The DTC microbiome testing industry needs more regulation.

Tests lack analytical and clinical validity, requiring more federal oversight to prevent consumer harm.

Methodological Comparison of Mapping the Expanded Prostate Cancer Index Composite to EuroQoL-5D-3L Using Cross-Sectional and Longitudinal Data: Secondary Analysis of NRG/RTOG 0415.

PURPOSE: To compare the predictive ability of mapping algorithms derived using cross-sectional and longitudinal data. METHODS: This methodological assessment used data from a randomized controlled noninferiority trial of patients with low-risk prostate cancer, conducted by NRG Oncology (ClinicalTrials.gov identifier: NCT00331773), which examined the efficacy of conventional schedule versus hypofractionated radiation therapy (three-dimensional conformal external beam radiation therapy/IMRT). Health-related quality-of-life data were collected using the Expanded Prostate Cancer Index Composite (EPIC), and health utilities were obtained using EuroQOL-5D-3L (EQ-5D) at baseline and 6, 12, 24, and 60 months postintervention. Mapping algorithms were estimated using ordinary least squares regression models through five-fold cross-validation in baseline cross-sectional data and combined longitudinal data from all assessment periods; random effects specifications were also estimated in longitudinal data. Predictive performance was compared using root mean square error. Longitudinal predictive ability of models obtained using baseline data was examined using mean absolute differences in the reported and predicted utilities. RESULTS: A total of 267 (and 199) patients in the estimation sample had complete EQ-5D and EPIC domain (and subdomain) data at baseline and at all subsequent assessments. Ordinary least squares models using combined data showed better predictive ability (lowest root mean square error) in the validation phase for algorithms with EPIC domain/subdomain data alone, whereas models using baseline data outperformed other specifications in the validation phase when patient covariates were also modeled. The mean absolute differences were lower for models using EPIC subdomain data compared with EPIC domain data and generally decreased as the time of assessment increased. CONCLUSION: Overall, mapping algorithms obtained using baseline cross-sectional data showed the best predictive performance. Furthermore, these models demonstrated satisfactory longitudinal predictive ability.

Mapping expanded prostate cancer index composite to EQ5D utilities to inform economic evaluations in prostate cancer: Secondary analysis of NRG/RTOG 0415.

PURPOSE: The Expanded Prostate Cancer Index Composite (EPIC) is the most commonly used patient reported outcome (PRO) tool in prostate cancer (PC) clinical trials, but health utilities associated with the different health states assessed with this tool are unknown, limiting our ability to perform cost-utility analyses. This study aimed to map EPIC tool to EuroQoL-5D-3L (EQ5D) to generate EQ5D health utilities. METHODS AND MATERIALS: This is a secondary analysis of a prospective, randomized non-inferiority clinical trial, conducted between 04/2006 and 12/2009 at cancer centers across the United States, Canada, and Switzerland. Eligible patients included men >18 years with a known diagnosis of low-risk PC. Patient HRQoL data were collected using EPIC and health utilities were obtained using EQ5D. Data were divided into an estimation sample (n = 765, 70%) and a validation sample (n = 327, 30%). The mapping algorithms that capture the relationship between the instruments were estimated using ordinary least squares (OLS), Tobit, and two-part models. Five-fold cross-validation (in-sample) was used to compare the predictive performance of the estimated models. Final models were selected based on root mean square error (RMSE). RESULTS: A total of 565 patients in the estimation sample had complete information on both EPIC and EQ5D questionnaires at baseline. Mean observed EQ5D utility was 0.90±0.13 (range: 0.28-1) with 55% of patients in full health. OLS models outperformed their counterpart Tobit and two-part models for all pre-determined model specifications. The best model fit was: "EQ5D utility = 0.248541 + 0.000748*(Urinary Function) + 0.001134*(Urinary Bother) + 0.000968*(Hormonal Function) + 0.004404*(Hormonal Bother)- 0.376487*(Zubrod) + 0.003562*(Urinary Function*Zubrod)"; RMSE was 0.10462. CONCLUSIONS: This is the first study to identify a comprehensive set of mapping algorithms to generate EQ5D utilities from EPIC domain/ sub-domain scores. The study results will help estimate quality-adjusted life-years in PC economic evaluations.

