, (3) diversity in the workforce, (4) identification and remedy of barriers to trial recruitment and retention, (5) incorporation of patient input into trial design, (6) health literacy, (7) multidimensional approaches to diversity, (8) sites with diverse providers and patient populations, (9) data collection after product approval, (10) diverse enrollment in every country where trials are conducted, (11) diverse enrollment should be a focus for all phases of clinical trials, not just later stage or pivotal trials, (12) varied trial design, (13) expanded access, and (14) public reporting of the personal characteristics of participants in trials. Applying this reference standard, 48% (24/50) of companies had no public policy on diversity in clinical trials; among those with policies, content varied widely. Large companies were more likely to have a public policy than non-large companies (21/25, 84% v 5/25, 20%, P<0.001). Large companies most frequently committed to using epidemiological based trial enrollment targets representing the prevalence of indicated conditions in various populations (n=15, 71%), dealing with barriers to trial recruitment (n=15, 71%), and improving patient awareness of trial opportunities (n=14, 67%). The location of the company was not associated with having a public diversity policy (P=0.17). The average company policy had five of the 14 commitments (36%, range 0-8) recommended in FDA and stakeholder guidance. Conclusions: The findings of the study showed that many pharmaceutical companies did not have public policies on diversity in clinical trials, although policies were more common in large than non-large companies. Policies that were publicly available varied widely and lacked important commitments recommended by stakeholder guidance. The results of the study suggest that corporate policies can be better leveraged to promote representation and fair inclusion in research, and implementation of FDA and stakeholder guidance.

Feasibility of using real-world data to emulate substance use disorder clinical trials: a cross-sectional study.

INTRODUCTION: Real-world evidence is receiving considerable attention as a way to evaluate the efficacy and safety of medical products for substance use disorders (SUDs). However, the feasibility of using real-world data (RWD) to emulate clinical trials evaluating treatments for SUDs is uncertain. The aim of this study is to identify the number of clinical trials evaluating treatments for SUDs with reported results that could be feasibly emulated using observational data from contemporary insurance claims and/or electronic health record (EHR) data. METHODS: In this cross-sectional study, all phase 2-4 trials evaluating treatments for SUDs registered on ClinicalTrials.gov with reported results were identified. Each trial was evaluated to determine if the indications, interventions, at least 80% of eligibility criteria, comparators, and primary end points could be ascertained using contemporarily available administrative claims and/or structured EHR data. RESULTS: There were 272 SUD trials on ClinicalTrials.gov with reported results. Of these, when examining feasibility using contemporarily available administrative claims and/or structured EHR data, 262 (96.3%) had indications that were ascertainable; 194 (71.3%) had interventions that were ascertainable; 21 (7.7%) had at least 80% of eligibility criteria that were ascertainable; 17 (6.3%) had active comparators that were ascertainable; and 61 (22.4%) had primary end points that were ascertainable. In total, there were no trials for which all 5 characteristics were ascertainable using contemporarily available administrative claims and/or structured EHR data. When considering placebo comparators as ascertainable, there were 6 (2.2%) trials that had all 5 key characteristics classified as ascertainable from contemporarily available administrative claims and/or structured EHR data. CONCLUSIONS: No trials evaluating treatments for SUDs could be feasibly emulated using contemporarily available RWD, demonstrating a need for an increase in the resolution of data capture within a public health system to facilitate trial emulation.

Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies.

Importance: The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used. Objective: To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points. Design, Setting, and Participants: This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024. Main Outcomes and Measures: Descriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments. Results: From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication. Conclusions and Relevance: In this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

At-Home Testing for Survivors of Sexual Assault-Empowerment or Exploitation?

In this Viewpoint, the accuracy, usefulness, and marketing of at-home rape kits is explored.

High-throughput Oxford Nanopore sequencing-based approach for the multilocus sequence typing analysis of large-scale avian Escherichia coli study in Mississippi.

