Leah Z. Rand, Daniel P. Carpenter, Aaron S. Kesselheim, Anushka Bhaskar, Jonathan J. Darrow, and William B. Feldman Reply.

The authors respond to a letter by Mitchell Berger in the March-April 2024 issue of the Hastings Center Report concerning their essay "Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines."

Securing the Trustworthiness of the FDA to Build Public Trust in Vaccines.

The Covid-19 pandemic highlighted the need to examine public trust in the U.S. Food and Drug Administration (FDA) vaccine approval process and the role of political influence in the FDA's decisions. Ensuring that the FDA is itself trustworthy is important for justifying public trust in its actions, like vaccine approvals, thereby promoting public health. We propose five conditions of trustworthiness that the FDA should meet when it reviews vaccines, even during emergencies: consistency with rules, proper expert or political decision-makers, proper decision-making and noninterference, connection to public preference, and transparency of both reasons and procedures. The five conditions provide a road map of procedural and substantive requirements, which the FDA has variably implemented, focused on ensuring appropriate influence of political interests. While being a trustworthy agency cannot guarantee the public's trust, implementing these conditions builds a groundwork for public trust.

The Revolving Door In Health Care Regulation.

Of people appointed to the Department of Health and Human Services between 2004 and 2020, 15 percent had been employed in private industry immediately before their appointment. At the end of their tenure, 32 percent exited to industry. The greatest net exits to industry were from the Centers for Disease Control and Prevention and the Centers for Medicare and Medicaid Services.

What Should Be Clinicians' Roles in Regulatory Assessment of Prospective Interventions' Risks of Exacerbating Inequity?

When there is an evidence base that could be used credibly to justify expedited US Food and Drug Administration review, emergency use authorization, or approval, interventions-in-development must be evaluated in terms of their possible downstream influence on public trust and confidence in regulatory processes during a national public health crisis. When regulatory decisions express overconfidence about a prospective intervention's success, there is risk that the costliness of or misinformation about the intervention will exacerbate health inequity. A converse risk is regulators' underestimation of an intervention's value in treating populations at risk for inequitable care. This article considers the nature and scope of clinicians' roles in regulatory processes in which such risks must be considered and balanced to promote public safety and public health.

Land use and soil characteristics affect soil organisms differently from above-ground assemblages.

BACKGROUND: Land-use is a major driver of changes in biodiversity worldwide, but studies have overwhelmingly focused on above-ground taxa: the effects on soil biodiversity are less well known, despite the importance of soil organisms in ecosystem functioning. We modelled data from a global biodiversity database to compare how the abundance of soil-dwelling and above-ground organisms responded to land use and soil properties. RESULTS: We found that land use affects overall abundance differently in soil and above-ground assemblages. The abundance of soil organisms was markedly lower in cropland and plantation habitats than in primary vegetation and pasture. Soil properties influenced the abundance of soil biota in ways that differed among land uses, suggesting they shape both abundance and its response to land use. CONCLUSIONS: Our results caution against assuming models or indicators derived from above-ground data can apply to soil assemblages and highlight the potential value of incorporating soil properties into biodiversity models.

Symptomatic aseptic loosening of a short humeral stem following anatomic total shoulder arthroplasty.