The Impact of Regulatory Policies on the Future of Fecal Microbiota Transplantation.

In this article, the authors explore the impact of a potential future regulatory decision by FDA whether or not to continue its enforcement discretion policy allowing physicians to perform, and stool banks to sell, stool product for fecal microbiota transplantation as a treatment for recurrent Clostridium Difficile infection without an Investigative New Drug (IND) application. The paper looks at the Agency's regulatory options in light of the current gut microbiota based products that are in the FDA pipeline for drug approval and the potential impact and repercussions of their approval on FDA action. In laying out FDA's options we consider the implications of market exclusivity and off-label use of newly approved drugs. Ultimately, we explore the potential impact of FDA's decision on patients, research, and innovation.

A proposed definition of microbiota transplantation for regulatory purposes.

The advent of fecal microbiota transplantation (FMT) and the prospect of other types of microbiota transplants (MT), e.g. vaginal, skin, oral and nasal, are challenging regulatory agencies. Although FDA is regulating FMT (as a biologic), there is currently no widely accepted or agreed upon scientific or legal definition of FMT or MT. The authors report on discussions regarding a definition of MT that took place among a working group of stakeholders convened under a National Institutes for Allergies and Infectious Diseases grant to address the regulation of MT. In arriving at a definition, the group considered the 1) nature of the material being transplanted; 2) degree of manipulation of the transferred materials prior to implantation; 3) ability to characterize the transplanted product using external techniques; and 4) origin of the stool product (single vs multiple donors).

Navigating Through a Complex and Inconsistent Regulatory Framework: Section 503B of the Federal Food Drug and Cosmetic Act Outsourcing Facilities Engaged in Clinical Investigation.

The integrity of unbiased clinical data is essential to the future of the health care system by facilitating the discovery of lifesaving medicines and ensuring investigational drugs are safe and effective. Since 2002, the US pharmaceutical industry has invested over $500 billion, which is the largest research and development investment of any sector of the US economy. As a consequence of this significant investment, pharmacy compounders and other stakeholders must be acutely aware of the consequences of noncompliance. Pharmacy compounders are required to navigate through a complex and ever-changing regulatory landscape governed by US federal and state authorities competing for oversight and enforcement authority. In particular, pharmacy compounders participating in clinical investigation are faced with inconsistent federal and state drug labeling regulations, which can lead to enforcement for violating acceptable standards for clinical investigation and informed consent. As FDA registrants, Outsourcing Facilities are able to produce large volumes of clinical supplies without the need for prescriptions for individually named patients. Some states, however, may have prescription drug labeling laws that could thwart the ability to provide these clinical supplies. Accordingly, researchers should be aware of the implications of federal and state laws, including any inconsistencies, prior to engaging in clinical investigation.

Relationships between antiparkinson medication nonadherence, regimen modifications, and healthcare utilization and expenditures.

OBJECTIVES: To examine 1) the effect of prior antiparkinson drug (APD) nonadherence on subsequent APD regimen modifications; and 2) the influence of modifications on healthcare utilization and costs by patients with Parkinson's disease (PD). METHODS: This retrospective cohort study included 7052 PD patients with ≥2 APD prescriptions who initiated a modification of APD regimens in 2007. Modification was assessed as changing from one APD to another and/or adding a new APD to an existing regimen. Nonadherence was measured using Medication Possession Ratio <0.8. Discrete-time survival analyses were used to estimate the effect of prior nonadherent behavior on initiating APD modifications. Generalized linear models were used to estimate the effect of initiating medication modifications on subsequent 3-month medical use and costs. RESULTS: Initiation of APD modifications in any given month was higher among patients who were nonadherent to APDs in the preceding month (adjusted hazard ratio [HR] = 1.23), compared to their adherent counterparts. Modifications significantly predicted higher risk of all-cause and PD-related hospitalizations (adjusted relative risk [RR] = 1.22 and 1.83, respectively), home health agency utilization (RR = 1.18 and 1.52), and use of physician services (RR = 1.14 and 1.41), as well as higher total all-cause healthcare expenditures (mean = $1064) in any given 3-month interval. CONCLUSIONS: Prior nonadherence to APDs might influence initiation of APD modification. APD modifications were associated with increased health care utilization and expenditures, with the caveats that indications of modifications and disease severity may still play roles. Prescribers should consider patients' medication adherence when changing APD regimens to lower the costs of medical services.

