EDITORIAL

CLINICAL TRIAL- L'ESSAI CLINIQUE DU MINAXOLONE ET THE MINAXOLONE STORY* SON HISTOIRE*

IT IS A TRUISM, perhaps, that the physician's first IL EST CONNU comme une v&it6 de La Palisse responsibility is to his patient; but for the physi- que la premi&e responsabilit6 du m6decin va/~ cian involved in the clinical investigations of a son malade; mais Iorsqu'il participe aux essais new drug, there is the additional responsibility of cliniques d'un nouveau produit pharm- ensuring that any new drug which is to be ad- maceutique, celui-ci s'impose une responsabilit6 ministered to humans will secure some improve- additionnelle: le moins qu'on puisse attendre ment or significant advance in the care of patients d'une nouvelle drogue qu'on administre/t I'hu- in the future. This responsibility has been clearly main, c'est qu'elle laisse entrevoir une am61iora- enunciated.t In anaesthesia, the situation is very tion de la qualit6 des soins dans un avenir plus ou clear. There are many satisfactory anaesthetic moins rapproch6. Cette responsabilit6 ne pour- agents available. For a new intravenous anaes- rait &re ~nonc6e de fa~:on plus claire. ~ En thetic agent to be acceptable, it must be either anesth6sie, cela saute aux yeux. Nous avons /~ more effective, or have fewer undesirable side notre disposition plusieurs agents satisfaisants. effects than its predecessor. Pour qu'un agent intra-veineux soit acceptable, il By the time a new drug is ready for clinical trial, doit 6tre plus efficica ou avoirs moins d'effets it has undergone extensive evaluation to deter- ind6sirables que ses pr6d6cesseurs. Au moment mine its efficiency and potential toxicity in both ob une drogue atteint le stade des essais isolated organ preparations and in intact animals. cliniques, elle a subi une 6valuation rigoureuse It was at this stage in its development that pour determiner son efficacit6 et sa toxicite Minaxolone was presented as a potent and potentielle tant chez les pr6parations d'organes rapidly acting new intravenous steroid anaesthe- isol6s que chez l'animal intact. tic with a short duration of action and a rapid C'est 5. ce stade de son d6veloppement que le recovery. It was considered suitable for both the minaxolone a 6t6 pr~sent6 comme un nouvel induction and maintenance of anaesthesia in ani- agent intraveineux puissant agissant rapidement mals and in man. A water soluble compound with et produisant un r6veil rapidc. On le considerait a potency in animal studies three times that of comme acceptable pour I'induction et le maintien alfathesin (CT 1341), it appeared to be devoid of de I'anesth6sie tant chez I'animal que chez the undesirable properties previously docu- l'homme. Hydrosoluble, ce produit avait une mented with steroid anaesthetics; in particular, puissance ~gale ~ trois fois celle de I'alfat&ine the thrombophlebitis associated with hydroxy- (CT 1341) et paraissait exempt des effets ind&ira- dione and the anaphylactoid effects seen with bles des anesth6siques st&oides: en particulier both propanidid and alfathesin. Extensive ani- la thrombophl6bite de I'hydroxydione et les mal investigations (in the mouse, rat, rabbit, propri&6s anaphylactoides du propanidid et de cat, dog and monkey) had indicated that it should I'alfat6sine. Des recherches pouss6es sur I'ani- prove at least as free from untoward effects as mal (souris, rat, lapin, chat, chien et singe) mon- other anaesthetic agents currently in use. The traient que ie minaxolone ne causait pas plus de drug was, then, ready for clinical trial in man. r6actions nocives que les autres agents A clinical trial is essentially a bioassay of the anesth6siques en usage pr6sentement. L'agent response of a new drug in man. There are four 6tait donc pr& pour 1"6preuve clinique sur logically necessary and distinct stages. In Phase 1 l'homme. trials the drug is introduced for the first time to Les essais cliniques se d6finissent essentielle-

