Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017.

Importance: Since the introduction of the Fast Track designation in 1988, the number of special regulatory programs available for the approval of new drugs and biologics by the US Food and Drug Administration (FDA) has increased, offering the agency flexibility with respect to evidentiary requirements. Objective: To characterize pivotal efficacy trials supporting the approval of new drugs and biologics during the past 3 decades. Design, Setting, and Participants: This cross-sectional study included 273 new drugs and biologics approved by the FDA for 339 indications from 1995 to 1997, from 2005 to 2007, and from 2015 to 2017. Main Outcomes and Measures: Therapeutics were classified by product type and therapeutic area as well as orphan designation and use of special regulatory programs, such as Priority Review and Accelerated Approval. Pivotal trials were characterized by use of randomization, blinding, types of comparators, primary end points, number of treated patients, and trial duration, both individually and aggregated by each indication approval. Results: A total of 273 new drugs and biologics were approved by the FDA in these 3 periods (107 [39.2%] in 1995-1997; 57 [20.9%] in 2005-2007; and 109 [39.9%] in 2015-2017), representing 339 indications (157 [46.3%], 64 [18.9%], and 118 [34.8%], respectively). The proportion of therapeutic approvals using at least 1 special regulatory program increased (37 [34.6%] in 1995-1997; 33 [57.9%] in 2005-2007; and 70 [64.2%] in 2015-2017), as did indication approvals receiving an orphan designation (20 [12.7%] in 1995-1997; 17 [26.6%] in 2005-2007, and 45 [38.1%] in 2015-2017). The most common therapeutic areas differed over time (infectious disease, 53 [33.8%] in 1995-1997 vs cancer, 32 [27.1%] in 2015-2017). When considering the aggregate pivotal trials supporting each indication approval, the proportion of indications supported by at least 2 pivotal trials decreased (80.6% [95% CI, 72.6%-87.2%] in 1995-1997; 60.3% [95% CI, 47.2%-72.4%] in 2005-2007; and 52.8% [95% CI, 42.9%-62.6%] in 2015-2017; P < .001). The proportion of indications supported by only single-group pivotal trials increased (4.0% [95% CI, 1.3%-9.2%] in 1995-1997; 12.7% [95% CI, 5.6%-23.5%] in 2005-2007; and 17.0% [95% CI, 10.4%-25.5%] in 2015-2017; P = .001), whereas the proportion supported by at least 1 pivotal trial of 6 months' duration increased (25.8% [95% CI, 18.4%-34.4%] in 1995-1997; 34.9% [95% CI, 23.3%-48.0%] in 2005-2007; and 46.2% [95% CI, 36.5%-56.2%] in 2015-2017; P = .001). Conclusions and Relevance: In this study, more recent FDA approvals of new drugs and biologics were based on fewer pivotal trials, which, when aggregated by indication, had less rigorous designs but longer trial durations, suggesting an ongoing need for continued evaluation of therapeutic safety and efficacy after approval.

Factors Associated With Postmarketing Research for Approved Indications for Novel Medicines Approved by Both the FDA and EMA Between 2005 and 2010: A Multivariable Analysis.

We examined whether drug-related characteristics-conditions, development, manufacturers, revenues-were associated with postmarketing research in terms of the number of trials and total population to be enrolled. We included 63 drugs, corresponding to 3,867 postmarketing trials of approved indications. On multivariable analysis, both the number of postmarketing trials and population to be enrolled were associated with expected length of treatment (ratio of means (RoM) = 2.35 and RoM = 8.65) and number of patients in pivotal trials (RoM = 1.11 and RoM = 1.25 per thousand patients). The number of postmarketing trials was increased for drugs approved with surrogate endpoints (RoM = 2.19), generating high revenues (RoM = 1.08 per billion dollars) and addressing greater disease burden (RoM = 1.90 per hundred million disability-adjusted life years). The population to be included was increased for drugs approved after an increased number of pivotal trials (RoM = 1.82) and those unaffected by safety concerns (RoM = 2.63). Postmarketing trials seem to be driven both by medical and market factors.

Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study.