Antiparkinson drug adherence and its association with health care utilization and economic outcomes in a Medicare Part D population.

OBJECTIVES: We examine the associations of adherence to antiparkinson drugs (APDs) with health care utilization and economic outcomes among patients with Parkinson's disease (PD). METHODS: By using 2006-2007 Medicare administrative data, we examined 7583 beneficiaries with PD who filled two or more APD prescriptions during 19 months (June 1, 2006, to December 31, 2007) in the Part D program. Two adherence measures--duration of therapy (DOT) and medication possession ratio (MPR)--were assessed. Negative binomial and gamma generalized linear models were used to estimate the rate ratios (RRs) of all-cause health care utilization and expenditures, respectively, conditional upon adherence, adjusting for survival risk, sample selection, and health-seeking behavior. RESULTS: Approximately one-fourth of patients with PD had low adherence (MPR < 0.80, 28.7%) or had a short DOT (≤ 400 days, 23.9%). Increasing adherence to APD therapy was associated with decreased health care utilization and expenditures. For example, compared with patients with low adherence, those with high adherence (MPR = 0.90-1.00) had significantly lower rates of hospitalization (RR = 0.86), emergency room visits (RR = 0.91), skilled nursing facility episodes (RR = 0.67), home health agency episodes (RR = 0.83), physician visits (RR = 0.93), as well as lower total health care expenditures (-$2242), measured over 19 months. Similarly, lower total expenditure (-$6308) was observed in patients with a long DOT versus those with a short DOT. CONCLUSIONS: In this nationally representative sample, higher adherence to APDs and longer duration of use of APDs were associated with lower all-cause health care utilization and total health care expenditures. Our findings suggest the need for improving medication-taking behaviors among patients with PD to reduce the use of and expenditures for medical resources.

Antiparkinson drug use and adherence in medicare part D beneficiaries with Parkinson's disease.

BACKGROUND: Antiparkinson drugs (APDs) are the mainstay of managing Parkinson's disease (PD). However, there is paucity of evidence documenting patterns of APD use and examining factors associated with adherence to APDs. OBJECTIVES: Our goal was to provide updated, comprehensive population-based data on APD use and adherence and to examine characteristics associated with adherence behaviors. METHODS: We analyzed data from 7583 beneficiaries with PD who had ≥ 2 APD prescription fills and were continuously enrolled in Medicare Parts A, B, and D for up to 19 months (from June 1, 2006, through December 31, 2007) or until death in 2007. We assessed 5 patterns of APD use: (1) concurrent use of ≥ 2 APD classes for ≥ 30 days; (2) switching of APDs from 1 to another; (3) augmentation of the existing regimen with a new APD; (4) duration of therapy, defined as days of APD treatment; and (5) adherence measured by using the medication possession ratio (MPR). We corrected for sample selection bias inherent in patients' self-selection into either a Part D plan or a Medicare Advantage Prescription Plan by using Heckman's 2-stage procedures. RESULTS: APD users were pre-dominantly aged ≥ 65 years (93.6%), female (59.9%), and white (89.3%). Almost one half (43.2%) of APD users concurrently used ≥ 2 APD classes. One in 4 APD users experienced changes in their APD regimen, with 16.4% switching medications and 21.1% augmenting their current regimen. Three quarters of APD users had therapy lasting ≥ 436 days (75.3%) and an MPR ≥ 0.8 (72.7%). Multivariate analyses revealed that patients aged ≥ 65 years, of non-white race, non-low-income subsidy recipients, late Part D enrollees, cognitively impaired, highly comorbid, and who experienced multiple changes in APD therapy were less likely to adhere to APD therapy. We were able to generalize our findings to all Part D enrollees by correcting for sample selection bias using the Heckman approach. These population-level, generalizable observations provide better understanding of APD use and adherence and assist in the design of interventions for poor adherence. Limitations include cross-sectional study design and constraints in administrative data that preclude measurement of other potential factors related to adherence. CONCLUSIONS: A substantial proportion of these Medicare beneficiaries with PD used multiple APDs concurrently, experienced switching and/or augmentation of APDs, and had poor adherence to APDs. Patient characteristics and clinical and drug-related factors were important predictors of APD adherence.

