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1.
Circulation ; 140(25): 2108-2118, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31841369

RESUMO

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

3.
Clin Pharmacol Ther ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31709525

RESUMO

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

4.
Circ Res ; 125(9): 855-867, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31600125

RESUMO

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

5.
Circulation ; 140(17): 1426-1436, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31634011

RESUMO

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

6.
Sci Rep ; 9(1): 15060, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636317

RESUMO

Drug-induced changes of the J to T peak (JTp) and J to the median of area under the T wave (JT50) were reported to differentiate QT prolonging drugs that are predominant blockers of the delayed potassium rectifier current from those with multiple ion channel effects. Studies of drug-induced JTp/JT50 interval changes might therefore facilitate cardiac safety evaluation of new pharmaceuticals. It is not known whether formulas for QT heart rate correction are applicable to JTp and JT50 intervals. QT/RR, JTp/RR, and JT50/RR profiles were studied in 523 healthy subjects aged 33.5 ± 8.4 years (254 females). In individual subjects, 1,256 ± 220 electrocardiographic measurements of QT, JTp, and JT50 intervals were available including a 5-minute history of RR intervals preceding each measurement. Curvilinear, linear and log-linear regression models were used to characterize individual QT/RR, JTp/RR, and JT50/RR profiles both without and with correction for heart rate hysteresis. JTp/RR and JT50/RR hysteresis correction needs to be included but the generic universal correction for QT/RR hysteresis is also applicable to JTp/RR and JT50/RR profiles. Once this is incorporated, median regression coefficients of the investigated population suggest linear correction formulas JTpc = JTp + 0.150(1-RR) and JT50c = JT50 + 0.117(1-RR) where RR intervals of the underlying heart rate are hysteresis-corrected, and all measurements expressed in seconds. The established correction formulas can be proposed for future clinical pharmacology studies that show drug-induced heart rate changes of up to approximately 10 beats per minute.

7.
JACC Heart Fail ; 7(11): 913-921, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401097

RESUMO

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

8.
Front Physiol ; 10: 934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31402872

RESUMO

Electrocardiogram (ECG) studies of drug-induced prolongation of the interval between the J point and the peak of the T wave (JTp interval) distinguished QT prolonging drugs that predominantly block the delayed potassium rectifier current from those affecting multiple cardiac repolarisation ion channel currents. Since the peak of the T wave depends on ECG lead, a "global" T peak requires to combine ECG leads into one-dimensional signal in which the T wave peak can be measured. This study aimed at finding the optimum one-dimensional representation of 12-lead ECGs for the most stable JTp measurements. Seven different one-dimensional representations were investigated including the vector magnitude of the orthogonal XYZ transformation, root mean square of all 12 ECG leads, and the vector magnitude of the 3 dominant orthogonal leads derived by singular value decomposition. All representations were applied to the median waveforms of 660,657 separate 10-s 12-lead ECGs taken from repeated day-time Holter recordings in 523 healthy subjects aged 33.5 ± 8.4 years (254 women). The JTp measurements were compared with the QT intervals and with the intervals between the J point and the median point of the area under the T wave one-dimensional representation (JT50 intervals) by means of calculating the residuals of the subject-specific curvilinear regression models relating the measured interval to the hysteresis-corrected RR interval of the underlying heart rate. The residuals of the regression models (equal to the intra-subject standard deviations of individually heart rate corrected intervals) expressed intra-subject stability of interval measurements. For both the JTp intervals and the JT50 intervals, the curvilinear regression residuals of measurements derived from the orthogonal XYZ representation were marginally but statistically significantly lower compared to the other representations. Using the XYZ representation, the residuals of the QT/RR, JTp/RR and JT50/RR regressions were 5.6 ± 1.1 ms, 7.2 ± 2.2 ms, and 4.9 ± 1.2 ms, respectively (all statistically significantly different; p < 0.0001). The study concludes that the orthogonal XYZ ECG representation might be proposed for future investigations of JTp and JT50 intervals. If the ability of classifying QT prolonging drugs is further confirmed for the JT50 interval, it might be appropriate to replace the JTp interval since with JT50 it appears more stable.

