Richard G. Frank

Clinical biomarkers in drug discovery and development

Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.

The impact of psychiatric disorders on work loss days.

BACKGROUND To examine relationships between recent DSM-III-R psychiatric disorders and work impairment in major occupational groups in the US labour force. METHOD Data are from the US National Comorbidity Survey (NCS), a survey of respondents ages 15-54 in the US. Employed people are the focus of the report. RESULTS There is substantial variation across occupations in the 30-day prevalences of NCS/ DSM-III-R psychiatric disorders, with an average prevalence of 18.2% (range: 11.0-29.6%) for any disorder. The average prevalences of psychiatric work loss days (6 days per month per 100 workers) and work cutback days (31 days per month per 100 workers), in comparison, do not differ significantly across occupations. Work impairment is more strongly concentrated among the 3.7% of the workforce with co-morbid psychiatric disorders (49 work loss days and 346 work cutback days per month per 100 workers) than the 14.5% with pure disorders (11 work loss days and 66 work cutback days per month per 100 workers) or the 81.8% with no disorder (2 work loss days and 11 work cutback days per month per 100 workers). The effects of psychiatric disorders on work loss are similar across all occupations, while effects on work cutback are greater among professional workers than those in other occupations. CONCLUSION The results reported here suggest that work impairment is one of the adverse consequences of psychiatric disorders. The current policy debate concerning insurance coverage for mental disorders needs to take these consequences into consideration.

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives

Advances in therapeutic strategies for Alzheimers disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimers disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.

What Is the Empirical Basis for Paying for Quality in Health Care

Despite more than a decade of benchmarking and public reporting of quality problems in the health care sector, changes in medical practice have been slow to materialize. To accelerate quality improvement, many private and public payers have begun to offer financial incentives to physicians and hospitals based on their performance on clinical and service quality measures. The authors review the empirical literature on paying for quality in health care and comparable interventions in other sectors. They find little evidence to support the effectiveness of paying for quality. The absence of findings for an effect may be attributable to the small size of the bonuses studied and the fact that payers often accounted for only a fraction of the targeted providers panel. Even in nonhealth settings, however, where the institutional features are more favorable to a positive impact, the literature contains mixed results on the effectiveness of analogous pay-for-performance schemes.

Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. RESULTS One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. CONCLUSION Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

Differences in the use of psychiatric outpatient services between the United States and Ontario

BACKGROUND The relation between health insurance and the use of mental health services is unclear. We compared the use of outpatient services for psychiatric problems in the United States and Ontario, Canada, among young and middle-aged adults according to self-reports of disorders listed in the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) and to other indicators of need. METHODS We analyzed two general-population surveys carried out separately in the United States and Ontario in 1990 that used identical assessments of need for services and questions about their use by persons 15 to 54 years of age. RESULTS Respondents in the United States were significantly more likely than those in Ontario to report having had psychiatric disorders, poor mental health, or workdays lost or cut short because of psychiatric problems in the previous year. A significantly higher proportion of respondents in the United States (13.3 percent) than in Ontario (8.0 percent) had obtained outpatient treatment in the previous 12 months for psychiatric problems. However, an analysis of subgroups found that the higher probability of the use of services in the United States was confined to people with less severe mental illness. The average number of visits did not differ significantly between the two countries among patients who had similar numbers of psychiatric disorders over the same time periods. There was a stronger match in Ontario than in the United States between the use of services and the measures of perceived need we considered. CONCLUSIONS Although the mental health care system in the United States provides treatment to a larger proportion of the population than that in Ontario, the match between some measures of need and treatment is not as strong in the United States. Any plans to expand coverage for psychiatric disorders in the United States must address this problem.

The use of outpatient mental health services in the United States and Ontario: the impact of mental morbidity and perceived need for care.

OBJECTIVES This study compared the associations of individual mental health disorders, self-rated mental health, disability, and perceived need for care with the use of outpatient mental health services in the United States and the Canadian province of Ontario. METHODS A cross-sectional study design was employed. Data came from the 1990 US National Comorbidity Survey and the 1990 Mental Health Supplement to the Ontario Health Survey. RESULTS The odds of receiving any medical or psychiatric specialty services were as follows: for persons with any affective disorder, 3.1 in the United States vs 11.0 in Ontario; for persons with fair or poor self-rated mental health, 2.7 in the United States vs 5.0 in Ontario; for persons with mental health-related disability. 3.0 in the United States vs 1.5 in Ontario. When perceived need was controlled for, most of the between country differences in use disappeared. CONCLUSIONS The higher use of mental health services in the United States than in Ontario is mostly explained by the combination of a higher prevalence of mental morbidity and a higher prevalence of perceived need for care among persons with low mental morbidity in the United States.

Economics and Mental Health

Abstract This paper is concerned with the economics of mental health. We argue that mental health economics is like health economics only more so: uncertainty and variation in treatments are greater; the assumption of patient self-interested behavior is more dubious; response to financial incentives such as insurance is exacerbated; the social consequences and external costs of illness are more formidable. We elaborate on these statements and consider their implications throughout the chapter. “Special characteristics” of mental illness and persons with mental illness are identified and related to observations on institutions paying for and providing mental health services. We show that adverse selection and moral hazard appear to hit mental health markets with special force. We discuss the emergence of new institutions within managed care that address longstanding problems in the sector. Finally, we trace the shifting role of government in this sector of the health economy.

Depression and work productivity : The comparative costs of treatment versus nontreatment

This article discusses the impact of depression on work productivity and the potential for improved work performance associated with effective treatment. We undertook a review of the literature by means of a computer search using the following key terms: cost of illness, work loss, sickness absence, productivity, performance, and disability. Published works were considered in four categories: (1) naturalistic cross-sectional studies that found greater self-reported work impairment among depressed workers; (2) naturalistic longitudinal studies that found a synchrony of change between depression and work impairment; (3) uncontrolled treatment studies that found reduced work impairment with successful treatment; and (4) controlled trials that usually, but not always, found greater reduction in work impairment among treated patients. Observational data suggest that productivity gains following effective depression treatment could far exceed direct treatment costs. Randomized effectiveness trials are needed before we can conclude definitively that depression treatment results in productivity improvements sufficient to offset direct treatment costs.

Demand Effects of Recent Changes in Prescription Drug Promotion

The release of clarified Food and Drug Administration (FDA) guidelines and independent changes in consumer behavior provide an opportunity to study the effects of direct-to-consumer advertising (DTCA) in the prescription drug market alongside the effects of various physician-oriented promotions. We examine the effects of DTCA and detailing for brands in five therapeutic classes of drugs, using monthly aggregate U.S. data from August 1996 through December 1999. In terms of impact of DTCA on demand, we provide evidence on two issues: (1) do increases in DTCA increase the market size of an entire therapeutic class? and (2) does DTCA increase within-class market share of advertised drugs? Our findings suggest that, for these classes of drugs, DTCA has been effective primarily through increasing the size of the entire class. Overall, we estimate that 13 to 22 percent of the recent growth in prescription drug spending is attributable to the effects of DTCA.