Workshop Report

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.

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Preparation of Radiochemical-Labeled Compounds for the US Army Drug Development Program

10.21236/adb155291 ◽

1991 ◽

Author(s):

John A. Kepler

Keyword(s):

Drug Development ◽

Development Program ◽

Labeled Compounds ◽

Us Army ◽

The Us ◽

Drug Development Program

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Valuation and Returns of Drug Development Companies: Lessons for Bioentrepreneurs and Investors

Therapeutic Innovation & Regulatory Science ◽

10.1007/s43441-021-00364-y ◽

2022 ◽

Author(s):

Daniel Tobias Michaeli ◽

Hasan Basri Yagmur ◽

Timur Achmadeev ◽

Thomas Michaeli

Keyword(s):

Drug Development ◽

Financial Risk ◽

Real Option ◽

Phase 1 ◽

Development Stage ◽

Success Rates ◽

Fda Approval ◽

The Us ◽

Status Number ◽

Real Option Value

Abstract Objectives This study evaluates the association of Biopharma company valuation with the lead drug’s development stage, orphan status, number of indications, and disease area. We also estimated annual returns Bioentrepreneurs and investors can expect from founding and investing in drug development ventures. Methods SDC Thomson Reuter and S&P Capital IQ were screened for majority acquisitions of US and EU Biopharma companies developing new molecular entities for prescription use (SIC code: 2834). Acquisition data were complemented with drug characteristics extracted from clinicaltrials.gov, the US Food and Drug Administration (FDA), and deal announcements. Thereafter, company valuations were combined with previously published clinical development periods alongside orphan-, indication-, and disease-specific success rates to estimate annual returns for investments in drug developing companies. Results Based on a sample of 311 Biopharma acquisitions from 2005 to 2020, companies developing orphan, multi-indication, and oncology drugs were valued significantly higher than their peers during later development stages (p < 0.05). We also estimated significantly higher returns for shareholders of companies with orphan relative to non-orphan-designated lead drugs from Phase 1 to FDA approval (46% vs. 12%, p < 0.001). Drugs developed across multiple indications also provided higher returns than single-indication agents from Pre-Clinic to FDA approval (21% vs. 11%, p < 0.001). Returns for oncology drugs exceeded other disease areas (26% vs. 8%, p < 0.001). Conclusions Clinical and economic conditions surrounding orphan-designated drugs translate to a favorable financial risk-return profile for Bioentrepreneurs and investors. Bioentrepreneurs must be aware of the upside real option value their multi-indication drug could offer when negotiating acquisition or licensing agreements.

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Meta-analysis of clinical trial safety data in a drug development program: Answers to frequently asked questions

Clinical Trials ◽

10.1177/1740774512465495 ◽

2012 ◽

Vol 10 (1) ◽

pp. 20-31 ◽

Cited By ~ 24

Author(s):

Jesse A Berlin ◽

Brenda J Crowe ◽

Edward Whalen ◽

H Amy Xia ◽

Carol E Koro ◽

...

Keyword(s):

Clinical Trial ◽

Drug Development ◽

Meta Analysis ◽

Safety Data ◽

Development Program ◽

Drug Development Program

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Army Drug Development Program. Phase 1. Clinical Testing

10.21236/ada148919 ◽

1981 ◽

Author(s):

John A. Johnson

Keyword(s):

Drug Development ◽

Phase 1 ◽

Development Program ◽

Clinical Testing ◽

Drug Development Program

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Preparation of Chemicals and Bulk Drug Substances for the U.S. Army Drug Development Program.

10.21236/adb232976 ◽

1997 ◽

Author(s):

Jaroslav F. Novotny

Keyword(s):

Drug Development ◽

Development Program ◽

Drug Substances ◽

Bulk Drug ◽

Drug Development Program ◽

The U.S

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Faster than warp speed: early attention to COVD-19 by anti-vaccine groups on Facebook

Journal of Public Health ◽

10.1093/pubmed/fdab093 ◽

2021 ◽

Author(s):

Seth C Kalichman ◽

Lisa A Eaton ◽

Valerie A Earnshaw ◽

Natalie Brousseau

Keyword(s):

