Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Physicians' Perspectives On FDA Regulation Of Drugs And Medical Devices: A National Survey.

Physicians' knowledge of Food and Drug Administration (FDA) approval processes is important in informing clinical decisions and patient discussions. Among a randomly selected national sample of 509 internists, cardiologists, and oncologists, 41 percent reported moderate or better understanding of the FDA's drug approval process, and 17 percent reported moderate or better understanding of the FDA's medical device approval process. Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be very important factors required to secure regulatory approval. Also, nearly all physicians thought that the FDA should revoke approval for accelerated-approval drugs or breakthrough devices that did not show benefit in postapproval studies. Our findings suggest that physicians commonly lack familiarity with drug and medical device regulatory practices and are under the impression that the data supporting FDA drug and high-risk device approvals are more rigorous than they often are. Physicians would value more rigorous premarket evidence, as well as regulatory action for drugs and devices that do not demonstrate safety and effectiveness in the postmarket setting.

Updating the Know Your Chances Website to Include Smoking Status as a Risk Factor for Mortality Estimates.

Importance: To make wise decisions about the health risks they face, people need information about the magnitude of the threats as well as the context, such as how risks compare. Such information is often presented by age, sex, and race but rarely accounts for smoking status, a major risk factor for many causes of death. Objective: To update the National Cancer Institute's Know Your Chances website to present mortality estimates for a broad set of causes of death and all causes combined by smoking status in addition to age, sex, and race. Design, Setting, and Participants: In this cohort study, mortality estimates using life table methods were calculated with the National Cancer Institute's DevCan software package, combining data from the US National Vital Statistics System, National Health Interview Survey-Linked Mortality Files, National Institutes of Health-AARP (American Association of Retired Persons), Cancer Prevention Study II, Nurses' Health and Health Professions follow-up studies, and Women's Health Initiative. Data were collected from January 1, 2009, to December 31, 2018, and analyzed from August 27, 2019, to February 28, 2023. Main Outcomes and Measures: Age-conditional probabilities of dying due to various causes and all causes combined, accounting for competing causes of death, for people aged 20 to 75 years over the next 5, 10, or 20 years by sex, race, and smoking status. Results: A total of 954 029 individuals aged 55 years or older (55.8% women) were included in the analysis. Regardless of sex or race, for never-smokers, coronary heart disease represented the highest 10-year chance of death after about 50 years of age, which is higher than for any malignant neoplasm. Among current smokers, the 10-year chance of death due to lung cancer was almost as high as for coronary heart disease in each group. For Black and White female current smokers aged from the mid-40s onward, the 10-year probability of death due to lung cancer was substantially higher than for breast cancer. After 40 years of age, the observed effect of never vs current smoking on the 10-year chance of death due to all causes approximated adding 10 years of age. After 40 years of age when conditioning on smoking status, mortality risk for Black individuals was approximately that of White individuals 5 years older. Conclusions and Relevance: Using life table methods and accounting for competing risks, the revised Know Your Chances website presents age-conditional mortality estimates according to smoking status for a broad set of causes in the context of other conditions and all-cause mortality. The findings of this cohort study suggest that failing to account for smoking status results in inaccurate mortality estimates for many causes-namely, they are too low for smokers and too high for nonsmokers.

Physician Perspectives on the Food and Drug Administration's Decision to Grant Accelerated Approval to Aducanumab for Alzheimer's Disease.

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab, a monoclonal antibody indicated for the treatment of Alzheimer's disease. The accelerated approval decision was controversial due to concerns about the use of an unvalidated surrogate measure, beta-amyloid, as the basis for approval and a lack of clinical outcome benefit. Between October 2021 and September 2022, we conducted a survey of a nationally representative group of internists, medical oncologists, and cardiologists to understand perspectives around aducanumab's approval and how this FDA decision may influence trust in other drugs approved through the accelerated approval program. Among 214 physician respondents familiar with the accelerated approval of aducanumab, 184 (86%) would not prescribe or recommend aducanumab. Further, 143 (67%) physicians reported losing trust in other drugs approved through the accelerated approval program due to the FDA's decision with aducanumab. As a growing number of similar novel Alzheimer's disease treatments are on the horizon, the first of which, lecanemab, already has received accelerated approval in January 2023, our survey findings provide insight into the impact of the FDA's regulatory decisions on the perspectives and prescribing behavior of physicians concerning these novel drug treatments.