INTRODUCTION: The rate of aseptic humeral component loosening with standard-length stems is historically so low (0.3%) that presence of humeral loosening was given substantial weight in defining periprosthetic shoulder infection by the International Consensus Meeting (ICM) in 2018. This study aims to confirm that the historically low rate of humeral stem aseptic loosening is not affected by the adoption of a novel short humeral stem. METHODS: Following institutional review board approval, this retrospective multi-institutional study was undertaken. A review of anatomic total shoulder arthroplasty (TSA) cases at 3 institutions provided 184 shoulders that received TSA with a grit-blasted, rectangular short humeral stem without ingrowth coating (Univers Apex; Arthrex). The average patient age was 62.1 years (range: 30-84), and 57.1% (105/184) were male. One-year radiographic follow-up was achieved in 64.7%. Patient clinical charts were reviewed for onset of newly painful shoulders, radiographic evidence of loosening, and return to the operating room for any reason. All patients with concern for clinically significant humeral loosening underwent workup for periprosthetic shoulder infection. Immediate postoperative films were reviewed to identify any differences in prosthetic canal fit. The definition of periprosthetic shoulder infection used was provided by the recent ICM shoulder guidelines. RESULTS: Twenty-three (12.5%) patients presented with a painful shoulder and radiographic concern for potential humeral loosening at a mean follow-up of 1.5 years (range: 1.5 months-3.4 years). Thirteen (7.1%) of these underwent revision shoulder arthroplasty where a loose stem was confirmed. All revisions underwent tissue culture, and 3 cases were consistent with probable or possible periprosthetic infection at the time of revision arthroplasty. The rate of symptomatic aseptic humeral loosening in this series was 10.9% (20/184), with 5.4% undergoing revision surgery. Patients with symptomatic aseptic humeral loosening were more likely to be male (90.5%) than those patients without symptoms (52.8%, P < .001). There were no differences in canal fit between patients with concern for symptomatic loosening and those with pain-free, stable implants. CONCLUSION: In this multisurgeon, multicenter study, the early humeral loosening rate for this stem design far outpaces previously reported rates, and this study likely under-reports the true incidence of clinically significant loosening as it only contains limited short-term follow-up. The perception that humeral loosening is nearly pathognomonic for periprosthetic shoulder infection should be reconsidered for certain short humeral stem designs.

Trends in open shoulder surgery among early career orthopedic surgeons: who is doing what?

BACKGROUND: The incidence of various open shoulder procedures has changed over time. In addition, various fellowships provide overlapping training in open shoulder surgery. There is a lack of information regarding the relationship between surgeon training and open shoulder procedure type and incidence in early career orthopedic surgeons. METHODS: The American Board of Orthopaedic Surgery Part-II database was queried from 2002 to 2016 for reported open shoulder procedures. The procedures were categorized as follows: arthroplasty, revision arthroplasty, open instability, trauma, and open rotator cuff. We evaluated procedure trends as well as their relationship to surgeon fellowship categorized by Sports, Shoulder/Elbow, Hand, Trauma, and "Other" fellowship as well as no fellowship training. We additionally evaluated complication data as it related to procedure, fellowship category, and volume. RESULTS: Over the 2002-2016 study period, there were increasing cases of arthroplasty, revision arthroplasty, and trauma (P < .001). There were decreasing cases in open instability and open rotator cuff (P < .001). Those with Sports training reported the largest overall share of open shoulder cases. Those with Shoulder/Elbow training reported an increasing overall share of arthroplasty cases and higher per candidate case numbers. The percentage of early career orthopedic surgeons reporting 5 or more arthroplasty cases was highest among Shoulder/Elbow candidates (P < .001). Across all procedures, those without fellowship training were least likely to report a complication (odds ratio [OR], 0.76; 95% confidence interval, 0.67-0.86; P < .001). Shoulder/Elbow candidates were least likely to report an arthroplasty complication (OR, 0.84, P = .03) as was any surgeon reporting 5 or more arthroplasty cases (OR, 0.81; 95% confidence interval, 0.70-0.94; P = .006). CONCLUSION: The type and incidence of open shoulder surgery procedures continues to change. Among early career surgeons, those with more specific shoulder training are now performing the majority of arthroplasty-related procedures, and early career volume inversely correlates with complications.

Clinical Outcomes and Cadaveric Biomechanical Analysis of Endoscopic Percutaneous Achilles Tendon Rupture Repair With Absorbable Suture.

