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.

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.

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.

Medical Marketing in the United States, 1997-2016.

IMPORTANCE: Manufacturers, companies, and health care professionals and organizations use an array of promotional activities to sell and increase market share of their products and services. These activities seek to shape public and clinician beliefs about laboratory testing, the benefits and harms of prescription drugs, and some disease definitions. OBJECTIVE: To review the marketing of prescription drugs, disease awareness campaigns, health services, and laboratory tests and the related consequences and regulation in the United States over a 20-year period (1997-2016). EVIDENCE: Analysis (1997-2016) of consumer advertising (Kantar Media data for spending and number of ads); professional marketing (IQVIA Institute for Human Data Science, Open Payments Data [Centers for Medicare & Medicaid Services]); regulations and legal actions of the US Food and Drug Administration (FDA), Federal Trade Commission (FTC), state attorneys general, and US Department of Justice; and searches (1975-2018) of peer-reviewed medical literature (PubMed), business journals (Business Source Ultimate), and news media (Lexis Nexis) for articles about expenditures, content, and consequences and regulation of consumer and professional medical marketing. Spending is reported in 2016 dollars. FINDINGS: From 1997 through 2016, spending on medical marketing of drugs, disease awareness campaigns, health services, and laboratory testing increased from $17.7 to $29.9 billion. The most rapid increase was in direct-to-consumer (DTC) advertising, which increased from $2.1 billion (11.9%) of total spending in 1997 to $9.6 billion (32.0%) of total spending in 2016. DTC prescription drug advertising increased from $1.3 billion (79 000 ads) to $6 billion (4.6 million ads [including 663 000 TV commercials]), with a shift toward advertising high-cost biologics and cancer immunotherapies. Pharmaceutical companies increased DTC marketing about diseases treated by their drugs with increases in disease awareness campaigns from 44 to 401 and in spending from $177 million to $430 million. DTC advertising for health services increased from $542 million to $2.9 billion, with the largest spending increases by hospitals, dental centers, cancer centers, mental health and addiction clinics, and medical services (eg, home health). DTC spending on advertising for laboratory tests (such as genetic testing) increased from $75.4 million to $82.6 million, although the number of ads increased more substantially (from 14 100 to 255 300), reflecting an increase in less expensive electronic media advertising. Marketing to health care professionals by pharmaceutical companies accounted for most promotional spending and increased from $15.6 billion to $20.3 billion, including $5.6 billion for prescriber detailing, $13.5 billion for free samples, $979 million for direct physician payments (eg, speaking fees, meals) related to specific drugs, and $59 million for disease education. Manufacturers of FDA-approved laboratory tests paid $12.9 million to professionals in 2016. From 1997 through 2016, the number of consumer and professional drug promotional materials that companies submitted for FDA review increased from 34 182 to 97 252, while FDA violation letters for misleading drug marketing decreased from 156 to 11. Since 1997, 103 financial settlements between drug companies and federal and state governments resulted in more than $11 billion in fines for off-label or deceptive marketing practices. The FTC has acted against misleading marketing by a single for-profit cancer center. CONCLUSIONS AND RELEVANCE: Medical marketing increased substantially from 1997 through 2016, especially DTC advertising for prescription drugs and health services. Pharmaceutical marketing to health professionals accounted for most spending and remains high even with new policies to limit industry influence. Despite the increase in marketing over 20 years, regulatory oversight remains limited.

How Do Women View Risk-Based Mammography Screening? A Qualitative Study.

BACKGROUND: Decades of persuasive messages have reinforced the importance of traditional screening mammography at regular intervals. A potential new paradigm, risk-based screening, adjusts mammography frequency based on a woman's estimated breast cancer risk in order to maximize mortality reduction while minimizing false positives and overdiagnosis. Women's views of risk-based screening are unknown. OBJECTIVE: To explore women's views and personal acceptability of a potential risk-based mammography screening paradigm. DESIGN: Four semi-structured focus group discussions about screening mammography and surveys before provision of information about risk-based screening. We analyzed coded focus group transcripts using a mixed deductive (content analysis) and inductive (grounded theory) approach. PARTICIPANTS: Convenience sample of 29 women (40-74 years old) with no personal history of breast cancer recruited by print and online media in New Hampshire and Vermont. RESULTS: Twenty-seven out of 29 women reported having undergone mammography screening. All participants were white and most were highly educated. Some women accepted the idea that early cancer detection with traditional screening was beneficial-although many also reported hearing inconsistent recommendations from clinicians and mixed messages from media reports about mammography. Some women were familiar with a risk-based screening paradigm (primarily related to cervical cancer, n = 8) and thought matching screening mammography frequency to personal risk made sense (n = 8). Personal acceptability of risk-based screening was mixed. Some believed risk-based screening could reduce the harms of false positives and overdiagnosis (n = 7). Others thought screening less often might result in missing a dangerous diagnosis (n = 14). Many (n = 18) expressed concerns about the feasibility of risk-based screening and questioned whether breast cancer risk estimates could be accurate. Some suspected that risk-based mammography was motivated by a desire to save money (n = 6). CONCLUSION: Some women thought risk-based screening made sense. Willingness to abandon traditional screening for the new paradigm was mixed. Broad acceptability of risk-based screening will require clearer communication about its rationale and feasibility and consistent messages from the health care team.

ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting for New Drug Approval Trials.

BACKGROUND: Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. PURPOSE: To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA. DATA SOURCES: ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews). STUDY SELECTION: 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015). DATA EXTRACTION: 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths. RESULTS: Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant. LIMITATION: Unknown generalizability to uncontrolled or crossover trial results. CONCLUSION: Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only "key outcomes" for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials. PRIMARY FUNDING SOURCE: National Library of Medicine.

