Misleading Results: Translational Challenges

Abstract

We agree completely with the news focus story “When mice mislead” (J. Couzin-Frankel, 22 November 2013, p. [922][1]). Many of the issues identified in this article, such as investigator bias, blinding, randomization, and inclusion and exclusion criteria, were clearly identified in the Stroke Therapy Academic Industry Round Table publication in 1999 ([ 1 ][2]) and discussed further by others ([ 2 ][3]). Tightening the standards for animal experimentation, especially for those experiments that test drugs for their neuroprotective effects, is critical as we try to translate these drugs into human stroke therapy. There have been hundreds of drugs tested for neuroprotective effects and many, if not most, have positive effects, in animal models. If a mouse or rat had a stroke, we would know exactly how to treat it. Unfortunately, none of these drugs has shown success in humans. It is unlikely that poor methods used in animal studies account for all the negative clinical trials that have been performed based on preclinical studies. After all, some investigators do perform appropriate experiments, and even those studies rarely lead to positive clinical trials. One important issue not mentioned in the News Focus piece could also account for the lack of positive clinical trials: Most researchers in the stroke field work with normal, young, healthy animals. Humans who participate in neuroprotective drug clinical trials are most often not normal, young, or healthy. They have a variety of comorbid diseases such as hypertension, diabetes, obesity, and vascular disease, which could alter the way in which drugs work in humans. We suggest that in future animal experiments, drugs be tested in animals that are aged, with comorbid diseases. Such studies may help to identify potentially effective drugs in an animal model that mimics more closely a human with stroke. 1. [↵][4]Stroke Therapy Academic Industry Round Table, Stroke 30, 2752 (1999). [OpenUrl][5][Abstract/FREE Full Text][6] 2. [↵][7]1. M. M. Macleod 2. et al ., J. Cerebral Blood Flow Met. 29, 221 (2009). [OpenUrl][8][Abstract/FREE Full Text][9] [1]: /lookup/doi/10.1126/science.342.6161.922 [2]: #ref-1 [3]: #ref-2 [4]: #xref-ref-1-1 View reference 1 in text [5]: {openurl}?query=rft.jtitle%253DStroke%26rft.stitle%253DStroke%26rft.volume%253D30%26rft.issue%253D12%26rft.spage%253D2752%26rft.epage%253D2758%26rft.atitle%253DRecommendations%2Bfor%2BStandards%2BRegarding%2BPreclinical%2BNeuroprotective%2Band%2BRestorative%2BDrug%2BDevelopment%26rft_id%253Dinfo%253Adoi%252F10.1161%252F01.STR.30.12.2752%26rft_id%253Dinfo%253Apmid%252F10583007%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToic3Ryb2tlYWhhIjtzOjU6InJlc2lkIjtzOjEwOiIzMC8xMi8yNzUyIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzQzLzYxNjkvMzY5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [7]: #xref-ref-2-1 View reference 2 in text [8]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2BCerebral%2BBlood%2BFlow%2Band%2BMetabolism%26rft.stitle%253DJ%2BCereb%2BBlood%2BFlow%2BMetab%26rft.aulast%253DMacleod%26rft.auinit1%253DM.%2BR.%26rft.volume%253D29%26rft.issue%253D2%26rft.spage%253D221%26rft.epage%253D223%26rft.atitle%253DReprint%253A%2BGood%2BLaboratory%2BPractice%253A%2BPreventing%2BIntroduction%2Bof%2BBias%2Bat%2Bthe%2BBench%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fjcbfm.2008.101%26rft_id%253Dinfo%253Apmid%252F18797473%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [9]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BqY2IiO3M6NToicmVzaWQiO3M6ODoiMjkvMi8yMjEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNDMvNjE2OS8zNjkuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9