A Comparative Assessment of Approvals and Discontinuations of Systemic Antibiotics and Other Therapeutic Areas.

Since 1980, the US Congress has passed legislation providing several incentives to encourage the development and regulatory approval of new drugs, particularly antibiotics. We assessed long-term trends and characteristics of approvals and discontinuations of all new molecular entities, new therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA), as well as reasons for discontinuations by therapeutic class, in the context of laws and regulations implemented over the past four decades. In the period 1980-2021, the FDA approved 1310 new drugs, of which 210 (16.0%) had been discontinued as of 31 December 2021, including 38 (2.9%) withdrawn for safety reasons. The FDA approved 77 (5.9%) new systemic antibiotics, of which 32 (41.6%) had been discontinued at the end of the observation period, including 6 (7.8%) safety withdrawals. Since the enactment of the FDA Safety and Innovation Act in 2012, which created the Qualified Infectious Disease Product designation for antiinfectives to treat serious or life-threatening diseases due to resistant or potentially resistant bacteria, the FDA has approved 15 new systemic antibiotics, all using non-inferiority trials, for 22 indications and five different infections. Only one of the infections had labeled indications for patients with drug-resistant pathogens.

Disentangling the Cost of Orphan Drugs Marketed in the United States.

The increasing number and high prices of orphan drugs have triggered concern among patients, payers, and policymakers about the affordability of new drugs approved using the incentives set by the Orphan Drug Act (ODA) of 1983. This study evaluated the factors associated to the differences in the treatment cost of new orphan and non-orphan drugs approved by the FDA from 2017 to 2021. A generalized linear model (GLM) with the Gamma log-link analysis was used to ascertain the association of drug characteristics with the treatment costs of orphan and non-orphan drugs. The results of the study showed that the median and interquartile range (IQR) drug cost was USD 218,872 (IQR = USD 23,105) for orphan drugs and USD 12,798 (IQR = USD 57,940) for non-orphan drugs (p < 0.001). Higher market entry prices were associated with biologics (108%; p < 0.001), orphan status (177%; p < 0.001), US sponsor companies (48%; p = 0.035), chronic use (1083%; p < 0.001), treatment intent (163%; p = 0.004), and indications for oncology (624%; p < 0.001) or genetic disorders (624%; p < 0.001). Higher market entry treatment cost for newly approved drugs were associated with biologics, orphan status, US sponsor companies, chronic use, therapeutic intent, and indications for oncology or genetic disorders.

Assessment of FDA-Approved Drugs Not Recommended for Use or Reimbursement in Other Countries, 2017-2020.

Importance: Drug expenditures in the US are higher than in any other country and are projected to continue increasing, so US health systems may benefit from evaluating international regulatory and reimbursement decision-making of new drugs. Objective: To evaluate regulatory decisions and health technology assessments (HTAs) in Australia, Canada, and the UK regarding new drugs approved by the US Food and Drug Administration (FDA) in 2017 through 2020, as well as to estimate the US cost per patient per year for drugs receiving negative recommendations. Design and Setting: In this cross-sectional study, recommendations issued by agencies in Australia, Canada, and the UK were collected for new drugs approved by the FDA in 2017 through 2020. All data were current as of May 31, 2022. Exposures: Authorizations and HTAs in selected countries. Main Outcomes and Measures: All FDA-approved drugs were matched by active ingredient to decision summary reports published by drug regulators and HTA agencies in Australia, Canada, and the UK. Regulatory approval concordance and reasons for negative recommendations were assessed using descriptive statistics. For drugs not recommended by an international agency, the annual US drug cost per patient was estimated from FDA labeling and wholesale acquisition costs. Results: The FDA approved 206 new drugs in 2017 through 2020, of which 162 (78.6%) were granted marketing authorization by at least 1 other regulatory agency at a median (IQR) delay of 12.1 (17.7) months following US approval. Conversely, 5 FDA-approved drugs were refused marketing authorization by an international regulatory agency due to unfavorable benefit-to-risk assessments. An additional 42 FDA-approved drugs received negative reimbursement recommendations from HTA agencies in Australia, Canada, or the UK due to uncertainty of clinical benefits or unacceptably high prices. The median (IQR) US cost of the 47 drugs refused authorization or not recommended for reimbursement by an international agency was $115 281 ($166 690) per patient per year. Twenty drugs were for oncology indications, and 36 were approved by the FDA through expedited regulatory pathways or the Orphan Drug Act. Conclusions and Relevance: This cross-sectional study assessed reasons for which drugs recently approved by the FDA were refused marketing authorization or not recommended for public reimbursement in other countries. Drugs with limited international market presence may require close examination by US health care professionals and health systems.

