Cardiovascular Drug Development

Fordyce, Christopher B.; Roe, Matthew T.; Ahmad, Tariq; Libby, Peter; Borer, Jeffrey S.; Hiatt, William R.; Bristow, Michael R.; Packer, Milton; Wasserman, Scott M.; Braunstein, Ned; Pitt, Bertram; DeMets, David L.; Cooper‐Arnold, Katharine; Armstrong, Paul W.; Berkowitz, Scott D.; Scott, Rob; Prats, Jayne; Galis, Zorina S.; Stockbridge, Norman; Peterson, Eric D.; Califf, Robert M.

doi:10.1016/j.jacc.2015.03.016

Cited by 172 publications

(89 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1 In conjunction with an overall ≈90% failure rate of drugs, 2 which impacts directly the rising cost of drug development, this is creating a perfect storm that is threatening to make the development of new drug therapies for CHD prohibitive (estimated currently at $2.6 billion/drug). 3 One potential solution is to use therapeutic targets that have support from genetic studies, such as Mendelian randomization (MR; Figure 1), which is estimated to double the probability that a drug target will succeed in phase III clinical trials.…”

mentioning

confidence: 99%

Deciphering the Causal Role of sPLA2s and Lp-PLA2 in Coronary Heart Disease

Talmud

Holmes

2015

ATVB

View full text Add to dashboard Cite

Abstract-Over the last 10 to 15 years, animal and human observational studies have identified elevated levels of both proinflammatory secretory phospholipase A2-IIA and lipoprotein-associated phospholipase A2 as potential risk factors for coronary heart disease. However, Mendelian randomization, a genetic tool to test causality of a biomarker, and phase III randomized controlled trials of inhibitors of theses enzymes (varespladib and darapladib) converged to indicate that elevated levels are unlikely to be themselves causal of coronary heart disease and that inhibition had little or no clinical utility. The concordance of findings from Mendelian randomization and clinical trials suggests that for these 2 drugs, and for other novel biomarkers in future, validation of potential therapeutic targets by genetic studies (such as Mendelian randomization) before embarking on costly phase III randomized controlled trials could increase efficiency and offset the high risk of drug development, thereby facilitating discovery of new therapeutics and mitigating against the exuberant costs of drug development. Arterioscler Thromb Vasc BiolNovember 2015 , all of which have been reported to be associated with atherothrombotic disease from animal and human observational studies. The predicted efficacy of their inhibition on the development of atherosclerosis and CHD has been tested using the genetic approach of MR (see Figure 1 for a description of MR and comparison to conventional RCT), and this, together with the outcome of the drug trials, is reviewed. Secretory PLA2s and AtherogenesisThe sPLA2 enzymes are the largest group of this family of enzymes, representing around 30% of all known phospholipases. They are small calcium-dependent, disulphide-rich enzymes with molecular weights ranging between ≈14 and 16 kDa, with the exception of sPLA2-III, which has a molecular weight of ≈55 kDa. 10 The reason for the biological requirement for so many sPLA2s may arise because of their specificity for different phospholipid substrates, as well as their cellular and tissue-specific diversity. 13 The purported impact of sPLA2s on inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, stems from their enzymatic action, generating proinflammatory biolipid mediators ( Figure 2B). Of the sPLA2s, sPLA2-IIA, 14 sPLA2-V, 15 and sPLA2-X 13 have been identified in atherosclerotic plaques by immunohistochemistry. The ability of sPLA2s to promote atherosclerosis is suggested to reflect their action on the phospholipid bilayer of low-density lipoprotein (LDL) particles, generating proatherogenic, small dense LDL with 50% less surface phospholipids. 16 This results in a conformational change in the apolipoprotein B on the LDL particle, exposing proteoglycan-binding sites. This leads to the aggregation and retention of the modified lipoprotein by proteoglycans in the intima, where they are prone to oxidation and subsequent uptake by macrophages, generating foam cells. 17 In the intima of the vessel wall, phospholipase hydrolysis conti...

show abstract

mentioning

confidence: 99%

Deciphering the Causal Role of sPLA2s and Lp-PLA2 in Coronary Heart Disease

Talmud

Holmes

2015

ATVB

View full text Add to dashboard Cite

show abstract

“…While contemporary trials seem to be becoming more complex, and costly, the emergence of EHR and registry data offer the possibility of novel PCT designs whose form and function are much more similar to the streamlined clinical trials of the 1970s and 80s 31, 32 . The key characteristics of PCTs have been previously reviewed 33, 34 .…”

Section: Pct Background Study Characteristics and Limitationsmentioning

confidence: 99%

Good Clinical Practice Guidance and Pragmatic Clinical Trials

et al. 2016

Self Cite

View full text Add to dashboard Cite

Randomized clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice (GCP) guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. While the application of GCP principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials (PCTs). The central tenets of GCP and PCTs represent potential tensions in trial design (stringent quality and highly efficient operations). In the present manuscript, we highlight potential areas of discordance between GCP guidelines and the principles of PCTs and suggest strategies to streamline study conduct in an ethical manner to optimally carry out clinical trials in the electronic age.

show abstract

“…1 Nevertheless, the development of new drugs for chronic heart failure has waned during the past 20 years; the quantity of novel agents in clinical testing and the number of welldesigned clinical trials have diminished to a small fraction of that seen in the 1980s and 1990s. 2 Some have suggested that investment in heart failure has declined because the primary mechanisms of the disorder are poorly understood, because the promising results of phase II trials are frequently not confirmed in large-scale definitive studies, and because the large-scale clinical trials needed for regulatory approval have often become prohibitively expensive. 2,3 We know that clinical research in heart failure is extremely challenging, and so we beg innovators in the pharmaceutical and device industries to be patient, and we plead with sponsors to invest in large-scale investigations because the need is so great.…”

mentioning

confidence: 99%

“…2 Some have suggested that investment in heart failure has declined because the primary mechanisms of the disorder are poorly understood, because the promising results of phase II trials are frequently not confirmed in large-scale definitive studies, and because the large-scale clinical trials needed for regulatory approval have often become prohibitively expensive. 2,3 We know that clinical research in heart failure is extremely challenging, and so we beg innovators in the pharmaceutical and device industries to be patient, and we plead with sponsors to invest in large-scale investigations because the need is so great. Yet, when we critically examine how we react to data, it may not be too surprising that meaningful clinical trials in heart failure are becoming increasingly scarce.…”

mentioning

confidence: 99%