FDA approval, clinical trial evidence, efficacy, epidemiology, and price for non-orphan and ultra-rare, rare, and common orphan cancer drug indications: cross sectional analysis.

OBJECTIVE: To analyze the US Food and Drug Administration (FDA) approval, trials, unmet needs, benefit, and pricing of ultra-rare (<6600 affected US citizens), rare (6600-200 000 citizens), and common (>200 000 citizens) orphan cancer drug indications and non-orphan cancer drug indications. DESIGN: Cross sectional analysis. SETTING: Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid. POPULATION: 170 FDA approved drugs across 455 cancer indications between 2000 and 2022. MAIN OUTCOME MEASURES: Comparison of non-orphan and ultra-rare, rare, and common orphan indications regarding regulatory approval, trials, epidemiology, and price. Hazard ratios for overall survival and progression-free survival were meta-analyzed. RESULTS: 161 non-orphan and 294 orphan cancer drug indications were identified, of which 25 were approved for ultra-rare diseases, 205 for rare diseases, and 64 for common diseases. Drugs for ultra-rare orphan indications were more frequently first in class (76% v 48% v 38% v 42%; P<0.001), monotherapies (88% v 69% v 72% v 55%; P=0.001), for hematologic cancers (76% v 66% v 0% v 0%; P<0.001), and supported by smaller trials (median 85 v 199 v 286 v 521 patients; P<0.001), of single arm (84% v 44% v 28% v 21%; P<0.001) phase 1/2 design (88% v 45% v 45% v 27%; P<0.001) compared with rare and common orphan indications and non-orphan indications. Drugs for common orphan indications were more often biomarker directed (69% v 26% v 12%; P<0.001), first line (77% v 39% v 20%; P<0.001), small molecules (80% v 62% v 48%; P<0.001) benefiting from quicker time to first FDA approval (median 5.7 v 7.1 v 8.9 years; P=0.02) than those for rare and ultra-rare orphan indications. Drugs for ultra-rare, rare, and common orphan indications offered a significantly greater progression-free survival benefit (hazard ratio 0.53 v 0.51 v 0.49 v 0.64; P<0.001), but not overall survival benefit (0.50 v 0.73 v 0.71 v 0.74; P=0.06), than non-orphans. In single arm trials, tumor response rates were greater for drugs for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications (objective response rate 57% v 48% v 55% v 33%; P<0.001). Disease incidence/prevalence, five year survival, and the number of available treatments were lower, whereas disability adjusted life years per patient were higher, for ultra-rare orphan indications compared with rare or common indications and non-orphan indications. For 147 on-patent drugs with available data in 2023, monthly prices were higher for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications ($70 128 (£55 971; €63 370) v $33 313 v $16 484 v $14 508; P<0.001). For 48 on-patent drugs with available longitudinal data from 2005 to 2023, prices increased by 94% for drugs for orphan indications and 50% for drugs for non-orphan indications on average. CONCLUSIONS: The Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases. These orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes. A distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.

The Healthcare Cost Burden of Asthma in Children: A Longitudinal Population-Based Study.

OBJECTIVES: This study aimed to investigate the extent of healthcare cost increase at population level due to childhood asthma. We aimed to investigate the cross-sectional relationship between asthma and healthcare costs among children aged 2 to 18 years and, in longitudinal analyses, whether costs increase with an increase in the duration of asthma prevalence. METHODS: Study participants are 4175 and 4482 children of birth and kindergarten cohorts from the nationally representative Longitudinal Study of Australian Children for whom the linked Medicare cost data are available. The children were followed in all waves from the year 2004 to 2018. Generalized linear models were used to estimate the excess healthcare costs associated with asthma. The sum of Medicare Benefits Schedule and Pharmaceutical Benefits Scheme costs constitutes the total healthcare costs. RESULTS: Total excess healthcare costs associated with asthma among the 2- to 18-year-old children were A$4316 per child. At the population level, the estimated total excess Medicare costs associated with current asthma treatment among 2- to 18-year-old children were, on average, A$190.6 million per year (2018 population and price). Compared with the non-asthmatic children, peers with persistent asthma morbidity and treatment requirements had excess costs up to A$20 727 for the B cohort children until 14 years of age, whereas excess costs for the K cohort children were A$19 571 until 18 years of age. CONCLUSIONS: Asthma in children imposes a significant financial burden on the public health system. Higher excess healthcare costs of all asthmatic children than the costs of nonasthmatic children provide further economic justification for promoting preventive efforts at early ages.