Cost-effectiveness analysis of androgen deprivation therapy with relugolix for the treatment of advanced prostate cancer.

BACKGROUND: Relugolix treatment of advanced prostate cancer (APC), like other gonadotropin-releasing hormone-antagonists, results in rapid decrease in testosterone concentrations without the risk of flare, as seen in leuprolide. Despite this benefit over leuprolide, no economic evaluation assessment to ascertain the cost-effectiveness of relugolix has been conducted. Therefore, this study aims to assess the cost-effectiveness of androgen deprivation therapy (ADT) with 120 mg relugolix against 7.5 mg leuprolide for the treatment of APC. METHODS: A Markov model was used to assess and compare the costs of APC treatment from a health care payer's perspective and the effectiveness of ADT with relugolix and leuprolide at the 3 lines of APC treatment among modified intent-to-treat patients. Relative progression-free (PFS) and overall survival (OS) rates were estimated. Outcomes measured in the analyses included costs of the drugs and therapies, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), cost-effectiveness acceptability, and probability curves. RESULTS: The cost-effectiveness analysis showed the ICER for ADT with relugolix to be US $49,571.1 per QALY. At the ICER value, the sensitivity analysis indicated that ADT with leuprolide was dominant in 100% of the simulations. ADT acceptance with relugolix was 100% when a willingness-to-pay threshold was set at US $100,000/QALY. At 5-years, the relative PFS and OS rates for relugolix at the first line of therapy were 72.7% and 86.0%, respectively, compared to 61.0% and 85.90% for leuprolide. CONCLUSION: Though the influence of adverse events was not considered in the analysis, ADT with relugolix was not a cost-effective choice for APC management. While the analysis revealed a slight chance of sustaining testosterone suppression with relugolix, ADT with relugolix provided no significant survival advantages over ADT with leuprolide. Therefore, this analysis confirms no need for further assessment of APC interventions to make informed decisions beneficial to the APC patients, oncologists, and other stakeholders.

Predictors of shortages of opioid analgesics in the US: Are the characteristics of the drug company the missing puzzle piece?

BACKGROUND: Shortages of opioid analgesics are increasingly common, interfere with patient care and increase healthcare cost. This study characterized the incidence of shortages of opioid analgesics in the period 2015-2019 and evaluated potential predictors to forecast the risk of shortages. METHODS: This was an observational retrospective study using the US Food and Drug Administration (FDA) drug shortages data. All FDA approved opioids were included in the study. Opioid analgesics were identified using the FDA National Drug Codes (NDC) and classified according to the Drug Enforcement Administration (DEA) schedule. We conducted Least Absolute Shrinkage and Selection Operator logistic regression analysis to assess direction of the association between risk of shortage and potential predictors. We used multivariable penalized logistic regression analysis to model predictors of shortages. We split the dataset into training and validation sets to evaluate the performance of the model. FINDINGS: The FDA approved 8,207 unique NDCs for opioid analgesics; 3,017 (36.8%) were in the market as of April 30, 2019 and 91(3.0%) of them were listed as in shortage by the FDA. All NDCs in shortage were schedule II opioids; 86 (94.5%) were injectable and 84 (92.3%) generics. There were 418 companies with at least one opioid NDC listed by the FDA. Three companies accounted for more than 4 in 5 of the schedule II active injectable opioids. For each unit increase in the number of prior instances of shortages of a company, the likelihood of an NDC shortage for that company increased by 3.4%. For each unit increase in number of NDCs marketed by a company, the odds of an NDC shortage for that company decreased by 1%. CONCLUSIONS: In the period 2015-2019, shortages of opioid analgesics disproportionally impacted schedule II and injectable opioids. The risk of shortage of opioid analgesics significantly increased with the incidence of previous instances of shortages of a manufacturing company and decreased with the number of NDCs marketed by a company. The characteristics of the manufacturing company, rather than the number of companies, might be the missing piece to the complex puzzle of drug shortages in the US.