Avian pathogenic Escherichia coli (APEC) cause avian colibacillosis and accurately distinguishing infectious isolates is critical for controlling its transmission. Multilocus sequence typing (MLST) is an accurate and efficient strain identification method for epidemiological surveillance. This research aimed to develop a fast and high-throughput workflow that simultaneously sequences the Achtman typing scheme's 7 housekeeping genes of multiple E. coli isolates using the Oxford Nanopore Technologies (ONT) platform for large-scale APEC study. E. coli strains were isolated from poultry farms, the housekeeping genes were amplified, and amplicons were sequenced on an R9.4 MinION flow cell using the Nanopore GridION sequencer (ONT, Oxford, UK) following the initial workflow (ONT-MLST). Moreover, the workflow was revised by introducing large-scale DNA extraction and multiplex PCR into the ONT-MLST workflow and applied to 242 new isolates, 18 isolates from the previous workflow, and 5 ATCC reference strains using Flongle flow cell on the Nanopore MinION Mk1C sequencer (ONT, Oxford, UK). Finally, the sequence type (ST) results of the 308 isolates collected from infected chickens and poultry farm environments were reported and analyzed. Data indicated that E. coli belonging to ST159, ST8578, and ST355 have the potential to infect multiple organs in broiler. In addition, zoonotic STs, ST69, ST10, ST38, and ST131, were detected from poultry farms. With the advantages of the high throughput of ONT, this study provides a rapid workflow for large-scale E. coli typing and identified frequently isolated sequence types related to APEC infection in poultry.

Estimating The Effects Of COVID-19 On Globalized Markets For Active Pharmaceutical Ingredients.

Global supply chains for active pharmaceutical ingredients (APIs) are highly centralized in certain countries and are susceptible to supply-chain shocks. However, there is no systematic monitoring or global coordination to manage risk and ensure equitable supply continuity during public health emergencies. In this study, we applied quasi-experimental methods on shipment-level customs data to determine how prices and export volume for APIs exported from India were affected by the COVID-19 pandemic. We found that API prices for key essential medicines not used for COVID-19 did not change significantly in the year after the World Health Organization pandemic declaration, but volume decreased by 80 percent. Prices for medicines speculatively repurposed for COVID-19, such as hydroxychloroquine and ivermectin, increased by as much as 250 percent compared with prices for nonrepurposed medicines, but only ivermectin saw a decrease in volume. Systematic monitoring of API markets, investments to promote supply diversification, and legal and political reforms to disincentivize price speculation could support supply-chain resilience and safeguard access to medicines.

Funding of evidence included within public comments submitted to inform Medicare national coverage determinations.

The Centers for Medicare & Medicaid Services (CMS) relies on public comments submitted in response to proposed national coverage determinations to assist the agency in determining the coverage of items and services for Medicare beneficiaries. In a cross-sectional study, we characterized the cited evidence and what funding supported the cited evidence submitted in public comments to CMS for all therapeutic medical device national coverage determinations finalized between June 2019 and June 2022. Of 681 public comments, 159 (23%) cited at least 1 identifiable published scientific journal article. Within these 159 public comments, 198 unique articles were cited, 170 (86%) of which included funding statements or author disclosures. Among these, 96 (56%) disclosed funding from manufacturers that would benefit from Medicare coverage and/or were written by author(s) who received funding from these manufacturers. In summary, most public commenters for national coverage determinations did not cite published scientific journal articles to support their positions. Among those who did, more than half of articles were directly funded by manufacturers that would benefit from coverage. Greater funding of independent, non-industry-supported research may help provide unbiased evaluations of benefits and harms to support Medicare coverage decisions.

Consent Form Reporting on ClinicalTrials.Gov, 2013-2023.

This cross-sectional study examines the availability of consent forms for National Institutes of Health­funded trials on ClinicalTrials.gov.

Evaluating the effects of virulence genotype, swarming motility, and multi-locus sequence types of Escherichia coli on layer chicken embryos.

AIMS: To determine the effects of swarming motility (SM) and multi-locus sequence types (MLST) on the main effect of virulence genotype of Escherichia coli through an embryos lethality assay between the 12th and 18th days of incubation. METHODS AND RESULTS: We collected 58 E. coli isolates from asymptomatic commercial hens (n = 42) and lesions of colibacillosis cases (n = 16), then classified their virulence genotype as avirulent, moderately virulent, virulent-healthy, and virulent-colibacillosis categories by the presence of five virulence-associated genes (iroN, ompT, hlyF, iutA, and iss). These isolates were further classified as non-motile, motile, or hyper-motile by SM assay. From the 58 isolates, we selected 29 for ELA and determined their MLST. Each isolate was inoculated into 15 embryonated eggs through the allantoic cavity. We found the avirulent isolates reduced the relative embryo weight compared to virulent-colibacillosis and moderately virulent isolates (37.49 vs. 41.51 and 40.34%, P = 0.03). Among the moderately virulent and virulent-colibacillosis categories, embryo lethality was lower when isolates were non-motile. Yolk retention was unaffected by virulence categories, motility, or MLST. CONCLUSION: Interaction between virulence genotype and SM substantially influenced the embryo lethality assay of E. coli isolates.