Does compulsory schooling affect health? Evidence from ambulatory claims data.

Using claims data on more than 23 million statutorily insured, we investigate the causal effect of schooling on health in the largest and most comprehensive analysis for Germany to date. In a regression discontinuity approach, we exploit changes in compulsory schooling in West Germany to estimate the reduced form effect of the reforms on health, measured by doctor diagnoses in ICD-10 format covering physical as well as mental health conditions. To mitigate the problem that empirical results depend on subjective decisions made by the researcher, we perform specification curve analyses to assess the robustness of findings across various model specifications. We find that the reforms have, at best, very small impacts on the examined doctor diagnoses. In most of the specifications we estimate insignificant effects that are close to zero and often of the "wrong" sign. Therefore, our study questions the presence of the large positive effects of education on health that are found in the previous literature.

The effects of audits and fines on upcoding in neonatology.

Upcoding is a common type of fraud in healthcare. However, how audit policies need to be designed to cope with upcoding is not well understood. We provide causal evidence on the effect of random audits with different probabilities and financial consequences. Using a controlled laboratory experiment, we mimic the decision situation of obstetrics staff members to report birth weights of neonatal infants. Subjects' payments in the experiment depend on their reported birth weights and follow the German non-linear diagnosis-related group remuneration for neonatal care. Our results show that audits with low detection probabilities only reduce fraudulent birth-weight reporting, when they are coupled with fines for fraudulent reporting. For audit policies with fines, increasing the probability of an audit only effectively enhances honest reporting, when switching from detectable to less gainful undetectable upcoding is not feasible. Implications for audit policies are discussed.

Causal Effect of Tooth Loss on Functional Capacity in Older Adults in England: A Natural Experiment.

BACKGROUND/OBJECTIVES: Tooth loss is associated with reduced functional capacity, but so far, there is no relevant causal evidence reported. We investigated the causal effect of tooth loss on the instrumental activities of daily living (IADL) among older adults in England. DESIGN: Natural experiment study with instrumental variable analysis. SETTING: The English Longitudinal Study of Aging (ELSA) combined with the participants' childhood exposure to water fluoride due to the community water fluoridation. PARTICIPANTS: Five thousand six hundred and thirty one adults in England born in 1945-1965 participated in the ELSA wave seven survey (conducted in 2014-2015; average age: 61.0 years, 44.6% men). MEASUREMENTS: The number of natural teeth predicted by the exogenous geographical and historical variation in exposure to water fluoride from age 5 to 20 years old (instrumental variable) was used as an exposure variable. The outcome, having any limitations in IADL (preparing a hot meal, shopping for groceries, making telephone calls, taking medications, doing work around the house or garden, or managing money), was assessed by self-reported questionnaires. RESULTS: Linear probability model with Two-Stage Least Squares estimation was fitted. Being exposed to fluoridated water was associated with having more natural teeth in later life (coefficient: 0.726; 95% confidence interval (CI) = 0.311, 1.142; F = 11.749). Retaining one more natural tooth reduced the probability of having a limitation in IADL by 3.1 percentage points (coefficient: -0.031; 95% CI = -0.060, -0.002). CONCLUSION: Preventing tooth loss maintains functional capacity among older adults in England. Given the high prevalence of tooth loss, this effect is considerable. Further research on the mechanism of the observed causal relationship is needed.

Prenatal exposure to the German food crisis 1944-1948 and health after 65 years.

Using data on 90% of the German population born 1930-1959, we investigate the long-term relationship between intra-uterine exposure to the German food crisis 1944-1948 and 16 doctor-diagnosed health conditions recorded in 2009 and 2015. Among the exposed, who are 60-70 years old in our data, we find elevated risks of being diagnosed with a wide range of conditions, including diabetes, depression, lung disease, and back pain. In terms of critical periods, malnutrition in the first trimester of pregnancy appears to have the strongest negative correlation with health at older ages.

Cognitive ability and teen smoking.

We use data on 11-15-year-old boys in the West Bank to study the empirical link between cognitive ability and health behavior, specifically (teen) smoking. Adjusting for both age in months and grade level allows us to effectively shut down any simultaneous effect of maturation and schooling on cognitive ability and smoking. We find that those at the lower end of the cognitive ability distribution are more than twice as likely to smoke than those at the upper end (approximately 25 versus 10%) also after adjusting for parental background and peer composition in a generalized propensity score approach. Further, we find that the cognitive ability-smoking gradient is fairly flat at the lower end of the cognitive ability distribution and steep at the upper end.