Using a Machine Learning System to Identify and Prevent Medication Prescribing Errors: A Clinical and Cost Analysis Evaluation.

BACKGROUND: Clinical decision support (CDS) alerting tools can identify and reduce medication errors. However, they are typically rule-based and can identify only the errors previously programmed into their alerting logic. Machine learning holds promise for improving medication error detection and reducing costs associated with adverse events. This study evaluates the ability of a machine learning system (MedAware) to generate clinically valid alerts and estimates the cost savings associated with potentially prevented adverse events. METHODS: Alerts were generated retrospectively by the MedAware system on outpatient data from two academic medical centers between 2009 and 2013. MedAware alerts were compared to alerts in an existing CDS system. A random sample of 300 alerts was selected for medical record review. Frequency and severity of potential outcomes of alerted medication errors of medium and high clinical value were estimated, along with associated health care costs of these potentially prevented adverse events. RESULTS: A total of 10,668 alerts were generated. Overall, 68.2% of MedAware alerts would not have been generated by the existing CDS system. Ninety-two percent of a random sample of the chart-reviewed alerts were accurate based on structured data available in the record, and 79.7% were clinically valid. Estimated cost of adverse events potentially prevented in an outpatient setting was more than $60 per drug alert and $1.3 million when extrapolating study findings to the full patient population. CONCLUSION: A machine learning system identified clinically valid medication error alerts that might otherwise be missed with existing CDS systems. Estimates show potential for cost savings associated with potentially prevented adverse events.

The Landscape of Cellular and Gene Therapy Products: Authorization, Discontinuations, and Cost.

Background: Cell and gene therapy products belong to a diverse class of biopharmaceuticals known as advanced therapy medicinal products. Cell and gene therapy products are used for the treatment and prevention of diseases that until recently were only managed chronically. The objective of this study was to examine the characteristics of market authorizations, discontinuations, and prices of cellular and gene therapy products worldwide. Data and Methods: We conducted an electronic search of authorized cell, tissue-engineered, and gene therapy products from the databases of the main drug regulatory agencies. The analysis excluded hematopoietic progenitor cell cord blood products authorized by the U.S. Food and Drug Administration. Price information was derived from the Red Book (Truven Health Analytics) for the United States, health technology assessment agencies for Europe, and other public sector sources and company news for other countries. We also searched the scientific literature for authorizations, discontinuations, and price information using MEDLINE/PubMed, Cochrane Library, Google Scholar, and EMBASE databases. All cost data were converted to U.S. dollars. Descriptive analysis was conducted in this study. Results: There were 52 different cell, tissue engineering and gene therapy products with 69 market authorizations in the world as of December 31, 2018. The products included 18 (34%) cell therapies, 23 (43.4%) tissue engineered products, and 12 (22.6%) gene therapies. There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%) tissue-engineered, and 22 (31.9%) gene therapy market authorizations. The EMA withdrew the authorization for two tissue engineering products, one cell therapy and one gene therapy, and New Zealand lapsed approval of one cell therapy. Most products were first authorized after 2010, including 10 (83.3%) gene therapies, 13 (72.2%) cell therapies, and 13 (56.5%) tissue-engineered products. The treatment price for four allogenic cell therapies varied from $2,150 in India to $200,000 in Canada. The treatment price for three autologous cell therapies ranged from $61,500 in the United Kingdom to a listed price of $169,206 in the United States. Tissue-engineered treatment prices varied from $400 in South Korea to $123,154 in Japan. Gene therapy treatment prices ranged from $5,501 for tonogenchoncel-L in South Korea to $1,398,321 for alipogene tiparvovec in Germany. Conclusions: A significant number of new cell, tissue, and gene therapies have been approved in the past decade. Most products were conditionally authorized and targeted rare cancers, genetic diseases, and other debilitating diseases. However, there are also products approved for cosmetic reasons. Cell, tissue, and gene therapies are among the most expensive therapies available. Healthcare systems are not prepared to assume the cost of future therapies for a myriad of rare diseases and common diseases of epidemic proportions.

A comparison of new drugs approved by the FDA, the EMA, and Swissmedic: an assessment of the international harmonization of drugs.