BACKGROUND: Percutaneous repair of acute Achilles tendon rupture (ATR) continues to gain in popularity. The primary aim of the study was to review the outcomes of a patient cohort undergoing a novel technique of endoscopic percutaneous Achilles tendon repair with absorbable suture. A secondary purpose of this study was to evaluate the basic biomechanical properties of the technique. METHODS: A cohort of 30 patients who underwent percutaneous ATR repair was retrospectively analyzed with Achilles Tendon Rupture Scores (ATRS), complications, and additional outcome measures. For a biomechanical analysis portion of the study, 12 cadaveric specimens were paired and randomized to either novel percutaneous repair or open Kessler repair with absorbable suture. These specimens were subjected to 2 phases of cyclical testing (100 cycles 10-43 N followed by 200 cycles 10-86 N) and ultimate strength testing. RESULTS: In the clinical portion of the study we report excellent patient reported outcomes (mean ATRS 94.1), high level of return to sport, and high patient satisfaction. One partial re-rupture was reported but with no major wound or neurologic complications. In the biomechanical portion of the study we found no significant difference in tendon gapping between percutaneous and open repairs in phase 1 of testing. In phase 2, increased gapping occurred between percutaneous (17.8 mm [range 10.7-24.1, SD 6.4]) and open repairs (10.8 mm [range 7.6-14.9, SD 2.7, P = .037]). The ultimate load at failure was not statistically different between the 2 repairs. CONCLUSIONS: A percutaneous ATR repair technique using endoscopic assistance and absorbable suture demonstrated low complications and good outcomes in a cohort of patients, with high satisfaction, and excellent functional outcomes including high rates of return to sport. Cadaveric biomechanical testing demonstrated excellent survival during testing and minimal increase in gapping compared with open repair technique, representing sufficient strength to withstand forces seen in early rehabilitation. A percutaneous Achilles tendon repair technique with absorbable suture may minimize risks associated with operative repair while still maintaining the benefit of operative repair. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Molecular weight distribution of raw and catalytic fast pyrolysis oils: comparison of analytical methodologies.

Comprehensive analysis of the molecular weight distribution of raw and catalytic fast pyrolysis oils derived from biomass remains a key technical hurdle to understanding oil quality as it relates to downstream use and multiple methods may be necessary to accurately represent all components present. Here, we report the molecular weight distribution metrics of fast pyrolysis (FP) and catalytic fast pyrolysis (CFP) oils as determined by gel permeation chromatography (GPC) combined with UV-diode array (UV), differential refractive index (RI), and multi-angle laser light scattering (MALS) detection. The measured molar mass distributions revealed that FP oil consisted of a higher proportion of larger products relative to the low molecular weight products contained in the CFP oil. GPC/RI and UV methods showed FP oil to have higher weight-average molecular weight (M w) and number-average molecular weight (M n) than CFP oil based on elution time. However, GPC/MALS, determined the two oils to have similar overall molecular weight distribution metrics (M w and M n) and yielded values significantly higher than those determined by RI and UV detectors relative to external standards. Overall, the use of a multiple detection GPC method could enable a more accurate comparison and determination of true molecular weight metrics of bio-oils.

US Nationwide Disclosure of Industry Payments and Public Trust in Physicians.