A Public Option for Clinical Trials? Lessons from Convalescent Plasma.

The case of clinical trials for convalescent plasma during COVID-19 illustrates important lessons for realizing public sector approaches to biomedical research and development. These lessons, centering on mission, transparency, and spillover effects, can be translated to wider efforts to develop a "public option" for clinical trials.

Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments.

Importance: Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals. Objective: To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases. Data sources: The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023. Study Selection: Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded. Data Extraction and Synthesis: Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes. Main Outcomes and Measures: Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized. Results: Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result. Conclusions and Relevance: Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Increase in temperature facilitates Campylobacter jejuni biofilm formation under both aerobic and microaerobic incubation.

The formation of Campylobacter jeuni biofilms on processing surfaces is a significant concern in poultry processing, contributing to food safety risks. This study focused on assessing the biofilm forming capabilities of 12 field isolates of C. jejuni of different aerotolerance categories on stainless steel surfaces, a prevalent material in poultry processing environments. Working cultures of each isolate were prepared to approximately 6 log CFU/mL and incubated on stainless steel coupons under microaerobic or aerobic conditions at room temperature or 42°C for 72 h. Biofilm attached cells were enumerated using direct plating and biofilm density was measured using a crystal violet assay by measuring the optical density (OD600) a. Data analysis was conducted using the PROC GLIMMIX procedure in SAS 9.4 with a significance level of 0.05. The study revealed a notable interaction between aerotolerance categories and temperature (P < 0.039) impacting the number of biofilms attached C. jejuni cells on stainless steel coupons. All isolates had significantly higher counts when incubated at 42°C compared to room temperature, regardless of oxygen level (P < 0.001). Furthermore, stronger biofilm density was observed at 42°C compared to room temperature, regardless of oxygen level. These findings underscore the influence of temperature on the biofilm forming ability of C. jejuni. The ability of these field isolates to form biofilms under various environmental conditions suggests a heightened potential for surface colonization and increased infection risk in poultry processing facilities.

Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study.

Objectives: To evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results of confirmatory trials after approval and based on status updates from the US Food and Drug Administration (FDA). Design: Cross sectional study. Setting: US FDA and NCCN guidelines. Population: Oncology therapeutic indications (ie, specific oncological conditions for which the drug is recommended) that have been granted accelerated approval in 2009-18. Main outcome measures: NCCN guideline reporting of accelerated approval status and postapproval confirmatory trials, and guideline recommendation alignment with postapproval confirmatory trial results and FDA status updates. Results: 39 oncology drug treatments were granted accelerated approval for 62 oncological indications. Although all indications were recommended in NCCN guidelines, accelerated approval status was reported for 10 (16%) indications. At least one postapproval confirmatory trial was identified for all 62 indications, 33 (53%) of which confirmed benefit; among these indications, NCCN guidelines maintained the previous recommendation or strengthened the category of evidence for 27 (82%). Postapproval confirmatory trials failed to confirm benefit for 12 (19%) indications; among these indications, NCCN guidelines removed the previous recommendation or weakened the category of evidence for five (42%). NCCN guidelines reflected the FDA's decision to convert 30 (83%) of 36 indications from accelerated to traditional approval, of which 20 (67%) had guideline updates before the FDA's conversion decision. NCCN guidelines reflected the FDA's decision to withdraw seven (58%) of 12 indications from the market, of which four (57%) had guidelines updates before the FDA's withdrawal decision. Conclusions: NCCN guidelines always recommend drug treatments that have been granted accelerated approval for oncological indications, but do not provide information about their accelerated approval status, including surrogate endpoint use and status of postapproval confirmatory trials. NCCN guidelines consistently provide information on postapproval trial results confirming clinical benefit, but not on postapproval trials failing to confirm clinical benefit. NCCN guidelines more frequently update recommendation for indications converted to traditional approval than for those approvals that were withdrawn.

Trans-Cinnamaldehyde Primes More Robust Channel Catfish Immune Responses to Edwardsiella ictaluri Infection.