Communicating health information with visual displays.

Well-designed visual displays have the power to convey health messages in clear, effective ways to non-experts, including journalists, patients and policymakers. Poorly designed visual displays, however, can confuse and alienate recipients, undermining health messages. In this Perspective, we propose a structured framework for effective visual communication of health information, using case examples of three common communication tasks: comparing treatment options, interpreting test results, and evaluating risk scenarios. We also show simple, practical ways to evaluate a design's success and guide improvements. The proposed framework is grounded in research on health risk communication, visualization and decision science, as well as our experience in communicating health data.

Association between tobacco product use and asthma among US adults from the Population Assessment of Tobacco and Health (PATH) Study waves 2-4.

BACKGROUND: Research on cigarettes and adult asthma offers mixed findings, perhaps due to overlap with chronic obstructive pulmonary disease (COPD) and inadequate adjustment for other smoke exposures. Associations between other tobacco products, including e-cigarettes, and asthma are also understudied. RESEARCH QUESTION: Using Population Assessment of Tobacco and Health Study waves 2-4 (2014/2015-2016/2017) data, we assessed the relation between tobacco product use and asthma in persons unlikely to have COPD. STUDY DESIGN AND METHODS: Prospective study of 10 267 adults aged 18-39 years without COPD diagnoses. Past-month tobacco use at wave 2 was modelled first as combustible versus non-combustible use and second as specific product categories (former, cigarettes, e-cigarettes, cigars, hookah, smokeless tobacco). Outcomes included lifetime asthma prevalence at wave 2, incidence (waves 3 and 4) and Asthma Control Test score (lower=worse). Multivariable regressions adjusted for predictors of asthma, including other smoke exposures: cigarette pack-years, secondhand smoke and marijuana use. Sensitivity analyses examined findings when persons >39 years and those with both COPD and asthma were added, and when smoke exposure adjustments were removed. RESULTS: No product, including cigarettes and e-cigarettes, was associated with prevalence or incidence of asthma. Among people with asthma at wave 2, combustible tobacco (beta=-0.86, 95% CI (-1.32 to -0.39)) and cigarettes (beta=-1.14, 95% CI (-1.66 to -0.62)) were associated with worse asthma control. No tobacco product was associated with asthma control over time. In sensitivity analyses, tobacco use became associated with incident asthma as adults >39 years and those with asthma+COPD were added, and as adjustments for other smoke exposures were omitted. INTERPRETATION: Although cigarette use was associated with worse asthma control, there were no longitudinal associations between combustible tobacco or e-cigarette use and new onset or worsening asthma in these preliminary analyses. Research on tobacco and asthma should exclude COPD and adjust for smoking history and other smoke exposures.

Therapeutic Value of Drugs Frequently Marketed Using Direct-to-Consumer Television Advertising, 2015 to 2021.

This cohort study assesses whether drugs with the most direct-to-consumer television advertising represent advances over existing treatments.

Cancer overdiagnosis: a challenge in the era of screening.

"Screening" is a search for preclinical, asymptomatic disease, including cancer. Widespread cancer screening has led to large increases in early-stage cancers and pre-cancers. Ubiquitous public messages emphasize the potential benefits to screening for these lesions based on the underlying assumption that treating cancer at early stages before spread to other organs should make it easier to treat and cure, using more tolerable interventions. The intuition is so strong that public campaigns are sometimes launched without conducting definitive trials directly comparing screening to usual care. An effective cancer screening test should not only increase the incidence of early-stage preclinical disease but should also decrease the incidence of advanced and metastatic cancer, as well as a subsequent decrease in cancer-related mortality. Otherwise, screening efforts may be uncovering a reservoir of non-progressive and very slowly progressive lesions that were not destined to cause symptoms or suffering during the person's remaining natural lifespan: a phenomenon known as "overdiagnosis." We provide here a qualitative review of cancer overdiagnosis and discuss specific examples due to extensive population-based screening, including neuroblastoma, prostate cancer, thyroid cancer, lung cancer, melanoma, and breast cancer. The harms of unnecessary diagnosis and cancer therapy call for a balanced presentation to people considering undergoing screening, even with a test of accepted benefit, with a goal of informed decision-making. We also discuss proposed strategies to mitigate the adverse sequelae of overdiagnosis.