Importance: Transparency of industry payments to physicians could engender greater public trust in physicians but might also lead to greater mistrust of physicians and the medical profession, adversely affecting the patient-physician relationship. Objective: To examine the association between nationwide public disclosure of industry payments and Americans' trust in their physicians and trust in the medical profession. Design, Setting, and Participants: Survey study using difference-in-difference analyses of a national longitudinal survey comparing changes in states where industry payments were newly disclosed by Open Payments with changes in states where payments information was already available because of state sunshine laws. The US population-based surveys were conducted in September 2014-shortly before the initial public disclosure of industry payments-and again in September 2016. Final analyses were conducted September through December 2018. Participants were adults 18 years and older (n = 1388). Exposures: National public disclosure through Open Payments of payments made by pharmaceutical and medical device firms to physicians. Main Outcomes and Measures: Wake Forest measure of trust in one's own physician and Wake Forest measure of trust in the medical profession. Results: Of the 3542 original survey respondents, 2180 (61.5%) completed the second survey 2 years later, and 1388 named the same most frequently seen physician in both surveys. The mean age of respondents at the time of the first survey was 53 years, and 749 (54.0%) were women. Race/ethnicity was white in 76.6% (1063 of 1388) and non-Hispanic black in 8.0% (111 of 1388). Public disclosure of payments was associated with lower trust in one's own physician regardless of whether respondents knew their physicians had received payments (decrease in Wake Forest measure of trust in one's own physician of 0.56 point; 95% CI, -0.79 to -0.32 point; P < .001). Open Payments was also associated with lower trust in the medical profession (decrease in Wake Forest measure of trust in the medical profession of 0.35 point; 95% CI, -0.58 to -0.12 point; P = .004). Conclusions and Relevance: Nationwide public disclosure of industry payments may be associated with decreased trust in physicians and in the medical profession. More judicious presentation of payments information may counteract unintended negative trust and spillover consequences of public disclosure.

Effect of the public disclosure of industry payments information on patients: results from a population-based natural experiment.

OBJECTIVE: To determine the effect of the public disclosure of industry payments to physicians on patients' awareness of industry payments and knowledge about whether their physicians had accepted industry payments. DESIGN: Interrupted time series with comparison group (difference-in-difference analyses of longitudinal survey). SETTING: Nationally representative US population-based surveys. Surveys were conducted in September 2014, shortly prior to the public release of Open Payments information, and again in September 2016. PARTICIPANTS: Adults aged 18 and older (n=2180). MAIN OUTCOME MEASURES: Awareness of industry payments as an issue; awareness that industry payments information was publicly available; knowledge of whether own physician had received industry payments. RESULTS: Public disclosure of industry payments information through Open Payments did not significantly increase the proportion of respondents who knew whether their physician had received industry payments (p=0.918). It also did not change the proportion of respondents who became aware of the issue of industry payments (p=0.470) but did increase the proportion who knew that payments information was publicly available (9.6% points, p=0.011). CONCLUSIONS: Two years after the public disclosure of industry payments information, Open Payments does not appear to have achieved its goal of increasing patient knowledge of whether their physicians have received money from pharmaceutical and medical device firms. Additional efforts will be required to improve the use and effectiveness of Open Payments for consumers.

Proximal Humeral Locking Plates: A Cadaveric Study of 5 Versus 7 Metaphyseal Locking Screws.

The most common operative treatment of proximal humerus fractures is internal fixation with fixed-angle locking plates. Although this surgical technique has been refined, a significant failure rate remains. This study aimed to determine whether the number of locking screws in the humeral head affects the biomechanical strength and stability of the construct in bone from elderly individuals. Ten pairs of embalmed cadaveric humeri were osteotomized in a gap model and fixed with periarticular locking plates placed in the standard position. Five or 7 proximal locking screws were inserted. Mechanical testing was performed, and cyclic displacements and maximum force to failure were recorded. No significant difference was found between 5 and 7 locking screws in mean cyclic displacement on the medial (1.09 mm vs 1.12 mm, P=.834) or posterior (0.45 mm vs 0.42 mm, P=.791) sides of the fracture model. On testing to failure, 7 and 5 screws showed similar stiffness (336 N/mm vs 292 N/mm, P=.176), force at ultimate load (745 N vs 662 N, P=.309), and displacement at ultimate load (5.90 mm vs 4.36 mm, P=.080). All samples failed at diaphyseal fixation, and no screw cutout or varus collapse was observed. Results from this study suggest that there is no significant difference between 5 and 7 metaphyseal locking screws for stiffness of fixation of proximal humeral fractures in elderly patients. With the inherent possibility of screw penetration of the humeral head, fewer screws may lead to fewer complications. [Orthopedics. 2018; 41(5):306-311.].