Post-marketing research in oncology has rarely been described. We aimed to characterize post-marketing trials for a consistent set of anticancer agents over a long period. We performed a cross-sectional analysis of post-marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post-marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2,345 post-marketing trials; 1,362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post-marketing trials (range 8-530) and overall population to be enrolled per trial (1-8,381). Post-marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post-marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3 to 26.1% depending on the analysis method. In conclusion, we found that post-marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low.

Association of Racial and Socioeconomic Disparities With Outcomes Among Patients Hospitalized With Acute Myocardial Infarction, Heart Failure, and Pneumonia: An Analysis of Within- and Between-Hospital Variation.

Importance: Although studies have described differences in hospital outcomes by patient race and socioeconomic status, it is not clear whether such disparities are driven by hospitals themselves or by broader systemic effects. Objective: To determine patterns of racial and socioeconomic disparities in outcomes within and between hospitals for patients with acute myocardial infarction, heart failure, and pneumonia. Design, Setting, and Participants: Retrospective cohort study initiated before February 2013, with additional analyses conducted during the peer-review process. Hospitals in the United States treating at least 25 Medicare fee-for-service beneficiaries aged 65 years or older in each race (ie, black and white) and neighborhood income level (ie, higher income and lower income) for acute myocardial infarction, heart failure, and pneumonia between 2009 and 2011 were included. Main Outcomes and Measures: For within-hospital analyses, risk-standardized mortality rates and risk-standardized readmission rates for race and neighborhood income subgroups were calculated at each hospital. The corresponding ratios using intraclass correlation coefficients were then compared. For between-hospital analyses, risk-standardized rates were assessed according to hospitals' proportion of patients in each subgroup. These analyses were performed for each of the 12 analysis cohorts reflecting the unique combinations of outcomes (mortality and readmission), demographics (race and neighborhood income), and conditions (acute myocardial infarction, heart failure, and pneumonia). Results: Between 74% (3545 of 4810) and 91% (4136 of 4554) of US hospitals lacked sufficient racial and socioeconomic diversity to be included in this analysis, with the number of hospitals eligible for analysis varying among cohorts. The 12 analysis cohorts ranged in size from 418 to 1265 hospitals and from 144 417 to 703 324 patients. Within included hospitals, risk-standardized mortality rates tended to be lower among black patients (mean [SD] difference between risk-standardized mortality rates in black patients compared with white patients for acute myocardial infarction, -0.57 [1.1] [P = .47]; for heart failure, -4.7 [1.3] [P < .001]; and for pneumonia, -1.0 [2.0] [P = .05]). However, risk-standardized readmission rates among black patients were higher (mean [SD] difference between risk-standardized readmission rates in black patients compared with white patients for acute myocardial infarction, 4.3 [1.4] [P < .001]; for heart failure, 2.8 [1.8] [P < .001], and for pneumonia, 3.7 [1.3] [P < .001]). Intraclass correlation coefficients ranged from 0.68 to 0.79, indicating that hospitals generally delivered consistent quality to patients of differing races. While the coefficients in the neighborhood income analysis were slightly lower (0.46-0.60), indicating some heterogeneity in within-hospital performance, differences in mortality rates and readmission rates between the 2 neighborhood income groups were small. There were no strong, consistent associations between risk-standardized outcomes for white or higher-income neighborhood patients and hospitals' proportion of black or lower-income neighborhood patients. Conclusions and Relevance: Hospital performance according to race and socioeconomic status was generally consistent within and between hospitals, even as there were overall differences in outcomes by race and neighborhood income. This finding indicates that disparities are likely to be systemic, rather than localized to particular hospitals.

New and incremental FDA black box warnings from 2008 to 2015.

BACKGROUND: The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval. METHODS: We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features. RESULTS: There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW. CONCLUSIONS: New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.

Postmarketing studies for novel drugs approved by both the FDA and EMA between 2005 and 2010: a cross-sectional study.

