Assessment of Variation in State Regulation of Generic Drug and Interchangeable Biologic Substitutions.

Importance: Brand-name drugs, including biologics, have been the primary source of increasing prescription drug spending in the US. Each state has drug product selection laws that regulate whether and how pharmacists can substitute prescriptions for brand-name drugs with more affordable equivalents, either small-molecule generic drugs or interchangeable biologics, but the details of these laws can vary. Objective: To examine the variation in state drug product selection laws with regard to factors that may affect which version of a drug is dispensed. Design, Setting, and Participants: A cross-sectional analysis was performed, using a legal database, to obtain information on state laws of all states plus Washington, DC, as they existed on September 1, 2019. Exposures: Whether substitution was mandatory or permissive, patient consent was needed prior to substitution, patient notification of substitution was required independent of the drug's packaging, and/or pharmacists were protected from special risk of liability for substitution. Main Outcomes and Measures: For small-molecule and biologic drugs, descriptive statistics were generated for the 4 exposure variables. In addition, for small-molecule drugs, a generic substitution score with a maximum of 1 point was assigned for each exposure variable (range, 0-4 points), with higher scores indicating regulatory requirements limiting substitution. Results: This cross-sectional analysis of the generic drug substitution regulations in the 50 US states and Washington, DC, found that for small-molecule drugs, 19 states required pharmacists to perform generic substitution; 7 states and Washington, DC, required patient consent; 31 states and Washington, DC, mandated patient notification independent of the drug's packaging, and 24 states did not explicitly protect pharmacists from greater liability. Nine states and Washington, DC, had a generic substitution score for small-molecule drugs of 3 or higher, and 45 states had more stringent requirements for interchangeable biologic substitution, most commonly mandatory physician notification. Conclusions and Relevance: The findings of this study suggest that there is a need for optimizing state drug product selection laws to promote generic and interchangeable biologic substitution, which may help improve medication adherence and reduce drug spending.

Correction to: Outcomes Associated with Generic Drugs Approved Using Product-Specific Determinations of Therapeutic Equivalence.

Page 432, Fig. 2 Plots of model-based outcome incidence rates (per 100 person-years of exposure) before and after introduction of first generic versions of study and control drugs.

"Impact of drug-reimbursement policies on prescribing: A case-study of a newly marketed long-acting injectable antipsychotic among relapsed schizophrenia patients".

OBJECTIVE: To quantify and explain variation in use of long-acting injectable antipsychotics (LAIs) in the United States, and understand the relationship between patient characteristics, drug reimbursement policies, and LAI prescribing after relapse. METHODS: A cohort of recently relapsed patients with schizophrenia ages 18 to 64, were identified immediately after discharge from a related inpatient hospitalization, partial hospitalization, or emergency room visit, drawn from 2004 to 2006 Medicaid claims, and followed for 90 days until LAI initiation. Data on state-level Medicaid prior authorization (PA) policies for LAIs were collected. Sequential longitudinal Poisson regression models were developed to understand the relationship between patient and PA policy variables and LAI prescribing, including prior adherence to oral antipsychotics, demographics, clinical variables, and presence of PA policy for LAI. RESULTS: Among 36 282 patients, 3.1% received risperidone LAI, and 3.8% received a first-generation (FGA) LAI with wide variation across states. Prior adherence ranged from 29% to 89% but was marginally associated with initiation and did not explain variation for LAI prescribing. FGA initiation was associated with geography and race/ethnicity but not PA policy. For risperidone LAI initiation, demographics and clinical factors explained, respectively, 5.0% and 3.0% of the variation; PA policy had a large negative association with initiation (RR = 0.41; 95%CI 0.20-0.87) and explained 8.4% of the variation. CONCLUSIONS: PA policies may represent a major treatment barrier for risperidone LAI among relapsed patients. Non-adherence plays a little role in predicting which patients receive LAIs. Policy makers and health insurers will need to consider these findings when guiding the use of LAIs. KEY POINTS Among a nationwide cohort of relapsed schizophrenia patients enrolled in US Medicaid, 3.1% received Risperdal Consta, a long-acting injectable antipsychotic (LAI), and 3.8% initiated a first-generation first-generation LAI within 90 days after discharge. During 2004 to 2006, there was marked variation in 90 day post-relapse initiation of Risperdal-Consta-a newly marketed medication during this period-and also marked variation in 90 day post-relapse initiation of any first-generation LAI, which appeared to be associated with race/ethnicity and geography. Prior authorization policies were associated with substantially lower initiation of Risperdal Consta in this cohort of relapsed patients even after accounting for clinical indication (non-adherence), relapse history, demographics, adjunctive medication, and mental health service use.

Do patients trust the FDA?: a survey assessing how patients view the generic drug approval process.