Racial/ethnic and age disparities in chemotherapy selection for colorectal cancer.

OBJECTIVES: To test the hypotheses that African American patients and older patients with stage IV colorectal cancer were less likely to receive newer chemotherapy agents. STUDY DESIGN: Retrospective cohort design. METHODS: Among 5068 Surveillance, Epidemiology, and End Results-Medicare patients diagnosed as having stage IV colorectal cancer between 2000 and 2002, a total of 2466 received chemotherapy and were included in the analysis. Irinotecan hydrochloride was the first of the "newer" chemotherapy agents and was marketed in 2000 as a first-line add-on agent. Descriptive statistics were generated, and a multivariable logistic regression was run to estimate the odds of receiving irinotecan among African American patients and older patients and within 2 months of chemotherapy initiation. RESULTS: African American patients had lower odds of initiating treatment with a newer chemotherapy than white patients (adjusted odds ratio, 0.641; 95% confidence interval, 0.453-0.907). An age disparity was also found, with all older age groups being significantly less likely to initiate treatment with a newer chemotherapy than the youngest age group: the adjusted odds of receiving newer chemotherapy agents (relative to patients aged 66-70 years) were lower and significant among patients aged 71 to 75, 76 to 80, and older than 80 years (odds ratios, 0.708, 0.527, and 0.213, respectively). CONCLUSIONS: Disparities in chemotherapy selection exist among patients receiving chemotherapy for stage IV colorectal cancer. On initiating chemotherapy, African American patients and older patients were less likely to receive a newer agent.

Formulary tier placement for commonly prescribed branded drugs: benchmarking and creation of a preferred placement index.

OBJECTIVES: To examine the relative preferred placement of commonly dispensed prescription drugs and to assess variations in drug coverage across a convenience sample of 12 health insurance plans. STUDY DESIGN: A cross-sectional analysis of the plans focused on all 67 patented brand-name prescription drugs from among the top 200 prescribed drugs in 2004. METHODS: For each plan, we created a preferred placement index representing the percentages of drugs that were positioned on the formulary with preferred placement, defined as tier 2 without restricted access. A separate cardiovascular index was also created. Sensitivity analyses determined the effect of limiting the sample to the top 25 patented branded drugs and examined the robustness of our index when prior authorization restrictions were allowed. RESULTS: Across 67 drugs and 12 insurance plans, drugs were rated as having preferred placement 59.1% of the time. The preferred placement index ranged from 31.3% to 88.1% across the plans for the full sample of 67 drugs; for the sample of cardiovascular drugs, the range was 25.0% to 100.0%. Results were robust across sensitivity analyses. CONCLUSIONS: Based on this convenience sample of 12 formularies, there is a wide variation in preferred placement of the most commonly prescribed branded medicines across insurers. The wide range implies that the specific insurance coverage a patient selects may have an effect on whether his or her prescribed drugs have preferred formulary placement and on his or her out-of-pocket drug expenditures.

Policy implications of drug importation.