Patients' self-reported measures of oral health-A validation study on basis of oral health questions used in a large multi-country survey for populations aged 50.

OBJECTIVE: To assess the validity of patient self-reported oral health measures as used in a large multi-country survey for populations aged 50+. BACKGROUND: Information on people's oral health status is important for assessing oral health needs within populations. However, clinical examination is not always possible. Patient self-reported measures may provide an alternative when time and other resources are scarce. MATERIALS AND METHODS: Using oral health items from the Survey of Health, Ageing and Retirement in Europe (SHARE), self-reported measures were collected from 186 patients receiving treatment at Heidelberg University Hospital. Self-reports were compared with subsequent clinical examinations. Analyses were conducted for patients of all age groups and separately for patients aged 50+ (analogous to the SHARE study population). Diagnostic accuracy, agreement and correlation of patient-reported information were examined using descriptive statistics and Bland-Altman plots. RESULTS: Patient-reported presence or absence of a full tooth count was closely related to clinical measurement, both for all age groups (sensitivity: 93%; specificity: 92%) and persons aged 50+ (sensitivity: 100% specificity: 94%). Bland-Altman plots indicate good agreement between patient- and clinical reports of the number of teeth at age 50+ (Concordance Correlation Coefficient = 0.95). Discriminatory power of patient-reporting was good regarding presence vs absence of artificial teeth, but less robust regarding partial vs full replacement of missing teeth. CONCLUSION: Patient self-evaluations provide reasonable estimates of clinical measures and appear sufficiently accurate for examining variations in the number of teeth, including among populations aged 50+. However, patient reports of the extent of replacement of missing teeth may not constitute reliable reflections of clinical conditions.

The Causal Effect of Education on Tooth Loss: Evidence From United Kingdom Schooling Reforms.

Associations between education and oral health have frequently been reported, but until now there has been no causal evidence. Exploiting exogenous variation in the duration of schooling due to 1947 and 1972 reforms in mandatory schooling in the United Kingdom, we examined the causal relationship between education and tooth loss in older age. We conducted a cross-sectional study using data from waves 3 (2006-2007), 5 (2010-2011), and 7 (2014-2015) of the English Longitudinal Study of Ageing. We used a 2-stage least squares instrumental variable approach and included 5,667 respondents (average age = 67.8 years; 44.4% were men) in the analyses, of whom 819 (14.5%) had no teeth. The schooling reforms increased the duration of education by an average of 0.624 years (95% confidence interval: 0.412, 0.835). For respondents born within ±6 years of the pivotal cohorts, a 1-year increment of education causally reduced the probability of edentulism by 9.1 (95% confidence interval: 1.5, 16.8) percentage points. The effects were stronger for the 1947 reform than for the 1972 reform. Results were robust to broadening of the cohort bandwidth and functional form of the cohort trend. The findings suggest that investment in education produces improved oral health later in life.

Dishonesty in health care practice: A behavioral experiment on upcoding in neonatology.

Dishonest behavior significantly increases the cost of medical care provision. Upcoding of patients is a common form of fraud to attract higher reimbursements. Imposing audit mechanisms including fines to curtail upcoding is widely discussed among health care policy-makers. How audits and fines affect individual health care providers' behavior is empirically not well understood. To provide new evidence on fraudulent behavior in health care, we analyze the effect of a random audit including fines on individuals' honesty by means of a novel controlled behavioral experiment framed in a neonatal care context. Prevalent dishonest behavior declines significantly when audits and fines are introduced. The effect is driven by a reduction in upcoding when being detectable. Yet upcoding increases when not being detectable as fraudulent. We find evidence that individual characteristics (gender, medical background, and integrity) are related to dishonest behavior. Policy implications are discussed.

Gain a child, lose a tooth? Using natural experiments to distinguish between fact and fiction.