PURPOSE: Skepticism about the safety and effectiveness of certain generic drugs remains, particularly related to generic drugs that are approved by the Food and Drug Administration (FDA) using product-specific bioequivalence studies that differ from the standard testing pathway. The current study was designed to assess patient knowledge and perceptions of the generic drug approval process. METHODS: We conducted a survey of patients with 10 different chronic diseases. We recruited survey participants from the CVS Advisor Panel, a proprietary database of 124 621 CVS customers pre-consented to participate in online research activities. We created a survey to collect data on patients' perceptions of the FDA's generic drug approval process, as well as their experiences with generic drugs approved using modified bioequivalence approaches used to treat their chronic medical conditions. RESULTS: Our survey of 753 patients with chronic diseases (65% response rate) showed that most (74%) expressed little familiarity with FDA's approval process for generic drugs, but nearly all (89%) believed that FDA approval ensures the safety and effectiveness of generic drugs. About one-fifth of respondents reported hearing concerns about their generic drugs, most commonly from physicians (35-36%) and the Internet (32-38%), but there were no differences in patients' reports of concerns about generic versions of the six study drugs approved using product-specific pathways versus comparator drugs. CONCLUSIONS: Patients have little knowledge about the generic drug approval system, but positive belief in the safety and effectiveness of generic drugs. Patients do not appear to have greater concern about generic drugs approved via product-specific pathways. Copyright © 2017 John Wiley & Sons, Ltd.

Outcomes Associated with Generic Drugs Approved Using Product-Specific Determinations of Therapeutic Equivalence.

OBJECTIVE: We sought to examine rates of clinical outcomes among patients before and after market introduction of generic versions of five drugs approved using product-specific equivalence determinations. METHODS: We used data from a large national insurer to identify patients who initiated a study (acarbose tablets, salmon calcitonin nasal spray, enoxaparin injection, vancomycin capsules, venlafaxine extended-release tablets) or control drug (nateglinide, glimepiride, alendronate, fondaparinux, metronidazole, sertraline, paroxetine) in each calendar month between 2003 and 2012 and to determine rates of claims-based proxies for lack of effectiveness outcomes following initiation. We used segmented time-series analyses to evaluate level (short-term) and slope (longer-term) changes in outcomes upon introduction of a generic study or control drug. RESULTS: Among study drugs, we observed three increases (one with p < 0.05) and three decreases (two with p < 0.05) in the level of outcome rates. All changes in slope indicated decreases in outcomes from the brand-only to the generic period; four had p < 0.05. For control drugs, we observed positive level changes for eight of nine drug-outcome pairs; two had p < 0.05. We observed negative slope changes for eight out of nine pairs; six had p < 0.05. We observed a significant increase in level change following the introduction of generic bupropion versions that were later found to be not bioequivalent (p < 0.01). CONCLUSIONS: We did not find evidence that introduction of generic drugs approved using product-specific therapeutic equivalence determinations was associated with worse clinical outcomes than those among initiators of the brand-name versions of the same products. We observed similar patterns for control drugs.

Physicians' Trust in the FDA's Use of Product-Specific Pathways for Generic Drug Approval.

BACKGROUND: Generic drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process. METHODS AND FINDINGS: A survey was administered to a national sample of primary care internists and specialists between August 2014 and January 2015. In total, 1,152 physicians comprising of internists with no reported specialty certification and those with specialty certification in hematology, infectious diseases, and endocrinology were surveyed. The survey assessed physicians' perceptions of the FDA's generic drug approval process, as well as their experiences prescribing six generic drugs approved between 2008 and 2012 using product-specific approval pathways and selected comparator drugs. Among 718 respondents (62% response rate), a majority were comfortable with the FDA's process in ensuring the safety and effectiveness of generic drugs overall (91%) and with letting the FDA determine which tests were necessary to determine bioequivalence in a particular drug (92%). A minority (13-26%) still reported being uncomfortable prescribing generic drugs approved using product-specific pathways. Overall, few physicians heard reports of concerns about generic versions of the study drugs or their comparators, with no differences between the two groups. Physicians tended to hear about concerns about the safety or effectiveness of generic drugs from patients, pharmacists, and physician colleagues. CONCLUSIONS: Physicians hold largely positive views of the FDA's generic drug approval process even when some questioned the performance of certain generic drugs in comparison to brand-name drugs. Better education about the generic drug approval process and standards may alleviate concerns among the physician community and support the delivery of cost-effective health care.

Switch-backs associated with generic drugs approved using product-specific determinations of therapeutic equivalence.