INTRODUCTION: This study compared the characteristics of new human drugs approved by the Food and Drug Administration (FDA), the European Medicine Agency (EMA), and Swissmedic (SMC) in the period 2007 to 2016. METHODS: The list of new drugs and therapeutic biologics approved by the FDA, the EMA, and SMC in the period 2007 to 2016 was collected from websites of those agencies. The study included regulatory information, approval date, and indication for each drug. Descriptive statistical t tests and x2-tests were performed for the analysis. RESULTS: From 2007 to 2016, 134 new drugs were approved by all three regulatory agencies. Overall, 66.4% of the drugs were first approved by the FDA, 30.6% by the EMA, and 3.0% by SMC. The difference in approval dates between SMC and the EMA, SMC and the FDA, and the FDA and the EMA were statistically significant. The indications approved by the FDA, the EMA, and SMC for the same drugs were similar in content for 23.1% drugs and different in 76.9% of the drugs. Significant differences in indications existed between the FDA and SMC and the FDA and the EMA, but not between the EMA and SMC. CONCLUSION: There were differences in the characteristics of new drugs approved by the EMA, the FDA, and SMC in the period 2007-2016. Overall, two thirds of the new drugs were first approved by the FDA. Differences in indications were found in three out of four new drugs approved by the three regulatory agencies. Despite international drug regulation harmonization efforts, significant differences in the characteristics of new drugs approved by different agencies persist.

Cost-effectiveness analysis of metformin+dipeptidyl peptidase-4 inhibitors compared to metformin+sulfonylureas for treatment of type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2D) typically use several drug treatments during their lifetime. There is a debate about the best second-line therapy after metformin monotherapy failure due to the increasing number of available antidiabetic drugs and the lack of comparative clinical trials of secondary treatment regimens. While prior research compared the cost-effectiveness of two alternative drugs, the literature assessing T2D treatment pathways is scarce. The purpose of this study was to evaluate the long-term cost-effectiveness of dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) as second-line therapy in combination with metformin in patients with T2D. METHODS: A Markov model was developed with four health states, 1 year cycle, and a 25-year time horizon. Clinical and cost data were collected from previous studies and other readily available secondary data sources. The incremental cost-effectiveness ratio (ICER) was estimated from the US third party payer perspective. Both, costs and outcomes, were discounted at a 3% annual discount rate. One way and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainty on the base-case results. RESULTS: The discounted incremental cost of metformin+DPP-4i compared to metformin+SU was $11,849 and the incremental life-years gained were 0.61, resulting in an ICER of $19,420 per life-year gained for patients in the metformin+DPP-4i treatment pathway. The ICER estimated in the probabilistic sensitivity analysis was $19,980 per life-year gained. Sensitivity analyses showed that the results of the study were not sensitive to changes in the parameters used in base-case. CONCLUSIONS: The metformin+DPP-4i treatment pathway was cost-effective compared to metformin+SU as a long-term second-line therapy in the treatment of T2D from the US health care payer perspective. Study findings have the potential to provide clinicians and third party payers valuable evidence for the prescription and utilization of cost-effective second-line therapy after metformin monotherapy failure in the treatment of T2D.

Cost-effectiveness of different strategies for treatment relapsing-remitting multiple sclerosis.

AIM: To compare the cost-effectiveness of different disease-modifying therapies' strategies for treatment of relapsing-remitting multiple sclerosis. METHODS: A Markov model was developed to assess the cost-effectiveness and incremental cost-effectiveness ratios for different strategies of using disease-modifying therapies from a US third-party payer perspective. All costs were converted to 2014 US$. RESULTS: Over 20 years, the total costs per patient were estimated at US$161,136.60 for Strategy 1 (symptom management [SM] alone), US$551,650.66 for Strategy 2 (SM and IFN-ß-1a), US$703,463.60 for Strategy 3 (SM and natalizumab) and US$670,985.24 for Strategy 4 (SM and alemtuzumab). The accumulated quality-adjusted life years were 10.49, 10.66, 10.69 and 10.71 for each of the four Strategies 1-4, respectively. The resulting incremental cost-effectiveness ratios were 2,297,141.53 comparing Strategy 2 to Strategy 1, and -1,623,918.00 comparing Strategy 4 to Strategy 3. CONCLUSION: Strategy 1 was the cost-effective strategy for treatment of relapsing-remitting multiple sclerosis when compared with other strategies.

Comparison of Ambulatory, High-Dose, Intravenous Diuretic Therapy to Standard Hospitalization and Diuretic Therapy for Treatment of Acute Decompensated Heart Failure.

