Cited by 417Pharmacovigilance and Adverse Drug ReactionsStatistical Methods in Clinical TrialsPharmaceutical Economics and Policy

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Why Drugs Fail - A Study on Side Effects in New Chemical Entities

Schuster, D., Laggner, C., Langer, T.·2005·Current Pharmaceutical Design

DOI 10.2174/138161205774414510

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Abstract

Our study focuses on the reasons for market withdrawals of drugs and drug development project terminations in clinical phases I-III from 1992 to 2002. Over 90% of the market withdrawals were caused by drug toxicity. Hepatotoxicity and cardiovascular toxicity proved to be the major causes for two out of three market withdrawals in the respective time period. In clinical phases I-III 43% of drug development project terminations were due to insufficient efficacy of the investigated compound. The second important issue, which caused one third of the projects to be closed, was toxicity. ADME parameters and economic and other reasons played a minor role. The results of our study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade. Keywords: market withdrawal, drug development termination, statistics

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Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay
Gaukler, S. M., Ruff, J. S., Galland, T., Kandaris, K. A., Underwood, T. K., Liu, N. M., Young, E. L., Morrison, L. C., Yost, G. S., & Potts, W. K. (2014) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2014.11.002 · Cited by 21
“…of pharmaceuticals fail during clinical trials (Lipsky and Sharp, 2001) and 10% of FDA approved pharmaceuticals are recalled after market release (Schuster et al., 2005), despite the 12–15 years of research and $1.4 billion average cost associated with each drug during development (Miller, 2012).”
BackgroundInfluential
A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions
Bale, S. S., Manoppo, A., Thompson, R. L., Markoski, A., Coppeta, J. R., Cain, B. P., Haroutunian, N. J., Newlin, V., Spencer, A., Azizgolshani, H., et al. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.26986 · Cited by 20
Pharmacogenomic Biomarkers for Personalized Medicine
Chen, J. J., Lin, W., & Chen, H.-C. (2013) · Pharmacogenomics · doi:10.2217/pgs.13.75 · Cited by 20
Compound Properties and their Influence on Drug Quality
Chen, H., Engkvist, O., & Kogej, T. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417205-0.00015-8 · Cited by 22
Investigation of the antiobesity and antioxidant properties of wild Plumbago europaea and Plumbago auriculata from North Palestine
Jaradat, N. A., Zaid, A. N., & Hussein, F. (2016) · Chemical and Biological Technologies in Agriculture · doi:10.1186/s40538-016-0082-4 · Cited by 20
OptNCMiner: a deep learning approach for the discovery of natural compounds modulating disease-specific multi-targets
Shin, S. H., Oh, S. M., Park, J. H. Y., Lee, K. W., & Yang, H. Y. (2022) · BMC Bioinformatics · doi:10.1186/s12859-022-04752-5 · Cited by 20
“Developing a new drug through this process typically costs in excess of 800 million US dollars [16].”
Background
In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance
Kaserer, T., Höferl, M., Müller, K., Elmer, S., Ganzera, M., Jäger, W. R., & Schuster, D. (2015) · Molecular Informatics · doi:10.1002/minf.201400192 · Cited by 19
Self-citation
Development, Optimization and Use of Preclinical Behavioral Models to Maximize the Productivity of Drug Discovery for Alzheimer's Disease
Lindner, M. D., McArthur, R. A., Deadwyler, S. A., Hampson, R. E., & Tariot, P. N. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373861-5.00016-3 · Cited by 20
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Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy
Adel, M., Serya, R. A. T., Lasheen, D. S., et al. (2018) · Drug Research · doi:10.1055/s-0044-101256 · Cited by 19
A human embryonic stem cell reporter line for monitoring chemical-induced cardiotoxicity
Tsai, S., Ghazizadeh, Z., Wang, H., Amin, S., Ortega, F. A., Badieyan, Z. S., Hsu, Z.-T., Gordillo, M., Kumar, R., Christini, D. J., et al. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz148 · Cited by 19
“About 90% of promising pharmaceutical compounds eventually fail and are withdrawn from the market primarily due to druginduced cardiovascular toxicity.(19,20) While several groups have used hPSC-derived CMs as a model for testing cardiotoxicity, it remains challenging to monitor in real-time cardiomyocyte arrhythmia o…”
Background
MitoToxy assay: A novel cell-based method for the assessment of metabolic toxicity in a multiwell plate format using a lactate FRET nanosensor, Laconic
Contreras‐Baeza, Y., Ceballo, S., Arce‐Molina, R., Sandoval, P. Y., Alegría, K., Barros, L. F., & Martín, A. S. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224527 · Cited by 19
“Hepatotoxicity is a significant cause of Drug-Induced Liver Injury (DILI) [52], being responsible for 11% of pre-clinical failures [53], 33% of clinical toxicity [53], and 18% of post-marketing withdrawal [7].”
Background
Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects
Dame, K., & Ribeiro, A. J. S. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370220959598 · Cited by 19
“These lineages are of interest to the drug development field because cardiac and hepatic adverse effects are the leading causes for drug attrition.(1) Relevant in vitro research with these two lineages seeks to understand drug mechanisms of action and improve the predictivity of drug effects at the preclinical stage.”
Background
Management of psychiatric disorders in patients with hepatic and gastrointestinal diseases
Menon, V., Ransing, R., & Praharaj, S. K. (2022) · Indian Journal of Psychiatry · doi:10.4103/indianjpsychiatry.indianjpsychiatry_18_22 · Cited by 19
“[31] Lamotrigine and topiramate are infrequently associated with liver enzyme elevation and idiosyncratic hepatotoxicity.”
Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells
Wang, W., Wan, Q., Li, M., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115218 · Cited by 18
A High-Throughput 1,536-Well Luminescence Assay for Glutathione S-Transferase Activity
Yasgar, A., Shultz, J. W., Zhou, W., Wang, H., Huang, F., Murphy, N., Abel, E. L., DiGiovanni, J., Inglese, J., & Simeonov, A. M. (2010) · Assay and Drug Development Technologies · doi:10.1089/adt.2009.0248 · Cited by 18
“3 While drug attrition due to ADMET issues has decreased recently, toxicity still remains one of the major reasons for failure 3,4 due to the lack of accurate in vivo toxicity models.”
Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins
Abrol, R., Kim, S., Bray, J. K., Griffith, A. R., & Goddard, W. A. (2011) · Methods · doi:10.1016/j.ymeth.2011.12.005 · Cited by 19
Biologics: the next generation of analgesic drugs?
Chessell, I. P., Dudley, A., & Billinton, A. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.03.005 · Cited by 18
Biocomputational Screening of Natural Compounds against Acetylcholinesterase
Ahmad, S. S., Khan, M. B., Ahmad, K., Lim, J. H., Shaikh, S., Lee, E. J., & Choi, I. (2021) · Molecules · doi:10.3390/molecules26092641 · Cited by 18
“In a recent analysis, it was reported that over 90% of candidate drug failures were due to hepatotoxicity and cardiovascular complications [29], and thus, in silico approaches have been utilized to predict some key absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) properties [30] (Table 2).”
Method
Advances in cell‐based biosensors using three‐dimensional cell‐encapsulating hydrogels
Zhou, L., Huang, G., Wang, S., Wu, J., Lee, W. G., Chen, Y., Xu, F., & Lu, T. (2011) · Biotechnology Journal · doi:10.1002/biot.201100098 · Cited by 17
“The increased number of chemical entities does not necessarily increase new drug approvals by the FDA, partly because of drug-drug interactions [60].”
Background
Serum microRNA-122-3p, microRNA-194-5p and microRNA-5099 are potential toxicological biomarkers for the hepatotoxicity induced by Airpotato yam
Yang, R., Yang, F., Huang, Z., Jin, Y., Sheng, Y., & Ji, L. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2017.08.017 · Cited by 17
Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells
de Souza, A. S., Dias, D. S., Ribeiro, R. C. B., Costa, D. C. S., de Moraes, M. G., Pinho, D. R., Masset, M. E. G., Marins, L. M., Valle, S. P., de Carvalho, C. J. C., et al. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117671 · Cited by 17
De-Risking Drug Discovery with ADDME — A voiding D rug D evelopment M istakes E arly
Tsaioun, K., & Jacewicz, M. S. (2009) · Alternatives to Laboratory Animals · doi:10.1177/026119290903701s10 · Cited by 17
“Now, lack of efficacy and human toxicity are the major reasons for failure (11).”
Background
A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations
Thiel, C., Cordes, H., Fabbri, L., Aschmann, H. E., Baier, V., Smit, I. A., Atkinson, F. L., Blank, L. M., & Kuepfer, L. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005280 · Cited by 16
“Drug-induced hepatotoxicity poses a significant problem in drug development and public health [1,2].”
Background
Safety and efficacy of treatment for chronic hepatitis C with a focus on pegylated interferons: the backbone of therapy today and in the future
Ferenci, P. (2011) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2011.555079 · Cited by 16
“Albinterferon is the latest in a list of investigational drugs under development for the treatment of HCV infection that has encountered safety concerns, and highlights the risks inherent in drug development, where most drugs that fail to progress to market do so because of safety issues rather than a lack of efficacy…”
Background
Improving Risk Assessment
Dambach, D. M., & Uppal, H. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003497 · Cited by 16