Infection with Edwardsiella ictaluri, a causative agent of enteric septicemia of catfish, threatens profitable catfish production through inventory losses. We previously demonstrated that trans-cinnamaldehyde (TC) enhances the survival of catfish following E. ictaluri infection. The present study was conducted to investigate catfish immune responses to TC feeding and E. ictaluri infection. The expression of 13 proinflammatory, innate, and adaptive immune-related genes was evaluated over time in two sets of experiments using real-time polymerase chain reaction (PCR). In the first experiment, catfish were fed a basal diet with or without TC supplementation, while in the second they were fed a TC-supplemented or normal diet followed by infection with E. ictaluri. The catfish group infected with E. ictaluri and fed a TC-diet showed significant changes in the expression of innate and adaptive immune-related genes compared to control group. At 21 and 28 days post-infection, recovered fish showed significant increases in the expression of IgM in the anterior kidney and spleen. These results suggest that the supplemental dietary intake of TC can improve the immune status of catfish via engaging innate and adaptive immune responses and the production of memory cells in immunocompetent tissues. Together, this study provides an important foundation for the potential application of TC as an antimicrobial alternative in aquaculture.

Lessons From Insulin: Policy Prescriptions for Affordable Diabetes and Obesity Medications.

Escalating insulin prices have prompted public scrutiny of the practices of drug manufacturers, pharmacy benefit managers, health insurers, and pharmacies involved in production and distribution of medications. As a result, a series of policies have been proposed or enacted to improve insulin affordability and foster greater equity in access. These policies have implications for other diabetes and obesity therapeutics. Recent legislation, at both the state and federal level, has capped insulin out-of-pocket payments for some patients. Other legislation has targeted drug manufacturers directly in requiring rebates on drugs with price increases beyond inflation rates, an approach that may restrain price hikes for existing medications. In addition, government negotiation of drug pricing, a contentious issue, has gained traction, with the Inflation Reduction Act of 2022 permitting limited negotiation for certain high expenditure drugs without generic or biosimilar competition, including some insulin products and other diabetes medications. However, concerns persist that this may inadvertently encourage higher launch prices for new medications. Addressing barriers to competition has also been a priority such as through increased enforcement against anticompetitive practices (e.g., "product hopping") and reduced regulatory requirements for biosimilar development and market entry. A novel approach involves public production, exemplified by California's CalRx program, which aims to provide biosimilar insulins at significantly reduced prices. Achieving affordable and equitable access to insulin and other diabetes and obesity medications requires a multifaceted approach, involving state and federal intervention, ongoing policy evaluation and refinement, and critical examination of corporate influences in health care.

Medicare Part B and Part D drug eligibility for center for Medicare and Medicaid Services price negotiation under the Inflation Reduction Act: estimates using 2016-2019 data.

Background: To reduce Medicare prescription drug expenditures, the 2022 Inflation Reduction Act (IRA) allows the Centers for Medicare & Medicaid Services (CMS) to directly negotiate with drug manufacturers on Medicare prices of high-expenditure drugs (≥$200m annual spending) which meet certain eligibility criteria. However, it is unclear what proportion of high-expenditure drugs covered by Medicare, and attributable annual drug spending, would typically be eligible for CMS negotiations in a given year. Methods: We used historical Medicare drug spending data to determine how many high-expenditure drugs, and attributable drug spending, would have been eligible for CMS negotiations had the IRA been in effect from 2016-2019, while also determining which of the IRA's eligibility criteria is most restrictive. Results: From 2016-2019, approximately one third (33.3% for Part B, 32.4% for Part D) of high-expenditure Medicare drugs would have been eligible for negotiation, with ineligible drugs accounting for 75.2% and 63.8% of spending on high-expenditure drugs in Medicare Part B and D, respectively. Most ineligible high-expenditure drugs were ineligible because they launched too recently. From 2016-2019, between 59 and 74 high-expenditure drugs were eligible per year, indicating that in some years there may not be enough eligible drugs for CMS to negotiate on the maximum number of drugs allowable by law. Conclusions: The IRA's current eligibility criteria may restrict CMS from being able to negotiate drug prices on approximately two-thirds of the high-expenditure drugs covered by Medicare and may not allow CMS to negotiate on the maximum number of drugs allowable by law. Congress could consider relaxing eligibility requirements for price negotiation, such as those pertaining to launch date recency, to ensure there are a sufficient number of high-expenditure drugs eligible for negotiation or make certain ineligible drugs contributing to significant annual Medicare spending eligible for negotiation on a case-by-case basis.

Implications for Public Health Regulation if Chevron Deference Is Overturned.

This Viewpoint describes implications for medicine and public health if the US Supreme Court decides to overturn or narrow Chevron deference.