Innovative treatment strategies for decompensated heart failure (HF) are required to achieve cost savings and improvements in outcomes. We developed a decision analytic model from a hospital perspective to compare 2 strategies for the treatment of decompensated HF, ambulatory diuretic infusion therapy, and hospitalization (standard care), with respect to total HF hospitalizations and costs. The ambulatory diuretic therapy strategy included outpatient treatment with high doses of intravenous loop diuretics in a specialized HF unit whereas standard care included hospitalization for intravenous loop diuretic therapy. Model probabilities were derived from the outcomes of patients who were treated for decompensated HF at Brigham and Women's Hospital (Boston, MA). Costs were based on Centers for Medicare and Medicaid reimbursement and the available reports. Based on a sample of patients treated at our institution, the ambulatory diuretic therapy strategy was estimated to achieve a significant reduction in total HF hospitalizations compared with standard care (relative reduction 58.3%). Under the base case assumptions, the total cost of the ambulatory diuretic therapy strategy was $6,078 per decompensation episode per 90 days compared with $12,175 per 90 days with standard care, for a savings of $6,097. The cost savings associated with the ambulatory diuretic strategy were robust against variation up to 50% in costs of ambulatory diuretic therapy and the likelihood of posttreatment hospitalization. An exploratory analysis suggests that ambulatory diuretic therapy is likely to remain cost saving over the long-term. In conclusion, this decision analytic model demonstrates that ambulatory diuretic therapy is likely to be cost saving compared with hospitalization for the treatment of decompensated HF from a hospital perspective. These results suggest that implementation of outpatient HF units that provide ambulatory diuretic therapy to well-selected subgroup of patients may result in significant reductions in health care costs while improving the care of patients across a variety of health care settings.

Price analysis of multiple sclerosis disease-modifying therapies marketed in the United States.

OBJECTIVES: This study assessed trends in the average wholesale price (AWP) at the market entry of disease-modifying therapies (DMTs) approved by Food and Drug Administration (FDA) in the period 1987-2014. METHODS: DMT regulatory information was derived from the FDA website. The AWPs per unit at market entry data were derived from the Red Book (Truven Health Analytics Inc.). The AWP history for each DMT was collected from its date of approval to 31 December 2014. The FDA approved label defined daily dose (DDD) for adult patients was obtained from FDA approved labels. The AWP per DDD and the AWP/DDD per year of therapy were computed. Descriptive statistics, Wilcoxon tests, t-test, and multiple linear regression were performed. The statistical significance level was set at 0.05. RESULTS: The FDA approved 12 multiple sclerosis (MS) DMTs, including five new drug applications (NDAs) and seven biologic license applications (BLAs) as of 31 December 2014. The FDA granted orphan designation to five DMTs. There was one DMT approved by the FDA in the 1980s, three in the 1990s, three in 2000s, and five in the period 2010-2014. The market entry inflation-adjusted AWP per DDD was $10.23 for the first DMT (mitoxantrone hydrochloride) that was approved in the 1980s. The median market entry inflation-adjusted AWP per DDD was $12.41 (interquartile range [IQR] = 4.51) for DMTs approved in the 1990s, $71.26 (IQR = 58.35) in the 2000s, and $172.56 (IQR = 84.97) in the period 2010-2014. The median AWP per DDD was statistically significantly different (p = 0.011) for orphan (median = $41.82, IQR = 56.077) compared to non-orphan drugs (median = $171.32, IQR = 199.29). Year of market entry was positively associated with DMT prices at US market entry (p = 0.01). CONCLUSIONS: The AWP per DDD for DMTs at market entry increased substantially over time. The increase in DMTs prices exceeded the general consumer price index.

OSTEOPOROSIS DRUGS MARKETED IN THE UNITED STATES: GENERIC COMPETITION, PRICING STRUCTURE, AND DISPERSION AMONG PAYERS.