Tobacco Use and Respiratory Symptoms Among Adults: Findings From the Longitudinal Population Assessment of Tobacco and Health (PATH) Study 2014-2016.

INTRODUCTION: We examined the relationship between current tobacco use and functionally important respiratory symptoms. METHODS: Longitudinal cohort study of 16 295 US adults without COPD in Waves 2-3 (W2-3, 2014-2016) of the Population Assessment of Tobacco and Health Study. Exposure-Ten mutually exclusive categories of tobacco use including single product, multiple product, former, and never use (reference). Outcome-Seven questions assessing wheezing/cough were summed to create a respiratory symptom index; cutoffs of ≥2 and ≥3 were associated with functional limitations and poorer health. Multivariable regressions examined both cutoffs cross-sectionally and change over approximately 12 months, adjusting for confounders. RESULTS: All tobacco use categories featuring cigarettes (>2/3's of users) were associated with higher risk (vs. never users) for functionally important respiratory symptoms at W2, for example, at symptom severity ≥ 3, risk ratio for exclusive cigarette use was 2.34 [95% CI, 1.92, 2.85] and for worsening symptoms at W3 was 2.80 [2.08, 3.76]. There was largely no increased symptom risk for exclusive use of cigars, smokeless tobacco, hookah, or e-cigarettes (adjustment for pack-years and marijuana attenuated the cross-sectional e-cigarette association from 1.53(95% CI 0.98, 2.40) to 1.05 (0.67, 1.63); RRs for these products were also significantly lower compared to exclusive use of cigarettes. The longitudinal e-cigarette-respiratory symptom association was sensitive to the respiratory index cutoff level; exclusive e-cigarette use was associated with worsening symptoms at an index cutoff ≥ 2 (RR = 1.63 [1.02, 2.59]) and with symptom improvement at an index cutoff of ≥ 3 (RR = 1.64 [1.04, 2.58]). CONCLUSIONS: Past and current cigarette smoking drove functionally important respiratory symptoms, while exclusive use of other tobacco products was largely not associated. However, the relationship between e-cigarette use and symptoms was sensitive to adjustment for pack-years and symptom severity. IMPLICATIONS: How noncigarette tobacco products affect respiratory symptoms is not clear; some studies implicate e-cigarettes. We examined functionally important respiratory symptoms (wheezing/nighttime cough) among US adults without COPD. The majority of adult tobacco users smoke cigarettes and have higher risk of respiratory symptoms and worsening of symptoms, regardless of other products used with them. Exclusive use of other tobacco products (e-cigarettes, cigars, smokeless, hookah) was largely not associated with functionally important respiratory symptoms and risks associated with their use was significantly lower than for cigarettes. The association for e-cigarettes was greatly attenuated by adjustment for cigarette pack-years and sensitive to how symptoms were defined.

Tobacco Product Use and Functionally Important Respiratory Symptoms Among US Adolescents/Young Adults.

OBJECTIVE: The relation between respiratory symptoms and the range of tobacco product use among US adolescents/young adults is not yet clear. This cross-sectional analysis examines tobacco product use and respiratory symptoms in a nationally representative sample of 21,057 adolescents/young adults aged 12-24 years from Wave 4 (2016-17) of the Population Assessment of Tobacco and Health Study. METHODS: Presence of functionally important respiratory symptoms was defined by questions regarding wheezing and nighttime cough at a cutoff score associated with poorer functional health status. Past-30-day tobacco use was analyzed 2 ways: never-tobacco users (reference) versus combustible users, noncombustible-only users, and former users; or frequency of use of cigarettes and/or e-cigarettes. Weighted Poisson regression adjusted for past-30-day marijuana use, secondhand smoke exposure, and asthma. RESULTS: Functionally important respiratory symptoms were present in 10.0% overall: 13.8% of combustible users, 9.0% of noncombustible users, 8.2% of noncurrent users and 9.7% of never users. Functionally important respiratory symptoms were associated with combustible tobacco use (relative risk [RR] = 1.52[95% CI 1.29, 1.80]), marijuana use (RR = 1.54[1.34, 1.77]) and secondhand smoke exposure (RR = 1.04[1.03, 1.05]). Higher cigarette smoking frequency was also associated with functionally important respiratory symptoms for frequency categories >14 days/month (eg, RR = 1.93[1.50, 2.49] for 15-29 days/month). Frequency of e-cigarette use was not associated with functionally important respiratory symptoms. CONCLUSIONS: During 2016-17, smoking cigarettes, marijuana use, and secondhand smoke exposure were cross-sectionally associated with functionally important respiratory symptoms in adolescents/young adults. Risk increased with increased frequency of cigarette use but not e-cigarette use. Given changes to contemporary e-cigarettes and use, findings may not generalize to newer products.