OBJECTIVES: To characterise postmarketing studies for drugs that were newly approved by the US Food and Drug Administration and the European Medicines Agency. DESIGN AND SETTING: Cross-sectional analysis of postmarketing studies registered in ClinicalTrials.gov until September 2014 for all novel drugs approved by both regulators between 2005 and 2010. Regulatory documents from both agencies were used. PRIMARY AND SECONDARY OUTCOME MEASURES: All identified postmarketing studies were classified according to planned enrolment, funding, status and geographical location, and we determined whether studies studied the originally approved indication. RESULTS: Overall, 69 novel drugs approved between 2005 and 2010 were eligible for inclusion. A total of 6679 relevant postmarketing studies were identified; 5972 were interventional (89.4%). The median number of studies per drug was 55 (IQR 33-119) and median number of patients to be enrolled per study was 60 (IQR 28-183). Industry was the primary sponsor of 2713 studies (40.6%) and was a primary or secondary sponsor in 4176 studies (62.5%). In all, 2901 studies (43.4%) were completed, 487 (7.3%) terminated, 1013 (15.2%) active yet not recruiting, 1895 (28.4%) recruiting and 319 (4.8%) not yet recruiting. A total of 80% of studies were conducted in only one country and 84.4% took place in Europe and/or North America; 2441 (36.5%) studied another indication than the originally approved indication. Studies designed in the originally approved indication were found to be more industry-sponsored than others 68.7%vs53.7%; P<0.0001. CONCLUSIONS: Postmarketing pharmaceutical research was highly variable and predominantly located in North America and Europe. Postmarketing studies were frequently designed to study indications other than the originally approved one. Although some findings were reassuring, others question the lack of coordination of postmarketing research.

Urban-Rural Comparisons in Hospital Admission, Treatments, and Outcomes for ST-Segment-Elevation Myocardial Infarction in China From 2001 to 2011: A Retrospective Analysis From the China PEACE Study (Patient-Centered Evaluative Assessment of Cardiac Events).

BACKGROUND: In response to urban-rural disparities in healthcare resources, China recently launched a healthcare reform with a focus on improving rural care during the past decade. However, nationally representative studies comparing medical care and patient outcomes between urban and rural areas in China during this period are not available. METHODS AND RESULTS: We created a nationally representative sample of patients in China admitted for ST-segment-elevation myocardial infarction in 2001, 2006, and 2011, using a 2-stage random sampling design in 2 urban and 3 rural strata. In China, evidence-based treatments were provided less often in 2001 in rural hospitals, which had lower volume and less availability of advanced cardiac facilities. However, these differences diminished by 2011 for reperfusion therapy (54% in urban versus 57% in rural; P=0.1) and reversed for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (66% versus 68%; P=0.04) and early ß-blockers (56% versus 60%; P=0.01). The risk-adjusted rate of in-hospital death or withdrawal from treatment was not significantly different between urban and rural hospitals in any study year, with an adjusted odds ratio of 1.13 (0.77-1.65) in 2001, 0.99 (0.77-1.27) in 2006, and 0.94 (0.74-1.19) in 2011. CONCLUSIONS: Although urban-rural disparities in evidence-based treatment for myocardial infarction in China have largely been eliminated, substantial gaps in quality of care persist in both settings. In addition, urban hospitals providing more resource-intensive care did not achieve better outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883.

Are non-ST-segment elevation myocardial infarctions missing in China?

Aims: ST-segment elevation myocardial infarctions (STEMI) in China and other low- and middle-income countries outnumber non-ST-segment elevation myocardial infarctions (NSTEMI). We hypothesized that the STEMI predominance was associated with lower biomarker use and would vary with hospital characteristics. Methods and results: We hypothesized that the STEMI predominance was associated with lower biomarker use and would vary with hospital characteristics. Using data from the nationally representative China PEACE-Retrospective AMI Study during 2001, 2006, and 2011, we compared hospital NSTEMI proportion across categories of use of any cardiac biomarker (CK, CK-MB, or troponin) and troponin, as well as across region, location, level, and teaching status. Among 15 416 acute myocardial infarction (AMI) patients, 14% had NSTEMI. NSTEMI patients were older, more likely female, and to have comorbidities. Median hospital NSTEMI proportion in each study year was similar across categories of any cardiac biomarker use, troponin, region, location, level, and teaching status. For instance, in 2011 the NSTEMI proportion at hospitals without troponin testing was 11.2% [inter quartile range (IQR) 4.4-16.7%], similar to those with ≥ 75% troponin use (13.0% [IQR 8.7-23.7%]) (P-value for difference 0.77). Analysed as continuous variables there was no relationship between hospital NSTEMI proportion and proportion biomarker use. With troponin use there was no relationship in 2001 and 2006, but a modest correlation in 2011 (R = 0.16, P = 0.043). Admissions for NSTEMI increased from 0.3/100 000 people in 2001 to 3.3/100 000 people in 2011 (P-value for trend < 0.001). Conclusion: STEMI is the dominant presentation of AMI in China, but the proportion of NSTEMI is increasing. Biomarker use and hospital characteristics did not account for the low NSTEMI rate. Clinical trial registration: www.clinicaltrials.gov (NCT01624883).