Spontaneous Healing of a Bucket-Handle Posterior Labral Detachment After Hip Dislocation in a Five-Year-Old Child: A Case Report.

CASE: We report the case of a 5-year-old girl who sustained a traumatic hip dislocation and a spontaneous reduction that was complicated by nonconcentric reduction and a large bucket-handle labral detachment. This injury was managed, via an anterior approach, with capsulotomy and reduction of the large interposed labral tear with an attached osteochondral fragment from the posterior aspect of the acetabulum. No additional surgical treatment was employed for the labral tear. CONCLUSION: The patient ultimately demonstrated radiographic healing and an asymptomatic, clinically stable hip. This case illustrates the spontaneous healing of a large posterior labral detachment in a young pediatric patient with a good outcome at 2.5 years after injury.

Tobacco industry response to a ban on lights descriptors on cigarette packaging and population outcomes.

OBJECTIVE: The WHO Framework Convention on Tobacco Control and its Guidelines recommend nations ban the use of misleading terms, such as 'light' and 'mild' on tobacco product advertising, packaging and labelling. Many nations, including the USA, have implemented such bans and some have introduced or passed legislation requiring plain packaging on tobacco products. We previously reported that manufacturers in the USA responded by replacing lights terms with colour terms and related colour-coding of packages. This study examines population outcomes and public health impact of the US ban. METHODS: We examined available data regarding a) per cent filter ventilation strata used to designate lights subbrand categories; b) market share per tar yield; c) initiation and use of cigarettes by lights categories and d) overall cigarette consumption to identify changes from before to after the ban. We used interrupted time series multivariable logistic regression and joinpoint regression models to test for changes in rates and temporal trends associated with the ban. RESULTS: The per cent filter ventilation strata used to designate lights subbrand categories were maintained in the colour named subbrands. No change was observed following the ban in lights market share, relative prevalence of lights versus non-lights smoking or relative smoking initiation on lights versus non-lights among all ages or among youth in particular. The rate of decline in per capita cigarette consumption slowed by 37% from the period 2007-2010 to 2010-2014. CONCLUSIONS: This study strongly suggests that manufacturers' circumvention prevented the lights descriptor ban from succeeding as intended, most likely perpetuating the misleading consumer perceptions about relative risks, while failing to increase smoking cessation and reduce initiation. Laws requiring generic (plain) and elimination of subbrand descriptors should prevent evasion of legislation banning the use of specific terms through marketing, regulatory and legal challenges.

Expert Consensus Survey on Medication Adherence in Psychiatric Patients and Use of a Digital Medicine System.

BACKGROUND: There is an unmet need to objectively assess adherence problems that are a common cause of unexplained or unexpected suboptimal outcome. A digital medicine system (DMS) has been developed to address this need in patients with serious mental illness. OBJECTIVE: To conduct a quantitative expert consensus survey to (1) assess relative importance of causes of suboptimal outcomes, (2) examine modalities used to assess adherence, (3) provide guidance on when and how to use the DMS in clinical practice once available, and (4) suggest interventions for specific reasons for nonadherence. METHODS: A panel of 58 experts in psychiatry completed a 23-question survey (October 13 through December 23, 2013) and rated their responses on a 9-point Likert scale. A χ² test of score distributions was used to determine consensus (P < .05). RESULTS: The panel rated adherence as the most important factor in suboptimal outcomes and yet the least likely to be assessed accurately. All predefined uses of the DMS received high mean first-line ratings (≥ 7.4). The experts recognized the utility of the DMS in managing adherence problems, identified clinical situations appropriate for DMS, and assessed potential benefits and challenges of this technology. Consensus was reached on first-line interventions for 10 of 11 reasons for nonadherence. CONCLUSIONS: The results provide a guide to clinicians on the evaluation of suboptimal outcomes, when and how to use the DMS, and the most appropriate interventions to address detected adherence problems.

Public Awareness of and Contact With Physicians Who Receive Industry Payments: A National Survey.