*The intravenous agent Minaxolone (CCI 12923, *L'agent intraveineux minaxolone (CCI 12923, Glaxo Group Research Ltd.) was withdrawn from clini- Glaxo Group Research Ltd) fut retir6 de la recherche cal trial in October, 1979. In withdrawing this drug the clinique en octobre 1979. Ce faisant, la compagnie a agi Company acted very responsibly. For this reason a de fa~on responsable. C'est la raison pour laquelle une general review of the Minaxolone story seems appro- revue g~n&ale de I'histoire du minaxolone parait ap- priate. propri6e. CANADIAN ANAESTHETISTS' SOCIETY JOURNAL human subjects. Single doses of the drug are ment comme la recherche syst6matique de la given to volunteers to determine the dose- r6activit6 biologique de l'humain mis en contact response curve and thus the therapeutic range. avec une drogue. On proc~de avec logique par Detailed laboratory investigations are carried out quatre 6tapes aussi distinctes qu'essentielles. to determine the response of all vital body sys- Dans la phase I, I'agent est administr6 ~t des tems. Pharmacokinetic studies are undertaken to volontaires sous forme d'une dose unique pour assess bioavailability, plasma clearance, and the d6terminer sa relation dose-effet et ainsi rate, route and character of excretion. If the re- connaitre sa port6e th6rapeutique. Des 6tudes de sults of these single dose studies are acceptable, laboratoire 61abor6es permettent de d6terminer la multiple dose trials and the assessment of succes- r6activit6 des syst~mes vitaux, pendant que des sive administrations then commence, again in 6tudes pharmacocin6tiques en 6valuent la volunteers. biodisponibilit6, la clearance plasmatique ainsi Following successful Phase I studies, new que la rapidit6, la vole et le mode d'excr&ion. Si drugs are assessed progressively in Phase II, les r6sultats de cette &ude h doses simples sont Phase Ill and Phase IV studies. Early Phase I1 favorables, on peut se permettre d'6valuer les aims to repeat, as closely as possible, the Phase 1 effets de I'administration de doses multiples et evaluation, but this time in patients. Late Phase II successives en faisant toujours appel ~. des studies aim to provide evidence that the drug is volontaires. therapeutically useful and to determine the role of Si la phase Iest couronn6e de succ~s, on entre- the drug in clinical practice. Phase III determines prend progressivement les phases II, III et IV. Au the precise role of the drug in clinical practice. d6but de la phase II, on reprend d'aussi pres que These studies must demonstrate that the drug is possible sur des patients les 6preuves de la phase both safe and effective even when used in the I. En fin de phase I1, 1'6tude cherche b. prouver relatively uncontrolled environment of the busy l'utilit6 th6rapeutique de I'agent et ~ d6terminer physician. In Phase IV the drug continues to be son rfle en clinique. La phase III d&ermine avec used under surveillance in general clinical prac- pr6cision son utilisation clinique. Cette 6preuve tice.l.~ doit d6montrer la s6curit6 et I'efficacit6 du pro- The introduction of new pharmacological prep- duit m~me Iorsqu'il est utilis~, darts des conditions arations is subject, of necessity, to thorough and normales d'exercice. En phase IV, on utilise severe testing. The historical development of I'agent sous surveillance en pratique courante. these controls has been well documented. 3 In Un nouveau produit pharmaceutique est North America, standards and conditions for the n6cessairement soumis ~ des 6preuves completes clinical evaluation of new agents are carefully laid et s6rieuses. L'histoire, comme 1'6volution de down: in the United States by the F.D.A.; in ces contr61es, a 6t6 fort bien document6e. En Canada by Health and Welfare Canada. Am6rique du Nord, les standards et les condi- Minaxolone was issued for clinical trial in Canada tions n6cessaires b. I'evaluation clinique de only after the Health Protection Branch had ap- nouveaux m6dicaments ont 6t6 d6termin6s avec proved the early Canadian studies under specific soin: aux Etats Unis par le Federal Drug Admi- sections of the Canadian Food and Drug Regula- nistration et