- Email: [email protected]
When do we have enough animal data?
Resuscitation, 25 (1993) 75-16 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0300-9572/93/$06.00
15
When do we have enough animal data? Paul A. Calle”, Walter A. Buylaerta and Marc G. Bogaertb ‘Department of Emergency Medicine, University Hospital, De Pintelaan 185, B-MOO Gent and bDepartment of Pharmacology, University Hospital, De Pintelaan 185, B-W?0 Gent (Belgium)
We fully endorse many of the points raised by Professor Steen. We would, however, like to comment on one of his remarks: we do not think that the fact that as many as 725 articles have been published on nimodipine, by itself justifies setting up a clinical trial. Firstly, only a very small number of papers out of these 725 concern animal experiments that were performed in a blind and randomised fashion by independent research groups, although for clinical trials these criteria have to be met for publication in a good journal. Secondly, many of these studies deal with pre-ischemic treatment and/or use end points, such as metabolic parameters, cerebral blood flow and electro-encephalographic parameters, that are known to correlate poorly with clinical outcome’. Frequently a model that has little to do with human pathology is applied2. Therefore, we believe that the motivation for the clinical evaluation of nimodipine - as for the barbiturates in the early eighties3 - was not strong, especially since it meant that critically ill patients were exposed to a potentially harmful drug. Consequently, we also believe that animal experiments such as those we performed”‘j should have been done before nimodipine was considered for evaluation in patients. The lack of a clear-cut effect of nimodipine in most clinical studies in stroke7p8 and cardiac arrest’ strengthens our point of view. Thirdly, the publication procedure should be evaluated critically. Indeed, peer review, usually done by experts known for their (mainly positive) experience with a drug, may lead to refusal of negative studies. Furthermore, editors usually give manuscripts describing negative studies lower priority, resulting in publication bias and ‘embellishment’ of a drug’s profile”‘. In this regard, it is likely that negative results, if published at all, frequently appear only after many years and mainly in journals with lower citation indices. In conclusion, we would urge clinical investigators to judge whether available animal data meet the standards mentioned above and to critically evaluate them before embarking on clinical trials.
Correspondence to: Paul A. Calle, Department of Emergency Medicine, University Hospital, De Pintelaan
185, B-9000 Gent, Belgium.
16
REFERENCES 1
2
3 4
Forsman M, Aarseth HP, Nordby HK, Skulberg A, Steen PA. Effects of nimodipine on cerebral blood flow and cerebrospinal fluid pressure after cardiac arrest: correlation with neurologic outcome. Anesth Analg 1989; 68: 436-443. Steen PA, Gisvold SE, Milde JH, Newberg LA, Scheithauer BW, Lanier WL, Michenfelder JD. Nimodipine improves outcome when given after complete cerebral ischemia in primates. Anesthesiology 1985; 62: 406-414. Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N EngJ J Med 1986; 314: 397-403. Calle PA, Bogaert MG, De Ridder L, Buylaert WA. Nimodipine has no beneficial effect on neurological outcome in a cardiopulmonary arrest model in the rat. Naunyn-Schmiedeberg’s Arch Pharmacol 1990; 341: 586-591. Calle PA, Bogaert MG, De Ridder L, Buylaert WA. Nimodipine decreases resuscitability in a cardiopulmonary arrest model in the rat. Resuscitation 1991; 21: 229-237. Calle PA, Paridaens K, De Ridder LI, Buylaert WA. Failure of nimodipine to prevent brain damage in a global brain ischemia model in the rat. Resuscitation 1993; 25: 59-71. Trust Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-1209. The American Nimodipine Study Group. Clinical trial of nimodipine in acute ischemic stroke. Stroke 1992; 23: 3-8. Roine RO, Kaste M, Kinnunen A, Nikki P, Sama S, Kajaste S. Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. J Am Med Assoc 1990; 264: 3171-3177. Angel1 M. Negative studies. N Engl J Med 1989; 321: 464-466.
15
When do we have enough animal data? Paul A. Calle”, Walter A. Buylaerta and Marc G. Bogaertb ‘Department of Emergency Medicine, University Hospital, De Pintelaan 185, B-MOO Gent and bDepartment of Pharmacology, University Hospital, De Pintelaan 185, B-W?0 Gent (Belgium)
We fully endorse many of the points raised by Professor Steen. We would, however, like to comment on one of his remarks: we do not think that the fact that as many as 725 articles have been published on nimodipine, by itself justifies setting up a clinical trial. Firstly, only a very small number of papers out of these 725 concern animal experiments that were performed in a blind and randomised fashion by independent research groups, although for clinical trials these criteria have to be met for publication in a good journal. Secondly, many of these studies deal with pre-ischemic treatment and/or use end points, such as metabolic parameters, cerebral blood flow and electro-encephalographic parameters, that are known to correlate poorly with clinical outcome’. Frequently a model that has little to do with human pathology is applied2. Therefore, we believe that the motivation for the clinical evaluation of nimodipine - as for the barbiturates in the early eighties3 - was not strong, especially since it meant that critically ill patients were exposed to a potentially harmful drug. Consequently, we also believe that animal experiments such as those we performed”‘j should have been done before nimodipine was considered for evaluation in patients. The lack of a clear-cut effect of nimodipine in most clinical studies in stroke7p8 and cardiac arrest’ strengthens our point of view. Thirdly, the publication procedure should be evaluated critically. Indeed, peer review, usually done by experts known for their (mainly positive) experience with a drug, may lead to refusal of negative studies. Furthermore, editors usually give manuscripts describing negative studies lower priority, resulting in publication bias and ‘embellishment’ of a drug’s profile”‘. In this regard, it is likely that negative results, if published at all, frequently appear only after many years and mainly in journals with lower citation indices. In conclusion, we would urge clinical investigators to judge whether available animal data meet the standards mentioned above and to critically evaluate them before embarking on clinical trials.
Correspondence to: Paul A. Calle, Department of Emergency Medicine, University Hospital, De Pintelaan
185, B-9000 Gent, Belgium.
16
REFERENCES 1
2
3 4
Forsman M, Aarseth HP, Nordby HK, Skulberg A, Steen PA. Effects of nimodipine on cerebral blood flow and cerebrospinal fluid pressure after cardiac arrest: correlation with neurologic outcome. Anesth Analg 1989; 68: 436-443. Steen PA, Gisvold SE, Milde JH, Newberg LA, Scheithauer BW, Lanier WL, Michenfelder JD. Nimodipine improves outcome when given after complete cerebral ischemia in primates. Anesthesiology 1985; 62: 406-414. Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N EngJ J Med 1986; 314: 397-403. Calle PA, Bogaert MG, De Ridder L, Buylaert WA. Nimodipine has no beneficial effect on neurological outcome in a cardiopulmonary arrest model in the rat. Naunyn-Schmiedeberg’s Arch Pharmacol 1990; 341: 586-591. Calle PA, Bogaert MG, De Ridder L, Buylaert WA. Nimodipine decreases resuscitability in a cardiopulmonary arrest model in the rat. Resuscitation 1991; 21: 229-237. Calle PA, Paridaens K, De Ridder LI, Buylaert WA. Failure of nimodipine to prevent brain damage in a global brain ischemia model in the rat. Resuscitation 1993; 25: 59-71. Trust Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-1209. The American Nimodipine Study Group. Clinical trial of nimodipine in acute ischemic stroke. Stroke 1992; 23: 3-8. Roine RO, Kaste M, Kinnunen A, Nikki P, Sama S, Kajaste S. Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. J Am Med Assoc 1990; 264: 3171-3177. Angel1 M. Negative studies. N Engl J Med 1989; 321: 464-466.