BACKGROUND: Dental diseases are among the most frequent diseases globally and tooth loss imposes a substantial burden on peoples' quality of life. Non-experimental evidence suggests that individuals with more children have more missing teeth than individuals with fewer children, but until now there is no causal evidence for or against this. METHODS: Using a Two-Stage Least Squares (2SLS) instrumental variables approach and large-scale cross-sectional data from the Survey of Health, Ageing, and Retirement in Europe (study sample: 34 843 non-institutionalised individuals aged 50+ from 14 European countries and Israel; data were collected in 2013), we investigated the causal relationship between the number of biological children and their parents' number of missing natural teeth. Thereby, we exploited random natural variation in family size resulting from (i) the birth of multiples vs singletons, and (ii) the sex composition of the two first-born children (increased likelihood of a third child if the two first-born children have the same sex). RESULTS: 2SLS regressions detected a strong causal relationship between the number of children and teeth for women but not for men when an additional birth occurred after the first two children had the same sex. Women then had an average of 4.27 (95% CI: 1.08 to 7.46) fewer teeth than women without an additional birth whose first two children had different sexes. CONCLUSIONS: This study provides novel evidence for causal links between the number of children and the number of missing teeth. An additional birth might be detrimental to the mother's but not the father's oral health.

Childhood socioeconomic conditions and teeth in older adulthood: Evidence from SHARE wave 5.

OBJECTIVES: Dental diseases are the most common chronic diseases worldwide. Healthy teeth are vital for quality of life, particularly diet and nutrition. However, little information exists to inform health policymakers about potentially long-lasting influences of early-life conditions. The purpose of this study was to investigate the relation between early-life socioeconomic conditions and number of natural teeth at age 50 and above. METHODS: Analyses were conducted on cross-sectional data from the Survey of Health, Ageing and Retirement in Europe (SHARE wave 5), which includes information on 41 560 respondents aged 50 years or older from 14 European countries and Israel. Using SHARE life history information, a series of regression models (OLS, Tobit) were estimated to analyse the relationship between socioeconomic conditions in earlier life and the number of teeth at age 50+. RESULTS: Childhood socioeconomic background was associated with the number of natural teeth at age 50 and above, even after controlling for current determinants of oral health. Respondents who had had more than 25 books in their childhood household had a mean 1.4 (95% CI: 1.2-1.5) more teeth than respondents with fewer books. Respondents who reported poor financial conditions during childhood had a mean 0.6 (95% CI: 0.3-0.9) fewer teeth than respondents who reported better financial conditions in childhood. CONCLUSION: These findings substantiate the association between socioeconomic conditions in the early years of life and tooth retention to older adulthood and highlight the long-lasting relation between childhood living conditions and oral health through the lifecourse.

Financial incentives, timing of births, and infant health: a closer look into the delivery room.

As a result of strong financial incentives created by the German parental leave reform on January 1, 2007, some 1000 births have been shifted from the last days of 2006 to the first days of 2007, especially by working mothers. This fact is already described in the literature, yet there is no evidence as to the mechanisms and only scarce evidence regarding the effects on newborn health. I use new data to study the timing of C-sections and the induction of births around the day the reform took effect. I estimate that postponed C-sections and inductions account for nearly 80 % of the pre-reform shortfall and nearly 90 % of the post-reform excess number of births. Despite concerns voiced by doctors before the reform, hardly any evidence can be found for detrimental health effects of those shifts, as measured by changes in gestational age, birth weight, APGAR scores, neonatal mortality, or hospitalization.

Causal inference from observational data.

Randomized controlled trials have long been considered the 'gold standard' for causal inference in clinical research. In the absence of randomized experiments, identification of reliable intervention points to improve oral health is often perceived as a challenge. But other fields of science, such as social science, have always been challenged by ethical constraints to conducting randomized controlled trials. Methods have been established to make causal inference using observational data, and these methods are becoming increasingly relevant in clinical medicine, health policy and public health research. This study provides an overview of state-of-the-art methods specifically designed for causal inference in observational data, including difference-in-differences (DiD) analyses, instrumental variables (IV), regression discontinuity designs (RDD) and fixed-effects panel data analysis. The described methods may be particularly useful in dental research, not least because of the increasing availability of routinely collected administrative data and electronic health records ('big data').

A comparison of tooth retention and replacement across 15 countries in the over-50s.