Authors: Schuster, D., Laggner, C., & Langer, T.
Affiliations: Universität Innsbruck (AT)
ORCID: Schuster, D.
Laggner, C.
Langer, T.
Venue: Current Pharmaceutical Design
Publisher: Bentham Science Publishers Ltd.
Published: 2005-10-01
Volume: 11
Issue: 27
Pages: 3545-3559
ISSN: 1381-6128 (ISSN-L)
DOI: 10.2174/138161205774414510
OpenAlex: W2141455139
Cited by: 417
References: 0
Citations by year: 2026: 7 · 2025: 10 · 2024: 14 · 2023: 30 · 2022: 17 · 2021: 11 · 2020: 21 · 2019: 17 · 2018: 21 · 2017: 23 · 2016: 27 · 2015: 30 · 2014: 21 · 2013: 22 · 2012: 32
FWCI: 13.04
Type: journal article
Language: en
Open access: closed
Locations: Current Pharmaceutical Design (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
Keywords: drug failure, drug toxicity, hepatotoxicity, cardiotoxicity, adverse drug reactions, new chemical entities, drug efficacy
MeSH terms: Humans, Product Surveillance, Postmarketing, Drugs, Investigational, Treatment Failure, Drug-Related Side Effects and Adverse Reactions

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Why Drugs Fail - A Study on Side Effects in New Chemical Entities

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