The Drug Facts Box: Improving the communication of prescription drug information.

Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label--the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing--may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and "spinning" unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies--including national randomized trials--demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3-5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information.

'The thing is not knowing': patients' perspectives on surveillance of an indeterminate pulmonary nodule.

BACKGROUND: The hundreds of thousands of patients found to have a potentially malignant pulmonary nodule each year are faced with tremendous uncertainty regarding what the nodule is and how it should be evaluated. OBJECTIVE: To explore patients' responses to the detection and evaluation of a pulmonary nodule. DESIGN: Qualitative study based on four focus-group discussions. We performed inductive analysis using principles of grounded theory to identify themes relating to responses to the nodule and strategies to manage uncertainty. SETTING AND PARTICIPANTS: Twenty-two patients from two medical centres who were undergoing surveillance for an indeterminate pulmonary nodule. RESULTS: Patient responses to an indeterminate pulmonary nodule were varied and evolved over time. Although almost all patients reported an initial fear about cancer, subsequent depictions of the nodule diverged into four types defined on two dimensions: cognitive ('it's cancer' vs. 'I don't know what it is' vs. 'it's nothing serious') and emotional (anxiety vs. equanimity). Most eventually accepted that the nodule was unlikely to be malignant; however, some remained anxious, convinced the nodule could turn into cancer at any time and should be aggressively monitored for life. Patients used results of surveillance tests as well as their own strategies (e.g. vigilance for symptoms, information-seeking, contemplating and controlling modifiable risk factors, avoidance, faith) to manage uncertainty. CONCLUSIONS: Surveillance for a pulmonary nodule can weigh heavily on some patients for months or years. Our findings may help clinicians prepare patients with a newly detected pulmonary nodule for the burden of the prolonged uncertainty of surveillance.

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.

Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States.

BACKGROUND: Unlike reduced mortality rates, improved survival rates and increased early detection do not prove that cancer screening tests save lives. Nevertheless, these 2 statistics are often used to promote screening. OBJECTIVE: To learn whether primary care physicians understand which statistics provide evidence about whether screening saves lives. DESIGN: Parallel-group, randomized trial (randomization controlled for order effect only), conducted by Internet survey. (ClinicalTrials.gov registration number: NCT00981019) SETTING: National sample of U.S. primary care physicians from a research panel maintained by Harris Interactive (79% cooperation rate). PARTICIPANTS: 297 physicians who practiced both inpatient and outpatient medicine were surveyed in 2010, and 115 physicians who practiced exclusively outpatient medicine were surveyed in 2011. INTERVENTION: Physicians received scenarios about the effect of 2 hypothetical screening tests: The effect was described as improved 5-year survival and increased early detection in one scenario and as decreased cancer mortality and increased incidence in the other. MEASUREMENTS: Physicians' recommendation of screening and perception of its benefit in the scenarios and general knowledge of screening statistics. RESULTS: Primary care physicians were more enthusiastic about the screening test supported by irrelevant evidence (5-year survival increased from 68% to 99%) than about the test supported by relevant evidence (cancer mortality reduced from 2 to 1.6 in 1000 persons). When presented with irrelevant evidence, 69% of physicians recommended the test, compared with 23% when presented with relevant evidence (P < 0.001). When asked general knowledge questions about screening statistics, many physicians did not distinguish between irrelevant and relevant screening evidence; 76% versus 81%, respectively, stated that each of these statistics proves that screening saves lives (P = 0.39). About one half (47%) of the physicians incorrectly said that finding more cases of cancer in screened as opposed to unscreened populations "proves that screening saves lives." LIMITATION: Physicians' recommendations for screening were based on hypothetical scenarios, not actual practice. CONCLUSION: Most primary care physicians mistakenly interpreted improved survival and increased detection with screening as evidence that screening saves lives. Few correctly recognized that only reduced mortality in a randomized trial constitutes evidence of the benefit of screening. PRIMARY FUNDING SOURCE: Harding Center for Risk Literacy, Max Planck Institute for Human Development.

Presenting quantitative information about decision outcomes: a risk communication primer for patient decision aid developers.

BACKGROUND: Making evidence-based decisions often requires comparison of two or more options. Research-based evidence may exist which quantifies how likely the outcomes are for each option. Understanding these numeric estimates improves patients' risk perception and leads to better informed decision making. This paper summarises current "best practices" in communication of evidence-based numeric outcomes for developers of patient decision aids (PtDAs) and other health communication tools. METHOD: An expert consensus group of fourteen researchers from North America, Europe, and Australasia identified eleven main issues in risk communication. Two experts for each issue wrote a "state of the art" summary of best evidence, drawing on the PtDA, health, psychological, and broader scientific literature. In addition, commonly used terms were defined and a set of guiding principles and key messages derived from the results. RESULTS: The eleven key components of risk communication were: 1) Presenting the chance an event will occur; 2) Presenting changes in numeric outcomes; 3) Outcome estimates for test and screening decisions; 4) Numeric estimates in context and with evaluative labels; 5) Conveying uncertainty; 6) Visual formats; 7) Tailoring estimates; 8) Formats for understanding outcomes over time; 9) Narrative methods for conveying the chance of an event; 10) Important skills for understanding numerical estimates; and 11) Interactive web-based formats. Guiding principles from the evidence summaries advise that risk communication formats should reflect the task required of the user, should always define a relevant reference class (i.e., denominator) over time, should aim to use a consistent format throughout documents, should avoid "1 in x" formats and variable denominators, consider the magnitude of numbers used and the possibility of format bias, and should take into account the numeracy and graph literacy of the audience. CONCLUSION: A substantial and rapidly expanding evidence base exists for risk communication. Developers of tools to facilitate evidence-based decision making should apply these principles to improve the quality of risk communication in practice.