PURPOSE: US Food and Drug Administration approval for generic drugs relies on demonstrating pharmaceutical equivalence and bioequivalence; however, some drug products have unique attributes that necessitate product-specific approval pathways. We evaluated rates of patients' switching back to brand-name versions from generic versions of four drugs approved via such approaches. METHODS: We used data from Optum LifeSciences Research Database to identify patients using a brand-name version of a study drug (acarbose tablets, salmon calcitonin nasal spray, enoxaparin sodium injection, and venlafaxine extended release tablets) or a control drug. We followed patients to identify switching to generic versions and then followed those who switched to identify whether they switched back to brand-name versions. We calculated switch and switch-back rates and used Kaplan-Meier and log-rank tests to compare rates between study and control drugs. RESULTS: Our cohort included 201 959 eligible patients. Brand-to-generic switch rates ranged from 66 to 106 switches per 100 person-years for study drugs and 80 to 110 for control drugs. Rates of switch-back to brand-name versions ranged from 5 to 37 among study drugs and 3 to 53 among control drugs. Switch-back rates were higher for venlafaxine vs. sertraline (p < 0.01) and calcitonin vs. alendronate (p = 0.01). Switch-back rates were lower for venlafaxine vs. paroxetine (p < 0.01) and acarbose vs. nateglinide (p < 0.01). Rates were similar for acarbose vs. glimepiride (p = 0.97) and for enoxaparin vs. fondiparinux (p = 0.11). CONCLUSION: As compared to control drugs, patients were not more likely to systematically switch back from generic to brand-name versions of the four study drugs. Copyright © 2016 John Wiley & Sons, Ltd.

Variations in Patients' Perceptions and Use of Generic Drugs: Results of a National Survey.

BACKGROUND: Over 84 % of all prescriptions in the US are filled as generic drugs, though in prior surveys, patients reported concerns about their quality. OBJECTIVE: We aimed to survey patients' perceptions and use of generic drugs. DESIGN: Our survey (administered August 2014) assessed patients' skepticism about generic drug safety and effectiveness and how often they requested brand-name drugs. Chi-square tests and two-sample t-tests assessed associations between patient demographics and the outcomes. PARTICIPANTS: Our sample frame was the CVS Advisor Panel, a national database of 124,621 CVS customers. We randomly selected 1450 patients with self-reported chronic conditions who filled at least one prescription in the prior 3 months. MAIN MEASURES: We assessed how often patients reported asking their physicians to prescribe a brand-name over a generic drug in the last year, and "generic skepticism," defined as not believing generic drugs were as safe, effective, had the same side effects, and contained the same active ingredients as brand-name drugs. KEY RESULTS: Of the 1,442 patients with valid addresses, 933 responded (65 % response rate) and 753 took the full survey. A vast majority (83 %) agreed that physicians should prescribe generic drugs when available, and 54 % said they had not asked their physicians to prescribe a brand-name drug over a generic in the past year. Most respondents considered generic drugs to be as effective (87 %) and safe (88 %) as their brand-name counterparts, and to have the same side effects (80 %) and active ingredients (84 %). Non-Caucasians were more likely than Caucasians to request a brand-name drug over a generic (56 % vs. 43 %, p < 0.01), and were also more skeptical of generic drugs' clinical equivalence (43 % vs. 29 %, p < 0.01). CONCLUSIONS: We found a substantial shift towards more patients having positive views of generic drugs, but lingering negative perceptions will have to be overcome to ensure continued cost-savings and improved patient outcomes from generic drugs.

Bisphosphonates and risk of cardiovascular events: a meta-analysis.

BACKGROUND AND OBJECTIVES: Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass. METHODS: A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed. RESULTS: Absolute risks over 25-36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs [95% CI]: 0.98 [0.84-1.14]; I2 = 0.0%), atrial fibrillation (41 trials; 1.08 [0.92-1.25]; I2 = 0.0%), MI (10 trials; 0.96 [0.69-1.34]; I2 = 0.0%), stroke (10 trials; 0.99 [0.82-1.19]; I2 = 5.8%), and CV death (14 trials; 0.88 [0.72-1.07]; I2 = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 [0.96-1.61]; I2 = 0.0%), not for oral bisphosphonates (26 trials; 1.02 [0.83-1.24]; I2 = 0.0%). The CV effects did not vary by subgroups or study quality. CONCLUSIONS: Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.

Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.

BACKGROUND: Generic drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations. OBJECTIVE: The aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches. DATA SOURCES: We conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations. DATA EXTRACTION: We extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding. DATA SYNTHESIS: After retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria-8 examining FDA-approved versions and 18 examining non-FDA-approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non-FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports. CONCLUSIONS: Pharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre-approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed.

Prescription drug insurance coverage and patient health outcomes: a systematic review.

Previous reviews have shown that changes in prescription drug insurance benefits can affect medication use and adherence. We conducted a systematic review of the literature to identify studies addressing the association between prescription drug coverage and health outcomes. Studies were included if they collected empirical data on expansions or restrictions of prescription drug coverage and if they reported clinical outcomes. We found 23 studies demonstrating that broader prescription drug insurance reduces use of other health care services and has a positive impact on patient outcomes. Coverage gaps or caps on drug insurance generally led to worse outcomes. States should consider implementing the Affordable Care Act expansions in drug coverage to improve the health of low-income patients receiving state-based health insurance.