A Procedure for Eliciting Women's Preferences for Breast Cancer Screening Frequency.

BACKGROUND: We evaluate the construct validity of a proposed procedure for eliciting lay preferences among health care policy options, suited for structured surveys. It is illustrated with breast cancer screening, a domain in which people may have heterogeneous preferences. METHODS: Our procedure applies behavioral decision research principles to eliciting preferences among policy options expressed in quantitative terms. Three-hundred women older than 18 y without a history of breast cancer were recruited through Amazon MTurk. Participants evaluated 4 screening options for each of 4 groups of women, with varying risk of breast cancer. Each option was characterized by estimates of 3 primary outcomes: breast cancer deaths, false alarms, and overdiagnosis resulting in unnecessary treatment of cancers that would not progress. These estimates were based on those currently being developed by the Breast Cancer Surveillance Consortium. For each risk group, participants stated how frequently they would wish to receive screening, if the predicted outcomes applied to them. RESULTS: A preregistered test found that preferences were robust enough to be unaffected by the order of introducing and displaying the outcomes. Other tests of construct validity also suggested that respondents generally understood the task and expressed consistent preferences. Those preferences were related to participants' age and mammography history but not to measures of their numeracy, subjective numeracy, or demographics. There was considerable heterogeneity in their preferences. CONCLUSIONS: Members of the public can be engaged more fully in informing future screening guidelines if they evaluate the screening options characterized by the expected health outcomes expressed in quantitative terms. We offer and evaluate such a procedure, in terms of its construct validity with a diverse sample of women. HIGHLIGHTS: A novel survey method for eliciting lay preferences for breast cancer screening is proposed and evaluated in terms of its construct validity.Participants were generally insensitive to irrelevant task features (e.g., order of presentation) and sensitive to relevant ones (e.g., quantitative estimates of breast cancer risk, harms from screening).The proposed method elicits lay preferences in terms that can inform future screening guidelines, potentially improving communication between the public and policy makers.

Difficulty Obtaining Behavioral Health Services for Children: A National Survey of Multiphysician Practices.

PURPOSE: In the United States, primary care practices rely on scarce resources to deliver evidence-based care for children with behavioral health disorders such as depression, anxiety, other mental illness, or substance use disorders. We estimated the proportion of practices that have difficulty accessing these resources and whether practices owned by a health system or participating in Medicaid accountable care organizations (ACOs) report less difficulty. METHODS: This national cross-sectional study examined how difficult it is for practices to obtain pediatric (1) medication advice, (2) evidence-based psychotherapy, and (3) family-based therapy. We used the National Survey of Healthcare Organizations and Systems 2017-2018 (46.9% response rate), which sampled multiphysician primary and multispecialty care practices including 1,410 practices that care for children. We characterized practices' experience as "difficult" relative to "not at all difficult" using a 4-point ordinal scale. We used mixed-effects generalized linear models to estimate differences comparing system-owned vs independent practices and Medicaid ACO participants vs nonparticipants, adjusting for practice attributes. RESULTS: More than 85% of practices found it difficult to obtain help with evidence-based elements of pediatric behavioral health care. Adjusting for practice attributes, the percent experiencing difficulty was similar between system-owned and independent practices but was less for Medicaid ACO participants for medication advice (81% vs 89%; P = .021) and evidence-based psychotherapy (81% vs 90%; P = .006); differences were not significant for family-based treatment (85% vs 91%; P = .107). CONCLUSIONS: Most multiphysician practices struggle to obtain advice and services for child behavioral health needs, which are increasing nationally. Future studies should investigate the source of observed associations.