Social Media ◽

Vaccine Development ◽

Rapid Development ◽

Development Program ◽

Vaccine Safety ◽

Vaccine Hesitancy ◽

Conspiracy Theories ◽

The Us ◽

Us Government ◽

Vaccine Information

Abstract Background The unprecedented rapid development of COVID-19 vaccines has faced SARS-CoV- (COVID-19) vaccine hesitancy, which is partially fueled by the misinformation and conspiracy theories propagated by anti-vaccine groups on social media. Research is needed to better understand the early COVID-19 anti-vaccine activities on social media. Methods This study chronicles the social media posts concerning COVID-19 and COVID-19 vaccines by leading anti-vaccine groups (Dr Tenpenny on Vaccines, the National Vaccine Information Center [NVIC] the Vaccination Information Network [VINE]) and Vaccine Machine in the early months of the COVID-19 pandemic (February–May 2020). Results Analysis of 2060 Facebook posts showed that anti-vaccine groups were discussing COVID-19 in the first week of February 2020 and were specifically discussing COVID-19 vaccines by mid-February 2020. COVID-19 posts by NVIC were more widely disseminated and showed greater influence than non-COVID-19 posts. Early COVID-19 posts concerned mistrust of vaccine safety and conspiracy theories. Conclusion Major anti-vaccine groups were sowing seeds of doubt on Facebook weeks before the US government launched its vaccine development program ‘Operation Warp Speed’. Early anti-vaccine misinformation campaigns outpaced public health messaging and hampered the rollout of COVID-19 vaccines.

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Cardiovascular Safety Profile of Romosozumab: A Pharmacovigilance Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS)

Journal of Clinical Medicine ◽

10.3390/jcm10081660 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1660

Author(s):

Annika Vestergaard Kvist ◽

Junaid Faruque ◽

Enriqueta Vallejo-Yagüe ◽

Stefan Weiler ◽

Elizabeth M. Winter ◽

...

Keyword(s):

Adverse Event ◽

Drug Administration ◽

Cardiovascular Events ◽

Reporting System ◽

Food And Drug Administration ◽

Adverse Event Reporting System ◽

Adverse Event Reporting ◽

Cardiovascular Safety ◽

Event Reporting ◽

The Us

Background: Cardiovascular safety concerns for major cardiovascular events (MACE) were raised during the clinical trials of romosozumab. We aimed to evaluate the cardiovascular safety profile of romosozumab in a large pharmacovigilance database. Methods: All cases reported between January 2019 and December 2020 where romosozumab was reported were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). The outcome of interest was MACE (myocardial infarction (MI), stroke, or cardiovascular death). A disproportionality analysis was conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals. Disproportionality analyses were stratified by sex and reporting region (US, Japan, other). Results: Of the 1995 eligible cases with romosozumab, the majority (N = 1188; 59.5%) originated from Japan. Overall, 206 suspected MACE reports were identified, of which the majority (n = 164; 13.8%) were from Japan, and 41 (5.2%) were from the United States (US). Among Japanese reports, patients were older and more frequently male than reports from the US. Similarly, cases with a reported MACE were older and had higher reports of cardioprotective drugs than those without cardiovascular events. Elevated reports for MACE (ROR 4.07, 95% CI: 2.39–6.93) was identified overall, which was primarily driven by the significant disproportionality measures in the Japanese reports. Conclusions: The current pharmacovigilance study identified a potential signal for elevated MACE, particularly in Japan. The results support the current safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk patients.

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The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

Neurotherapeutics ◽

10.1007/s13311-021-01027-4 ◽

2021 ◽

Author(s):

Adam J. Schwarz

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Neurological Disorders ◽

Amyloid Β ◽

Development Program ◽

Imaging Biomarkers ◽

Common Disease ◽

Structural Imaging ◽

Target Engagement ◽

Pharmacodynamic Effect

AbstractImaging biomarkers play a wide-ranging role in clinical trials for neurological disorders. This includes selecting the appropriate trial participants, establishing target engagement and mechanism-related pharmacodynamic effect, monitoring safety, and providing evidence of disease modification. In the early stages of clinical drug development, evidence of target engagement and/or downstream pharmacodynamic effect—especially with a clear relationship to dose—can provide confidence that the therapeutic candidate should be advanced to larger and more expensive trials, and can inform the selection of the dose(s) to be further tested, i.e., to “de-risk” the drug development program. In these later-phase trials, evidence that the therapeutic candidate is altering disease-related biomarkers can provide important evidence that the clinical benefit of the compound (if observed) is grounded in meaningful biological changes. The interpretation of disease-related imaging markers, and comparability across different trials and imaging tools, is greatly improved when standardized outcome measures are defined. This standardization should not impinge on scientific advances in the imaging tools per se but provides a common language in which the results generated by these tools are expressed. PET markers of pathological protein aggregates and structural imaging of brain atrophy are common disease-related elements across many neurological disorders. However, PET tracers for pathologies beyond amyloid β and tau are needed, and the interpretability of structural imaging can be enhanced by some simple considerations to guard against the possible confound of pseudo-atrophy. Learnings from much-studied conditions such as Alzheimer’s disease and multiple sclerosis will be beneficial as the field embraces rarer diseases.

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