OBJECTIVES: Oral diseases are still among the most common chronic diseases globally with substantial detrimental impact especially on elderly people's health and well-being. However, limited evidence exists on international variation in the oral health status of the older population. We aimed to examine international variation in tooth loss and tooth replacement in the general population aged between 50 and 90 years. METHODS: A cross-sectional analysis of data from the fifth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE) was conducted. The data cover 14 European countries (Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Italy, Luxembourg, the Netherlands, Slovenia, Spain, Sweden, and Switzerland) and Israel, and they were collected during the year 2013. Age-specific percentages of the population having all natural teeth, the age-specific numbers of natural (and artificial) teeth, and the age-specific percentages of full, partial, or no replacement of missing teeth were assessed with stratification by country. It was further evaluated to which extent proposed oral health goals concerning tooth loss at higher ages had been achieved. RESULTS: In total, 62,763 individuals were included in the study. Age-standardized mean numbers of natural teeth exhibited substantial variation, ranging from 14.3 (Estonia) to 24.5 (Sweden). The oral health goal of retaining at least 20 teeth at age 80 years was achieved by 25% of the population or less in most countries. A target concerning edentulism (≤15% in population aged 65-74 years) was reached in Sweden, Switzerland, Denmark, France, and Germany. Tooth replacement practices varied especially for a number of up to five missing teeth which were more likely to be replaced in Austria, Germany, Luxembourg, and Switzerland than in Israel, Denmark, Estonia, Spain, and Sweden. CONCLUSIONS: This study suggests that the age-specific number of natural teeth and the practice of tooth replacement in the over 50s differ substantially among the included countries. The present results may be helpful in the formulation and evaluation of oral health goals in the older population.

What explains DRG upcoding in neonatology? The roles of financial incentives and infant health.

We use the introduction of diagnosis related groups (DRGs) in German neonatology to study the determinants of upcoding. Since 2003, reimbursement is based inter alia on birth weight, with substantial discontinuities at eight thresholds. These discontinuities create incentives to upcode preterm infants into classes of lower birth weight. Using data from the German birth statistics 1996-2010 and German hospital data from 2006 to 2011, we show that (1) since the introduction of DRGs, hospitals have upcoded at least 12,000 preterm infants and gained additional reimbursement in excess of 100 million Euro; (2) upcoding rates are systematically higher at thresholds with larger reimbursement hikes and in hospitals that subsequently treat preterm infants, i.e. where the gains accrue; (3) upcoding is systematically linked with newborn health conditional on birth weight. Doctors and midwives respond to financial incentives by not upcoding newborns with low survival probabilities, and by upcoding infants with higher expected treatment costs.

Compulsory schooling reforms, education and mortality in twentieth century Europe.

Education yields substantial non-monetary benefits, but the size of these gains is still debated. Previous studies report causal effects of education and compulsory schooling on mortality ranging anywhere from zero to large and negative. Using data from 18 compulsory schooling reforms implemented in Europe during the twentieth century, we quantify the average mortality gain and explore its dispersion across gender, time and countries. We find that more education yields small mortality reductions in the short- and long-run for men. In contrast, women seem to experience no mortality reductions from compulsory schooling reforms.

Are anchoring vignettes ratings sensitive to vignette age and sex?

Anchoring vignettes are commonly used to study and correct for differential item functioning and response bias in subjective survey questions. Self-assessed health status is a leading example. A crucial assumption of the vignette methodology is 'vignette equivalence': The health status of the person described in the vignette must be perceived by all respondents in the same way. We use data from a survey experiment conducted with a sample of almost 5000 older Americans to validate this assumption. We find weak evidence that respondents' vignette ratings may be sensitive to the sex and, for older respondents, also to the age (implied by the first name) of the person described in the vignette. Our findings suggest that vignette equivalence may not hold, at least if the potentially subtle connotations of vignette persons' names are not fully controlled.

Collateral damage: the German food crisis, educational attainment and labor market outcomes of German post-war cohorts.

Using the German 1970 census to study educational and labor market outcomes of cohorts born during the German food crisis after World War II, I document that those born between November 1945 and May 1946 have significantly lower educational attainment and occupational status than cohorts born shortly before or after. Several alternative explanations for this finding are tested. Most likely, a short spell of severe undernutrition around the end of the war has impaired intrauterine conditions in early pregnancies and resulted in long-term detriments among the affected cohorts. This conjecture is corroborated by evidence from Austria.

Do workers underreport morbidity? The accuracy of self-reports of chronic conditions.

We use matched Danish health survey and register data to investigate discrepancies between register-based diagnoses and self-reported morbidity. We hypothesize that false negatives (medical diagnoses existing in the register but not reported in the survey) arise partly because individuals fear career repercussions of being discovered suffering a chronic or severe illness that potentially lowers productivity. We find evidence of substantial underreporting, which is indeed systematically higher for individuals in the labor market.