au Canada par Sant6 et Bien-~tre tions. Minaxolone was being issued for trial in Canada. Le minaxolone a 6t6 distribu6 pour Canada at the same time as it was to be assessed 6preuve clinique au Canada seulement une fois elsewhere in the world, and three Canadian que la Direction G6n6rale de la Protection de la centres were to be involved. This important Sant6 efit approuv6 les 6tudes canadiennes event was a "first" for Canadian anaesthesia. pr61iminaires entreprises sous des sections Of all of the centres concerned, a few planned sp6cifiques de la loi des Aliments et Drogues du Phase I trials. All others planned to assess the Canada. Le minaxolone parvenait ~ y trois centres agent initially in patients undergoing surgical canadiens impliqu6s darts l'6valuation en m~me procedures. These centres were in fact becoming temps qu'ailleurs darts le monde. Cet 6v~nement involved in Phase II studies. At Dalhousie Uni- 6tait une "premiere" pour I'anesth6siologie versity it was decided to produce dose response canadienne. curves in volunteers to establish the EDs0 of this Dans certains des centres choisis, on entreprit drug for the induction of anaesthesia. Further- des &udes de phase II sur des patients qui subis- more, it was decided to conduct a small initial saient une intervention chirurgicale. A l'Univer- study in the baboon (Papio cynocephalus/ sit6 Dalhousie, on d6cida de tracer des courbes de anubis). There were several reasons for this. relation dose-effet sur des volontaires darts le but EDITORIAL

The highest order sub-human primate previ- de connaitre la dose efficace pour cinquante p. ously exposed to Minaxolone had been the cent des sujets (EDs0) lots de l'induction de Cynomolgus monkey (Macaca fascicularis). l'anesth6sie. De plus, il fut d6cid6 de mener une Macaca fascicularis is the lightest of the petite 6tude preliminaire sur le babouin (papio macaques, with a weight range of 3.5-8.3 kg for cynophalus/anubis). I1 y avait plusieurs raisons males and 2.5-5.7 kg for females. 4 Relatively pour cel~t. small animals of body weight range 2.06-2.34 kg Le primate le plus ~.volu6 auquel on avait ad- had been used in the pre-clinical animal studies. ministr6 auparavant le minaxolone avait 6t6 le Experience with a larger primate, the baboon, singe Cynomolgus (Macacaca Fascicularis). with a 6-40 kg body weight range would hope- C'est le plus petit de I'esp~:ce des macaques, avec fully allow a better prediction of dosage for in- un poids situ6 entre 3.5 et 8.3 kg pour les m~.les et duction of anaesthesia in man. entre 2.5 et 5.7 kg pour les fernelles. Des animaux In addition, in the study of Hope et al. s when relativement petits de l'ordre de 2.06 ~ 2.34 kg alfathesin was given to unpremedicated volun- avait 6t6 utilis6s pour les &udes pr6-cliniques. teers in a Balanced Incomplete Block Design Gr~ce ~ l'exp6rience obtenue chez un primate (BIBD), the severity and quantity of untoward plus gros, le babouin, pesant entre 6 et 40 kg, on excitatory effects (muscle movements, hic- esp6rait obtenir une pr6diction plus appropri6e coughing, coughing, etc.) and salivation was such de la dose d'induction requise pour I'homme. that it was considered advantageous to have di- De plus, dans l'6tude de Hope et collaborateurs rect experience of Minaxolone in primates, and lorsqu'on administrait l'alfatesine ~ des volon- only thereafter to finalize the human volunteer taires non pr6m6diqu6s dans un test de bloc in- protocol. It was known that excitatory effects complet casualls~, la gravit~ et le nombre des had been seen with Minaxolone in the Cynomol- r6acti0ns d'excitation ind6sirables (mouve- gus monkey after both intramuscular and in- ments musculaires, hoquets, toux, ext...) et la travenous injection although, in all other aspects, salivation furent telles qu'on a d6cid6 qu'il serait the drug appeared to have the properties of an avantageux d'obtenir une exp6rience directe du ideal induction agent. minaxolone sur les primates, et de ne finaliser le The results of the baboon study spelled disas- protocole