Describing the performance of U.S. hospitals by applying big data analytics.

Public reporting of measures of hospital performance is an important component of quality improvement efforts in many countries. However, it can be challenging to provide an overall characterization of hospital performance because there are many measures of quality. In the United States, the Centers for Medicare and Medicaid Services reports over 100 measures that describe various domains of hospital quality, such as outcomes, the patient experience and whether established processes of care are followed. Although individual quality measures provide important insight, it is challenging to understand hospital performance as characterized by multiple quality measures. Accordingly, we developed a novel approach for characterizing hospital performance that highlights the similarities and differences between hospitals and identifies common patterns of hospital performance. Specifically, we built a semi-supervised machine learning algorithm and applied it to the publicly-available quality measures for 1,614 U.S. hospitals to graphically and quantitatively characterize hospital performance. In the resulting visualization, the varying density of hospitals demonstrates that there are key clusters of hospitals that share specific performance profiles, while there are other performance profiles that are rare. Several popular hospital rating systems aggregate some of the quality measures included in our study to produce a composite score; however, hospitals that were top-ranked by such systems were scattered across our visualization, indicating that these top-ranked hospitals actually excel in many different ways. Our application of a novel graph analytics method to data describing U.S. hospitals revealed nuanced differences in performance that are obscured in existing hospital rating systems.

Quality of Care in Chinese Hospitals: Processes and Outcomes After ST-segment Elevation Myocardial Infarction.

BACKGROUND: China has gaps in the quality of care provided to patients with ST-elevation myocardial infarction, but little is known about how quality varies between hospitals. METHODS AND RESULTS: Using nationally representative data from the China PEACE-Retrospective AMI Study, we characterized the quality of care for ST-elevation myocardial infarction at the hospital level and examined variation between hospitals. Two summary measures were used to describe the overall quality of care at each hospital and to characterize variations in quality between hospitals in 2001, 2006, and 2011. The composite rate measured the proportion of opportunities a hospital had to deliver 6 guideline-recommended treatments for ST-elevation myocardial infarction that were successfully met, while the defect-free rate measured the proportion of patients at each hospital receiving all guideline-recommended treatments for which they were eligible. Risk-standardized mortality rates were calculated. Our analysis included 12 108 patients treated for ST-elevation myocardial infarction at 162 hospitals. The median composite rate increased from 56.8% (interquartile range [IQR], 45.9-72.0) in 2001 to 80.5% (IQR, 74.7-84.8) in 2011; however, substantial variation remained in 2011 with defect-free rates ranging from 0.0% to 76.9%. The median risk-standardized mortality rate increased from 9.9% (IQR, 9.1-11.7) in 2001 to 12.6% (IQR, 10.9-14.6) in 2006 before falling to 10.4% (IQR, 9.1-12.4) in 2011. CONCLUSIONS: Higher rates of guideline-recommended care and a decline in variation between hospitals are indicative of an improvement in quality. Although some variation persisted in 2011, very top-performing hospitals missed few opportunities to provide guideline-recommended care. Quality improvement initiatives should focus on eliminating residual variation as well as measuring and improving outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883.

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010.

IMPORTANCE: Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. OBJECTIVES: To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. DESIGN AND SETTING: Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. EXPOSURES: Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near-regulatory deadline approval, and regulatory review time. MAIN OUTCOMES AND MEASURES: A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. RESULTS: From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near-regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). CONCLUSIONS AND RELEVANCE: Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near-regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review.

Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence.Design Systematic review.Data sources Drugs@FDA database and PubMed.Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators-67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials-and examined surrogate markers of efficacy as primary endpoints-51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

Admission Glucose and In-hospital Mortality after Acute Myocardial Infarction in Patients with or without Diabetes: A Cross-sectional Study.

BACKGROUND: Hyperglycemia on admission has been found to elevate risk for mortality and adverse clinical events after acute myocardial infarction (AMI), but there are evidences that the relationship of blood glucose and mortality may differ between diabetic and nondiabetic patients. Prior studies in China have provided mixed results and are limited by statistical power. Here, we used data from a large, nationally representative sample of patients hospitalized with AMI in China in 2001, 2006, and 2011 to assess if admission glucose is of prognostic value in China and if this relationship differs depending on the presence or absence of diabetes. METHODS: Using a nationally representative sample of patients with AMI in China in 2001, 2006, and 2011, we categorized patients according to their glucose levels at admission (Results: Compared to patients with euglycemia (5.8%), patients with moderate hyperglycemia (13.1%, odds ratio [OR] = 2.44, 95% confidence interval [CI, 2.08-2.86]), severe hyperglycemia (21.5%, OR = 4.42, 95% CI [3.78-5.18]), and hypoglycemia (13.8%, OR = 2.59, 95% CI [1.68-4.00]), all had higher crude in-hospital mortality after AMI regardless of the presence of recognized diabetes mellitus. After adjustment for patients' characteristics and clinical status, however, the relationship between admission glucose and in-hospital mortality was different for diabetic and nondiabetic patients (P for interaction = 0.045). Among diabetic patients, hypoglycemia (OR = 3.02, 95% CI [1.20-7.63]), moderate hyperglycemia (OR = 1.75, 95% CI [1.04-2.92]), and severe hyperglycemia (OR = 2.97, 95% CI [1.87-4.71]) remained associated with elevated risk for mortality, but among nondiabetic patients, only patients with moderate hyperglycemia (OR = 2.34, 95% CI [1.93-2.84]) and severe hyperglycemia (OR = 3.92, 95% CI [3.04-5.04]) were at elevated mortality risk and not hypoglycemia (OR = 1.12, 95% CI [0.60-2.08]). This relationship was consistent across different study years (P for interaction = 0.900). CONCLUSIONS: The relationship between admission glucose and in-hospital mortality differs for diabetic and nondiabetic patients. Hypoglycemia was a bad prognostic marker among diabetic patients alone. The study results could be used to guide risk assessment among AMI patients using admission glucose. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01624883; https://clinicaltrials.gov/ct2/show/NCT01624883.

Assessing the potential clinical impact of reciprocal drug approval legislation on access to novel therapeutics in the USA: a cohort study.

OBJECTIVE: To quantify the potential effect of reciprocal approval legislation on access to clinically impactful therapeutics in the USA. DESIGN: A cohort study. SETTING: New therapeutics approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA) and/or Health Canada between 2000 and 2010. MAIN OUTCOME MEASURES: Characteristics of new therapeutics approved by the EMA and/or Health Canada before the FDA, including mechanistic novelty, likely clinical impact, size of the affected population and FDA review outcome. RESULTS: From 2001 to 2010, 282 drugs were approved in the USA, Europe or Canada, including 172 (61%) first approved in the USA, 24 (9%) never approved in the USA, and 86 (30%) approved in the USA after Europe and/or Canada. Of the 110 new drugs approved in Europe and/or Canada before the USA, 37 (34%) had a novel mechanisms of action compared with drugs already approved by the FDA, but only 10 (9%) were for conditions lacking alternate available therapies in the USA at the time of ex-US approval-of which the majority (9/10; 90%) were indicated for rare diseases. 12 of the 37 agents with novel mechanisms of action approved first in Europe and/or Canada (32%) had their initial FDA submissions rejected for safety reasons-including 2 drugs that were ultimately withdrawn from the market in Europe due to safety concerns. CONCLUSIONS: If enacted, reciprocal approval legislation would most likely benefit only a small number of US patients receiving treatment for rare diseases, and the benefit may be somewhat mitigated by an increased exposure to harms.