BACKGROUND: Despite the cost of pharmaceuticals, studies assessing prices of osteoporosis drugs are lacking. This study examined trends in prices of osteoporosis drugs in the United States in the period 1988-2014, assessed pricing structure of osteoporosis drugs, and evaluated price trends before and after generic drugs market entry. METHODS: Data were derived from the U.S. Food and Drug Administration, the RedBook, the Centers for Medicare & Medicaid Services, and the Federal Supply Schedule (FSS). Descriptive statistics and segmented linear regression analyses were performed. RESULTS: In the period 1988-2014, osteoporosis drug prices increased faster than the inflation. The average wholesale price (AWP) of generic products at market entry represented 90 percent of the AWP for the corresponding brand. Prices of brand products continued to increase after generic entry. Drug prices showed a significant variation when compared with the brand AWP. The brand wholesale acquisition cost (WAC) was typically set at 83.3 percent of the AWP. Community pharmacies acquired osteoporosis brand drugs at a median of 80.5 percent of the brand AWP. Significant reductions in brand AWP were observed for Medicare Part B (78.5 percent of the brand AWP), generic National Average Drug Acquisition Cost (33.7 percent), and FSS (22.5 percent). CONCLUSIONS: There are significant differences in the manufacturer prices, pharmacy acquisition costs and reimbursement rates of osteoporosis drugs. Pharmaceutical companies listed prices are higher than the pharmacy actual estimated acquisitions costs, and the prices used for reimbursement to providers. Generic drugs entry significantly drives down prices; still, prices of branded drugs facing generic competition continued to increase after generic market entry.

Fixed-dose combination and single active ingredient drugs: a comparative cost analysis.

BACKGROUND: Fixed-dose combination (FDC) drugs are formulations of two or more active ingredients. OBJECTIVES: To assess the pricing structure and price difference of all US FDA-approved FDCs and single drugs included in the combination. METHODS: Data were collected from the FDA Orange Book and Drugs@FDA. Average Wholesale Price (AWP) unit price data were derived from The Red Book. RESULTS: The FDA approved 117 FDC. The average AWP difference percentage between the FDC and the sum of the single drugs in the FDC is 84.9 ± 26.2%, and varied by therapeutic class (p < 0.001). The FDC AWP averaged 83.3 ± 23.4% of the single drug AWP sum when there are no generics, and 95.1 ± 42.3% (p < 0.01) when there are two generic single active ingredients in the FDC. CONCLUSIONS: The price difference between FDC and single active ingredients in the combination is correlated with the therapeutic class, the year of FDC approval, and the number of single ingredients in the combination that have generics.

Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals.

INTRODUCTION: Fixed-dose combinations (FDC) contain two or more active ingredients. The effective patent and exclusivity life of FDC compared to single active ingredient has not been assessed. OBJECTIVES: Trends in FDA approved FDC in the period 1980-2012 and time lag between approval of FDC and single active ingredients in the combination were assessed, and the effective patent and exclusivity life of FDC was compared with their single active ingredients. MATERIALS AND METHODS: New molecular entities (NMEs), new therapeutic biologics license applications (BLAs) and FDC data were collected from the FDA Orange Book and Drugs@FDA. Analysis included FDC containing one or more NMEs or BLAs at first FDA approval (NMEs-FDC) and only already marketed drugs (Non-NMEs-FDC). Descriptive, Kruskal-Wallis and Wilcoxon Rank Sum analyses were performed. RESULTS: During the study period, the FDA approved 28 NMEs-FDC (3.5% of NMEs) and 117 non-NMEs-FDC. FDC approvals increased from 12 in the 1980s to 59 in the 2000s. Non-NMEs-FDC entered the market at a median of 5.43 years (interquartile range 1.74, 10.31) after first FDA approval of single active ingredients in the combination. The Non-NMEs-FDC entered the market at a median of 2.33 years (-7.55, 2.39) before approval of generic single active ingredient. Non-NME-FDC added a median of 9.70 (2.75, 16.24) years to the patent and exclusivity life of the single active ingredients in the combination. CONCLUSION: FDC approvals significantly increased over the last twenty years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs included in the combination.

Examination of risk evaluation and mitigation strategies and drug safety in the US.