sur les volontaires humains que plus ter. The observed and measured cardio- tard. On savait que les r6actions d'excitation respiratory responses showed no significant al- avaient 6t6 constat6es avec le minaxolone sur le teration attributable to Minaxolone; the neuro- singe de race Cynomolgus apr~s l'administration logical and motor responses appeared equivalent intramusculaire ou veineuse mais que sous tous to those described for the Cynomolgus monkey; les autres aspects, l'agent n'6tait pas loin de but the untoward excitatory events appeared to poss6der .les propri6t6s de l'agent d'induction be significantly greater than those described in id6al. any previous study. In the baboon, the response Sur le babouin, les 6tudes furent d6sastreuses. varied within and between animals, from fine Les r6actions cardio-respiratoires observ6es et tremor and localized motor twitching and jerking mesur6es ne d6montraient pas d'alt6rations through major and prolonged twitching and jerk- significatives imputables au minaxolone; la r6ac- ing, to tonic-clonic convulsive activity. Phases of tivit6 neurologique et motrice, semblait iclentique hypertonus and hyper-reflexia and ophisthotonus celle d6crite avec le singe Cynomolgus; mais les were seen. Spontaneous in onset, this activity effets secondaires ind6sirables apparurent plus could be provoked and magnified by tactile and grands que ceux qu'on avait d~.crits auparavant. auditory stimuli. During this activity, obvious Sur le babouin, la r6ponse &ait variable d'une fear and awareness were shown by the animals lois et d'un animal ~. l'autre, passant des trem- which otherwise might euphemistically be con- blements fins, des fasciculations et des secousses sidered to be under pharmacological restraint. prolong6es jusqu'a l'hyperr6flexie et I'opis- These unwanted responses, once established, thotomos. Le declenchement de ces ph6nom~nes could not always be suppressed by additional se faisaient de fagon spontann6 mais pouvait 8tre administration of Minaxolone. In one animal, in- amplifi6s par des stimuli tactiles et auditifs. Pen- travenous diazepam was administered until the dant cette activit6 un.6tat de peur et de con- eyelash reflex was lost, but even this did not science ont 6t6 constat6s chez ces animaux qui suppress the excitatory effects completely. auraient du 6tre sous contrainte pharmacologique The baboon study was halted and the observa- si on peut se permetrre cet euph6misme. Les tions reported to Glaxo. A request for all possible r6actions ind6sirables une lois &ablies ne CANADIAN ANAESTHETISTS' SOCIETY JOURNAL information concerning excitatory events ob- pouvaient pas toujours ~tre supprim6es par I'ad- served in other trials resulted in the receipt of ministration additionnelle de minaxolone. A un detailed observations of untoward events which animal, on a administr~ du diazepam par voie were known to the Company. The early Phase 1I veineuse jusqu'5, la disparition complete du studies had shown an incidence of excitatory r6flexe palp6bral mais sans r6ussir :~ supprimer events somewhere between ten and seventy per- compl&ement les r6actions d'excitation. cent. Many of these were minor. A major incident L'6tude sur le babouin rut arr~t~e et ses r~sul- was defined by Glaxo as an event which had tats rapport~.s a Glaxo. Une demande pour tous interfered with either the well-being of the patient les renseignements possibles concernant les or the anaesthetic or surgical procedure and r6actions d'excitation observ6es pendant d'au- which required active intervention from the tres essais permit I'obtention de toutes les obser- anaesthetist. A total of 28 such events occurring vations de r~.actions ind6sirables connues par la in 306 patients had been noted. It may be true, as compagnie. Les 6tudes initiales de deuxi~me was suggested, that the criteria were too strict phase avaient montr6 une incidence de and that the anaesthetists were 'actively' looking ph6nom~nes d'excitations de I'ordre de 10 h 70 p. for such events. The incidents may even have