BACKGROUND: The Physician Payments Sunshine Act, part of the Affordable Care Act, requires pharmaceutical and medical device firms to report payments they make to physicians and, through its Open Payments program, makes this information publicly available. OBJECTIVE: To establish estimates of the exposure of the American patient population to physicians who accept industry payments, to compare these population-based estimates to physician-based estimates of industry contact, and to investigate Americans' awareness of industry payments. DESIGN: Cross-sectional survey conducted in late September and early October 2014, with data linkage of respondents' physicians to Open Payments data. PARTICIPANTS: A total of 3542 adults drawn from a large, nationally representative household panel. MAIN MEASURES: Respondents' contact with physicians reported in Open Payments to have received industry payments; respondents' awareness that physicians receive payments from industry and that payment information is publicly available; respondents' knowledge of whether their own physician received industry payments. KEY RESULTS: Among the 1987 respondents who could be matched to a specific physician, 65% saw a physician who had received an industry payment during the previous 12 months. This population-based estimate of exposure to industry contact is much higher than physician-based estimates from the same period, which indicate that 41% of physicians received an industry payment. Across the six most frequently visited specialties, patient contact with physicians who had received an industry payment ranged from 60 to 85%; the percentage of physicians with industry contact in these specialties was much lower (35-56%). Only 12% of survey respondents knew that payment information was publicly available, and only 5% knew whether their own doctor had received payments. CONCLUSIONS: Patients' contact with physicians who receive industry payments is more prevalent than physician-based measures of industry contact would suggest. Very few Americans know whether their own doctor has received industry payments or are aware that payment information is publicly available.

Neurogenic Edema from Complex Regional Pain Syndrome Resulting in Fulminant Infection Necessitating Below Elbow Amputation.

We report a case of severe upper extremity complex regional pain syndrome type 1 (CRPS-1) and neurogenic edema that ultimately led to a medically necessary below-elbow amputation. The patient presented with a history of remote bilateral carpal tunnel release complicated by debilitating and recalcitrant bilateral CRPS-1. Following years of severe neurogenic edema of the left upper extremity, the patient had full-thickness skin sloughing on the dorsum of her hand due to massive edema. This subsequently led to maggot infestation of the soft tissues of the left hand ultimately necessitating amputation. We present the case as an illustration of an extreme case of neurogenic edema, a potential physical manifestation of CRPS-1. The case presented discusses upper extremity amputation as an end treatment option for CRPS-1, though in this case amputation was primarily indicated secondary to medical necessity.

Substantial Equivalence Standards in Tobacco Governance: Statutory Clarity and Regulatory Precedent for the FSPTCA.

The Family Smoking Prevention and Tobacco Control Act (FSPTCA) of 2009 creates the first national system of premarket regulation of tobacco products in American history. The FDA must now review and give marketing authorization to all new tobacco products, based on a public health standard, before they can be legally marketed. Yet the law also contains an alternative pathway for market entry-the substantial equivalence (SE) clause-by which novel and altered tobacco products can be marketed by demonstrating their substantial equivalence to existing products. Over 99 percent of tobacco product applications sent to the FDA under the new law have used this mechanism, and loose application of the SE mechanism carries the risk of undoing the FDA's gatekeeping power under the law. We review the statutory and regulatory precedent for SE, examining the FSPTCA itself as well as regulatory precedent from drug and device regulation (from which the term substantial equivalence and much of the associated statutory language was derived). Our review of standards and scientific precedent demonstrates that exacting scrutiny under the public health standard should govern all SE reviews and that clinical data incorporating social scientific evidence should be routinely required for SE claims by tobacco product sponsors.

Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results.

IMPORTANCE: Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research. OBJECTIVE: To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results. DESIGN, SETTING, AND PARTICIPANTS: Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product. MAIN OUTCOMES AND MEASURES: For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval. RESULTS: Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved. CONCLUSIONS AND RELEVANCE: Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.