BACKGROUND: The Food and Drug Administration Amendment Act of 2007 (FDAAA 2007) enabled the US Food and Drug Administration (FDA) to require risk evaluation and mitigation strategies (REMS) for a drug or biologic to ensure that its benefits outweigh the risks. OBJECTIVE: This study sought to evaluate REMS approved and released by the FDA since the program inception in 2008, to assess the characteristics of REMS approved and to calculate the time lag between FDA drug application approval and REMS approval. METHODS: Data were derived from Approved Drug Products with Therapeutic Equivalence Evaluations, Approved REMS and Drugs@FDA. Data included generic availability, application type and approval date, therapeutic class and FDA review class, orphan designation, priority review and market status. RESULTS: The FDA approved REMS for 259 marketing applications (217 new drug applications -NDAs, 10 abbreviated NDAs, and 32 biologic license applications) in the study period. The FDA granted orphan designation to 11.4% of active ingredients with REMS and priority review to 38.4% of the NDAs with REMS. The largest number of REMS approvals was for nervous system products (31.8% of total approved REMS) and antineoplastic and immunomodulating agents (15.3%). CONCLUSIONS: The FDA approved REMS for one in three biologics and one in thirteen chemical entities available in the market. A pharmaceutical product can be in the market for an average of 14 years before the FDA identifies and evaluates the risk problems that warrant the approval of a REMS.

Changes in FDA enforcement activities following changes in federal administration: the case of regulatory letters released to pharmaceutical companies.

BACKGROUND: The United States (US) Food and Drug Administration (FDA) is responsible for the protection of the public health by assuring the safety, effectiveness and security of human drugs and biological products through the enforcement of the Federal Food, Drug and Cosmetic Act (FDCA) and related regulations. These enforcement activities include regulatory letters (i.e. warning letters and notice of violation) to pharmaceutical companies. A regulatory letter represents the FDA's first official notification to a pharmaceutical company that the FDA has discovered a product or activity in violation of the FDCA.This study analyzed trends in the pharmaceutical-related regulatory letters released by the FDA during the period 1997-2011 and assessed differences in the average number and type of regulatory letters released during the last four federal administrations. METHODS: Data derived from the FDA webpage. Information about the FDA office releasing the letter, date, company, and drug-related violation was collected. Regulatory letters were classified by federal administration. Descriptive statistics were performed for the analysis. RESULTS: Between 1997 and 2011 the FDA released 2,467 regulatory letters related to pharmaceuticals. FDA headquarters offices released 50.6% and district offices 49.4% of the regulatory letters. The Office of Prescription Drug Promotion released the largest number of regulatory letters (850; 34.5% of the total), followed by the Office of Scientific Investigations (131; 5.3%), and the Office of Compliance (105; 4.3%). During the 2nd Clinton Administration (1997-2000) the average number of regulatory letters per year was 242.8 ± 45.6, during the Bush Administration (2001-2008) it was 120.4 ± 33.7, and during the first three years of the Obama administration (2009-2011) it was 177.7.0 ± 17.0. The average number of regulatory letters released by the Office of Prescription Drug Promotion also varied by administration: Clinton (122.3 ± 36.4), Bush (29.5 ± 16.2) and Obama (41.7 ± 11.1). CONCLUSIONS: Most regulatory letters released by FDA headquarters were related to marketing and advertising activities of pharmaceutical companies. The number of regulatory letters was highest during the second Clinton administration, diminished during the Bush administrations, and increased again during the Obama administration. A further assessment of the impact of changes in federal administration on the enforcement activities of the FDA is required.

Comparing the cost of community pharmacy and mail-order pharmacy in a US retirement system.

Although community pharmacies have been the mainstay for drug distribution in the USA, plan members are encouraged to use mail-order pharmacies as a cost-containment strategy. Both channels differ with respect to reimbursement rates, utilization, and costs. We evaluated the differences in reimbursement rates and in ingredient costs between the two dispensing channels. We used pharmacy claims from a large Midwestern retirement system for the period 2000-2005. A representative sample of drug products was selected. We estimated the aggregated gross reimbursement, the ingredient cost, dispensing fee, pharmacy incentives for drug substitution, professional fee for other services, sales tax, and reimbursement per payer. The sample contained 1964 observations-four million claims. There were 58.5% observations for single source brands and 39.0% for generics. Observations with lower unit gross reimbursement rate in community pharmacy increased from 10.3% to 16.5%. Unit ingredient cost and dispensing fees were higher in community pharmacy than in mail-order pharmacy. Community pharmacy had a lower reimbursement rate per unit of medication (33.5-44.6% observations) compared with mail-order pharmacy. There were 87.3-98.1% observations with a higher patient co-financing per unit of medication in community pharmacy. Gross pharmaceutical reimbursement rates and unit ingredient costs were higher in community pharmacy than in mail-order pharmacy; but in more than 10% of the observations, the costs were higher in mail-order pharmacy than in community pharmacy.