9.
Front Physiol ; 10: 635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275152

RESUMO

The accuracy of studies of drug-induced QTc changes depends, among others, on the accuracy of heart rate correction of QT interval. It has been recognized that when a drug leads to substantial heart rate changes, fixed universal corrections cannot be used and that alternative methods such as subject-specific corrections established for each study participant need to be considered. Nevertheless, the maximum heart rate change that permits use of fixed correction with reasonable accuracy has not been systematically investigated. We have therefore used full QT/heart-rate profiles of 751 healthy subjects (mean age 34.2 ± 9.6, range 18-61 years, 335 females) and compared their subject-specific corrections with 6 fixed corrections, namely Bazett, Fridericia, Framingham, Hodges, Rautaharju, and Sarma formulae. The comparison was based on statistical modeling experiments which simulated clinical studies of N = 10 or N = 50 female or male subjects. The experiments compared errors of ΔQTc intervals calculated as differences between QTc intervals at an initial heart rate (in the range of 40 to 120 beats per minute, bpm) and after a heart rate change (in the range from -20 to +20 bpm). The experiments also investigated errors due to spontaneous heart rate fluctuation and due to omission of correction for QT/RR hysteresis. In each experiment, the absolute value of the single-sided 90th percentile most remote from zero was used as the error estimate. Each experiment was repeated 10,000 times with random selection of modeled study group. From these repetitions, median and upper 80th percentile was derived and graphically displayed for all different combinations of initial heart rate and heart rate change. The results showed that Fridericia formula might be reasonable (with estimated errors of ΔQTc below 8 ms) in large studies if the heart rate does not change more than ± 10 bpm and that the errors by fixed corrections and the errors due to omission of QR/RR hysteresis are additive. Additionally, the results suggest that the variability introduced into QTc data by not correcting for the underlying heart rate accurately might have a greater impact in smaller studies. The errors by Framingham formula were practically the same as with the Fridericia formula. Other investigated fixed heart rate corrections led to larger ΔQTc errors.

10.
Circulation ; 140(3): 240-261, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31116032

RESUMO

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.

11.
Eur Heart J ; 40(31): 2632-2653, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31116395

RESUMO

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.

15.
Drug Saf ; 42(3): 475, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30725335

RESUMO

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License which permits unrestricted use.

17.
Clin Pharmacol Ther ; 105(4): 857-866, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610746

RESUMO

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real-world conditions with longer follow-up periods. In "efficacy-to-effectiveness (E2E) trials," if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an "efficacy and effectiveness too (EE2) trial." Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort.

18.
Clin Pharmacol Ther ; 105(4): 943-953, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30447156

RESUMO

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.

19.
Drug Saf ; 42(3): 415-426, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30255348

RESUMO

INTRODUCTION: In studies of drug-induced corrected QT (QTc) changes, fixed universal heart rate (HR) corrections (e.g., the Fridericia correction) are potentially misleading when assessing the effects of drugs that change HR. When data-specific corrections are designed, tests of their validity are needed. The proposed tests include zero correlations between QTc and corresponding RR values in the complete study data (pooling on-treatment and off-treatment interval measurements). OBJECTIVE: To document that this approach is potentially highly misleading, a statistical modeling study was conducted based on the full profiles of QT/RR data of 523 healthy subjects-254 females, mean age 33.5 years. METHODS: In each of the subjects, 50 baseline QT/RR readings were selected to model baseline data. In repeated experiments, groups of ten and 50 subjects were randomly selected and drug-induced HR increases between 0 and 25 beats per minute combined with QTc changes between - 20 and + 20 ms were modeled. In each experiment, subject-specific as well as population-specific HR corrections were designed so that the QTc interval data were uncorrelated to the corresponding RR interval data. RESULTS: The simulation experiments showed that when zero correlations of QTc data with RR data are combined with more than trivial HR increases, the HR corrections are substantially biased and underestimate or fully eliminate any drug-induced QTc interval changes. This result is in full agreement with theoretical considerations of HR correction principles. CONCLUSIONS: The lack of correlation of QTc versus RR durations including on-treatment data does not prove any validity of HR corrections. Correlations of QTc versus RR in study data pooling on- and off-drug measurements should not be used to prove the appropriateness of HR corrections.

20.
Drug Saf ; 42(3): 401-414, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30255349

RESUMO

INTRODUCTION: Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Instead of individual-specific corrections, population-specific corrections are occasionally used based on QT/RR data pooled from all study subjects. OBJECTIVE: To investigate the performance of individual-specific and population-specific corrections, a statistical modeling study was performed using QT/RR data of 523 healthy subjects. METHODS: In each subject, full drug-free QT/RR profiles were available, characterized using non-linear regression models. In each subject, 50 baseline QT/RR readings represented baseline data of standard QT studies. Using these data, linear and log-linear heart rate corrections were optimized for each subject and for different groups of ten and 50 subjects. These corrections were applied in random combinations of heart rate changes between - 10 and + 25 beats per minute (bpm) and known QTc interval changes between - 25 and + 25 ms. RESULTS: Both the subject-specific and population-specific corrections based on the 50 baseline QT/RR readings tended to underestimate/overestimate the QTc interval changes when heart rate was increasing/decreasing, respectively. The result spread was much wider with population-specific corrections, making the estimates of QTc interval changes practically unpredictable. CONCLUSION: Subject-specific heart rate corrections based on limited baseline drug-free data may lead to inconsistent results and, in the presence of underlying heart rate changes, may potentially underestimate or overestimate QTc interval changes. The population-specific corrections lead to results that are much more influenced by the combination of individual QT/RR patterns than by the actual QTc interval changes. Subject-specific heart rate corrections based on full profiles derived from drug-free baseline recordings with wide QT/RR distribution should be used when studying drugs expected to cause heart rate changes.

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