cent. Plusieurs de ces ph6nom~nes 6taient been 'due to causes other than those relating to mineurs. Un incident majeur 6tait d6fini par Minaxolone'.6 However, this information Glaxo comme un 6v6nement qui g~nait, spit le coupled with the results of the baboon study bien-&re du patient spit le d6roulement de made it impossible to proceed with the Phase 1 I'anesth6sie ou de l'op6ration et n~cessitait une trial in volunteers at Dalhousie. intervention directe de la part de I'anesth6siste. Glaxo arranged a conference for all those in- Un total de vingt-huit 6v~nements de ce type pot volved in the clinical trial of Minaxolone, in Lon- ~.t6 d6montr6s sur 306 patients. IIa 6t6 sugg6r6, don, England, in October, 1979; but even before que les crit~res 6taient trop stricts et que la re- it met, Minaxolone was withdrawn from clinical cherche systb.matique de ces 6vbnements pouvait trial by the Company. This withdrawal was pre- fausser les r6sultats. Ces incidents auraient cipitated by observations made in each of two m6me pu survenir sans I'administration de rats following a long-term, small-scale tox- minaxolone. Cependant, ces renseignements icological investigation of Minaxolone made by s'ajoutant aux r6sultats de 1'6tude sur le babouin Glaxo Group Research Ltd. 7 The Committee on rendirent impossible la continuationdes essais de the Safety of Medicines in the U.K. and the Reg- phase I sur les volontaires de l'Universit6 ulatory Authorities in all relevant countries were Dalhousie. informed. Glaxo organisa une conf6rence pour tous ceux At the Conference the early clinical data was qui participaient aux essais cliniques sur le presented. The Phase I trials showed the drug to minaxolone ~. Londres en octobre 1979, mais have marked excitatory effects, and to have a avant m~me cette r6union l'6preuve clinique du prolonged recovery particularly after repeat dos- mlnaxolone ~tait interrompue par la compagnie. age and in infusion studies. Furthermore, the Ce retrait rut pr6cipite par des observations faites half-life of the drug and the ability to recover it or sur deux groupes de rats apres une 6tude toxi- its metabolites completely in man came under cologique de Iongue dur6e mais sur une petite scrutiny. Phase II results also demonstrated that 6chelle men6e pour le groupe de recherche de the drug had marked excitatory effects, although Glaxo. Le comit6 sur la s6curit6 de la m6decine many of the clinicians involved felt that these au Royaume-Uni etles organismes r6gulisateurs unwanted effects could easily be "tamed", in de tous les pays concern6s furent avertis. most instances, with other drugs commonly used On pr6senta 5. la conf6rence les donn6es in anaesthesia. cliniques initiales. Les essais de la phase Iont However, to be able to "tame" this agent with d6montr6 les r6actions d'excitation du produit, et other drugs (e.g. narcotics, general anaesthetics) la pgriode d'6veil prolong6e particuli~rement is not the answer for coping with its untoward apr~s la rgp&ition des doses etles perfusions effects. Such a prerequisite for the administration continues. De plus, la demie-vie du produit, la of Minaxolone could never be assured. rgcupgration compl/:te ou incomplete sous forme Many questions remain to be answered about de metabolite chez l'humain pot 6t6 remis en Minaxolone. Already further toxicological cause. Les essais i'galis6s h la phase II pot aussi studies have been established by Glaxo to inves- fait la preuve que l'agent anesthgsique poss6dait tigate the problem with Minaxolone. These will une activit6, excitatoire importante, bien que EDITORIAL 5 take some time to complete. It is unlikely that plusieurs parmi les ciiniciens engages dans Minaxolone, in its present formulation, will be l'Etude avaient I'impression que ces effets seen again. indEsirables pouvaient &re ais(:ment contrElEs One fact is clear: Phase 1I studies are not the dans la plupart des cas/a l'aide d'autres mEdica- vehicle for the initial assessment of the phar- ments d'usage courant en anesthEsie. macological response of a new