BACKGROUND: Importation of prescription drugs into the United States has been a major health policy issue for some time. The original objective of personal importation was to allow patients to have access to drugs that were not available to them in the United States either for continuation of therapy begun in another country or when all US Food and Drug Administration (FDA)-approved drug options for their condition had been exhausted. An increasing proportion of personally imported drugs are currently marketed in the United States, but imported drugs are presumably available at a lower cost to the consumer. As US consumers opt for importation through Internet sites and other means of purchase from other countries, potential risks of exposure to counterfeit products have increased, presenting challenges to both the US regulatory system and pharmaceutical companies. OBJECTIVE: This commentary summarizes the current state of importation of prescription drugs into the United States. CONCLUSIONS: Regulators and policymakers are under increasing pressure to address the high cost of branded drugs in the United States and the desires of many US patients to purchase less expensive formulations of these products through importation. In many cases, the historical policies surrounding personal importation of prescription drugs that are not sold in the United States have been blatantly ignored, leaving the FDA in a quandary. While current legislative proposals would allow for greater access to drugs directly to consumers from other countries, they do not address the fact that the FDA has no ability to monitor the safety and efficacy of imported products. As such, the possibility of the entry of counterfeit medications and the related potential harm remain concerns.

Variability and growth in spending for outpatient specialty pharmaceuticals.

Specialty pharmaceuticals are a unique group of drug agents used to treat complex clinical conditions. Many specialty pharmaceuticals are biological in nature and administered through injection or infusion. Tracking spending on these pharmaceuticals is complex, because these products may be processed as either medical or pharmacy claims. This benchmarking study of ten Blue Cross Blue Shield plans, representing almost eighteen million covered lives, documents large expenditures on select specialty pharmaceutical categories and much variation in spending across plans, age groups, and time. Our results underscore the need for insurers to scrutinize trends in specialty pharmaceutical spending and identify appropriate management strategies.

White paper: value of specialty certification in pharmacy.

OBJECTIVE: To address the value of Board of Pharmaceutical Specialties (BPS) certification, particularly as perceived by different stakeholders (pharmacists, employers, government, and academia), and to draw a parallel between specialization and certification in pharmacy and in medicine. DATA SOURCES: Electronic databases (Medline, International Pharmaceutical Abstracts, Sociological Abstracts), associations/health care organizations Web sites, outside reports, and clinical pharmacists involved in certification processes. STUDY SELECTION: Studies and reports that addressed the value of specialty certification were selected by the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Pharmacists with specialty certification report enhanced feelings of self-worth, improved competence, and greater marketability. Other values of certification include increased acceptance by health care professionals, salary increases, and job promotions. Employers have acknowledged board-certified pharmacists through public recognition, increase in responsibility, and some types of monetary compensation. In some governmental organizations, certified pharmacists receive salary raises and are granted prescribing authority. However, the overall value of specialty certification in pharmacy as perceived by the public or payers lags behind when compared with the status of specialty certification in medicine. CONCLUSION: Board-certified pharmacists appreciate the value of pharmacy specialty certification, and in a number of organizations and practice settings, board-certified pharmacists are perceived as valuable. Still, unlike board-certified physicians, board-certified pharmacists are not widely recognized outside or even within the pharmacy profession. To address this challenge, board-certified pharmacists ought to market their services to assure that other stakeholders recognize their value.

ISPOR Code of Ethics for Researchers background article--report of the ISPOR Task Force on Code of Ethics for Researchers.

In 2001, ISPOR convened a Task Force on Code of Ethics for Researchers (The Task Force). This Task Force was to build on the previous work of ISPOR Health Science Policy Task Forces and develop a code of ethics that would be applicable to all ISPOR members and to ISPOR itself. The Task Force developed a code of ethics that was subsequently adopted by the ISPOR Board of Directors. The Code of Ethics is appended to this article and can be found on ISPOR's Web page at http://www.ispor.org/workpaper/code_ethic.htm. This article provides supportive information and justification for the ISPOR Code of Ethics for Researchers and includes a discussion of the stakeholders as well as ethical considerations for the researcher on research practices, research sponsorship, research publication and dissemination, and relationships with others. It also includes a discussion of the ethical considerations for the Society.