Stroke Drug Development
Usually, But Not Always, Animal Models
In 2005, the standard mode of drug development is to determine its biologic mechanism, efficacy, dosage, and time window in preclinical animal models. The only licensed acute pharmacologic intervention for stroke is tPA, which traveled this conventional route before proof of its efficacy in pivotal clinical trials.1 Many stroke clinicians have been perplexed by the failure of other compounds trialed over the past 2 decades, despite strong evidence for efficacy in animal models. Indeed, the specter of investigator fatigue is raised in the face of continued negative results, chiefly from trials of neuroprotectants.
Fisher nicely argues that there are many reasons why translation of neuroprotectants from animal models to clinical practice has not occurred and, indeed, this has been the theme of a series of STAIR recommendations. Our personal bias is that a large number of neuroprotectants have had inadequate preclinical testing in differing models, species, and appropriate time windows. For example, there is little justification for human studies of an agent that reduces infarct volumes in a single rat model by 30% with inappropriately short time windows.
As argued by Fisher, there is also often a poor understanding of the model itself; knowledge of the presence and duration of the ischemic penumbra is critical. Trial methodology has now become much more sophisticated, and negative results are more like to be the result of biologically weak compounds.2 In addition, treatment effect sizes are likely to have been overestimated, and we would not expect an absolute risk reduction of more than approximately 3% to 5% for neuroprotectants, substantially lower than for thrombolytic therapy. We are firmly of the view that larger sample sizes are required for these trials than are currently used.
One inescapable fact highlighted by Kaste is that the rigor of case selection and patient management in clinical trials has driven the standards of acute stroke care. This may be a factor in the lower-than-expected mortality rates in many trials. Also, such efficiencies may explain the impressive record door-to-needle time of 12 minutes from the center of our protagonist from Finland!
One striking exception to the conventional pathway of drug development has been the positive results using recombinant factor VIIa to attenuate hematoma growth in patients with primary intracerebral hemorrhage.3 The biologic plausibility of this approach was based on clinical studies of the dynamics of hematoma growth documented by repeated computed tomography scans rather than animal models. The compound was already in clinical use as a hemostatic agent for another indication. This illustrates our view that although the majority of candidate stroke compounds need to be evaluated in preclinical animal models, there is always a place for astute clinicians to recognize the potential of compounds already in use for another clinical indication.
Despite the recent history of failure of translation of neuroprotectants into clinical practice, promising trial results have been recently released for a free radical trapping agent. The development of this compound was based on a rigorous preclinical program, including multiple animal models and careful adherence to the STAIR criteria.4 This message should not be lost on investigators hoping for success in the tough world of translational stroke research.
- Received May 11, 2005.
- Accepted May 18, 2005.
Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science. 1985; 230: 1289–1292.
Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA, for ASTIN Study Investigators. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose–response study of UK-279,276 in acute ischemic stroke. Stroke. 2003; 34: 2543–2548.
AstraZeneca Press Release, May 4, 2005. Available at: http://www.astrazeneca.com/pressrelease/4979.a01spx. Accessed May 5, 2005.