drug in man. It is Cependant, "dompter" un agent avec d'autres understandable, perhaps, because Minaxolone is drogues (v.g. les narcotiques, anesth~siques an agent capable of inducing anaesthesia, and as gEnEraux) n'est pas une solution acceptable. Plus such is less likely to be used on its own, that encore darts le cas du minaxolone. Beaucoup de Phase II trials were begun before adequate Phase questions sur le minaxolone restent sans rEponse. I data were available. DEjS, des ~:tudes plus poussEes sur la toxocologie Nevertheless, it is difficult to justify just be- ont 6.16 enlreprises. Elles nEcessileront encore cause it is an anaesthetic drug. Many anaesthetic beaucoup de temps. I1 est peu probable que le drugs are already available. A new agent should minaxolone sous sa forme actuelle soit remis en be more effective or have markedly reduced side circulation. effects or have other benefits. Had the results of Un fait demeure certain: les Etudes de phase I1 the baboon studies, and the Phase I clinical trials ne devraient jamais servir au depart pour 6valuer been available before Phase II trials of l'activit6 pharmacologique d'un nouveau mEdi- Minaxolone began, it is questionable that these cament chez l'homme. Le minaxolone 6tant un Phase I1 trials would have been inaugurated. agent d'induction pour I'anesth~sie ne pouvant The responsibility for maintaining the highest @tre utilise b. d'autres fins, on peut comprendre standards in the clinical trial of new drugs must be qu'on ait debut6 les essais de phase II avant que shared equally by the Pharmaceutical Companies les donnEes recueillies dans la phase 1 ne soient and the clinical investigators. The rules are there disponibles. for guidance of both. Cependant, cela est difficilement justifiable car As an interesting sidelight, the Dalhousie Uni- plusiet,rs agents sont prEsentement disponibles. versity group has since conducted trials of Un nouvel agent devrait ~tre plus efficace et sodium thiopentone, sodium methohexitone and possEder robins d'effets secondaires ou encore alfathesin in the baboon. One of the questions procurer d'autres avantages. Si les r~sultats des raised in relation to the Minaxolone results was Etudes effectuEes sur le babouin et les essais whether they were species specific. The re- cliniques de la phase I avaient 6t6 disponibles sponses in the baboon, for each of these drugs, avant qu'on ne commence les essais de la phase are directly comparable with those seen in man. II, on peut se demander si la phase II aurait CHARLES E. HOPE dEbutE. La responsabilitE pour le maintien des plus REFERENCES hauts standards Iors d'essais cliniques de nouvelles drogues doit ~tre r~partie ~galement 1. MELMON, K.L. & MORELLI, H.F. (Eds.) Clinical Pharmacology - Basic Principles in Therapeutics, entre les compagnies pharmaceutiques et les in- I st ed. The Macmillan Company, New York. 1972. vestigateurs cliniciens et ils doivent ~:tre regis par 2. PAULUS,H.E. Development of New Drugs, Ch. 6 les m~mes r~gles. in Essentials of Pharmacology, 1st ed., Ed: J.A. De fa~:on parall~:le, le groupe de I'UniversitE Bevan, Harper & Row, New York, 1976. 3. PENN, R.G. The state control of medicines: the first Dalhousie a conduit des essais avec le thiopenthal 3000 years. Brit. J. Clin. Pharm. 8:307 (1979). sodique, le methohexital sodique et l'alfatEsine 4. ROONWAL, M.L. & MAHNOT, S.M. Primates of sur le babouin. Une des questions soulevEes au South Asia, Harvard University Press, Cambridge sujet du minaxolone concernait la spEcificit~ des and London (1977). reactions pour une esp~ce. La rEponse du 5. HOPE, C.E., WILSON, T.W. & WVANT, G.M. Some Pharmacological Properties of AIthesin (CT babouin pour chacun des agents mentionn~es 1341) in Man. Canad. Anaesth. Soc. J.,22:572-586 plus haut est comparable ~ celle qu'on rencontre (1975). chez l'homme. 6. WALKER, S.R. Report of untoward events. Glaxo CHARLES E. HOPE Group Research Ltd. Communication. 19th June, 1979. 7. HARRIS, D.M. & WALTER, S.R. Glaxo Group Re- search Ltd. Letter. 3rd October, 1979.